Obesity in the 21st Century [1st ed. 2023] 3031391675, 9783031391675

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Alfred Poulos

Obesity in the 21st Century

Obesity in the 21st Century

Alfred Poulos

Obesity in the 21st Century

Alfred Poulos Thornbury, VIC, Australia

ISBN 978-3-031-39167-5    ISBN 978-3-031-39168-2 (eBook) https://doi.org/10.1007/978-3-031-39168-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Preface

It is somewhat sobering that, with a large proportion of the world’s population living in developing countries, barely having enough to eat, the developed world is faced with an “epidemic” of obesity. According to the World Health Organization, in 2016 more than 1.9 billion people were overweight while 600 million of these or roughly a third were classified as obese [1]. The severity of the problem, which according to the US Surgeon General is associated with increased disability, decreased quality of life, increased healthcare costs, and increased mortality, is perhaps not fully appreciated [2]. And the problem is not just confined to the developed world because the increased incidence of excess body weight or obesity has even spread to developing countries as well as remote indigenous communities [4–6]. Our view of obesity has certainly changed since prehistoric times when the carrying of excess body fat was probably thought to be advantageous at a time when food supplies were not always predictable and extra body fat may have ensured survival. It is important to note that what is now considered a “healthy” weight is probably different from what was believed even in the early part of the twentieth century when a lean body mass was thought to mean that there may have been insufficient body reserves to cope with diseases such as tuberculosis and pneumonia [3, 4]. There is a generally accepted view that the fats found in the food we eat are not healthy because they provide the source of much of the excess body fat that is stored in the body. However, it is more complex than this because there is a variety of fats in food, and some, including the fat-soluble vitamins, e.g., vitamins D and E, are essential for our health and wellbeing. While fats are found in all tissues in our bodies, and are integral and important components of most tissues, for most of us the focus is on the fats that are deposited at v

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different sites throughout the body, particularly around the waist, buttocks, and thighs, because they are considered unattractive. However, there are numerous other sites throughout the body and there is increasing evidence that they contain more than just fats. Indeed, many of these sites are now believed to have some of the properties of glands and contain components other than fats. But these sites, referred to as adipose tissue, store fats. Are they all the same? While the ready availability of cheap food in developed nations is thought to be a contributory factor, the type of food consumed, overeating, lack of exercise, and genetics have all been proposed as possible explanations for the steady growth in obesity in the developed world. Genetic factors are of considerable interest, but what are these factors and how do they affect our body weight? More recently, other factors have been proposed which may help explain the increased rates of obesity in many parts of the world. One of these is the obesogens, certain chemicals present in food and in the environment and which may have an impact on the various hormonal and other processes that regulate food uptake and utilisation. Yet another factor is the microbiome, the diverse microbial population which inhabits our digestive systems generating mixtures of a variety of chemical substances. But what are these chemicals and what is the evidence that they can have an impact on the complex processes that determine our body weight? There is little doubt that the amount and type of food we eat plays an important role in determining our body weight. But diet varies greatly in different parts of the world. Do all diets have the same impact on our potential to put on weight? One type of food that has been linked to the rising rate of obesity, particularly in the developed world, is ultraprocessed food. It seems that through the Internet, social media, television, and even sporting events, we are subjected to a daily barrage of advertising about this type of food. But what is ultraprocessed food, and more importantly, what is in it that may increase body weight? Once we have put on weight, we may then decide we have to find some way of losing the added weight. For the young, media images of thin and apparently happy young people have led to an almost exponential growth in weight loss diets with the weight loss industry and its associated industries, for example gyms, personal trainers, health coaches, nutritionists/dietitians, and special food manufacturers, generating millions of dollars a year worldwide. Even a cursory examination of the media and Internet reveals a staggering number of weight loss diets including low fat, low carbohydrate, high protein, raw food, macrobiotic, vegetarian, blood type, calorie restriction, and low glycemic index diets to name just a few. The problem for the ordinary

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consumer is how to make sense out of all of these diets and strategies that are being promoted by so many vested interests. And if the diets work, how easy are they to follow, and what happens when the desired weight is reached? Can the weight loss be maintained? For many people, particularly the young, the main reason for attaining, and maintaining, a normal body weight is image. Appearance is considered to be of major importance, particularly for young women. While there is no denying its importance for the young, there seems to be a limited appreciation of the health consequences of excess body weight. We now know that obesity increases the risk of a variety of disease states but, until recently, we had a limited understanding of how the increased storage of fat at various sites throughout the body affected our health. Also, what has not been clear is whether, in relation to their impact on our health, all fat storage sites are the same or whether some sites may be potentially more harmful. Those wanting to lose weight are confronted with an overwhelming number of strategies as any search of the Internet can attest. While most of us are aware that diet is the main strategy, there are a great number of weight loss diets. But how effective are these diets and do they work for everyone or are there factors which influence their efficacy? And if diets are not effective, what other methods are there for most of us are aware that diet is not the only way to go if you want to lose weight. Because of their relative ease, the use of drugs to lose weight has increased as have supplements, devices, surgery, and even more controversial treatments such as acupuncture, Ayurvedic medicine, and Chinese traditional medicine, but there is really little information as to their efficacy. It is clear that a lot of questions spring to mind and are really not just about what we eat. This book is about one of the most serious health issues facing the developed world, its causes, and the many and varied treatments. Its aim is to inform the reader of the many and complex processes involved in the regulation of food intake and utilisation and some of the factors which can interfere with these processes and lead to increases in fat deposits at different sites throughout the body. It aims to do this by reference only to properly researched information published in international medical and scientific journals not to the websites of companies and individuals marketing products and procedures relating to the treatment of obesity. It also aims to inform the reader that obesity, the result of this increase in body fat, is not simply a matter of appearance but is increasingly being considered to be a disease with serious health implications. Thornbury, Australia

Alfred Poulos

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References 1. WHO (2020) Obesity and overweight. https://www.who.int/news-­room/fact-­ sheets/detail/obesity-­and-­overweight 2. Jackson Y et al (2002) Summary of the 2000 Surgeon General’s listening session: towards a national action plan on overweight and obesity. Obes Res 10(12):1299–1305 3. Komaroff M (2016) For researchers on obesity: Historical review of extra body weight definition. J Obes 2460285 4. Haslam D (2007) Obesity: a medical history. Obes Rev 8(Suppl 1):31–36 5. Ng M et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 84(9945):766–781 6. Schultz R (2012) Prevalences of overweight and obesity among children in remote Aboriginal communities in central Australia. Rural Remote Health 12:1872

Contents

1 Body  Composition: What Are We Made of?  1 What Are Fats?   2 What Is the Function of Our Body Fats?    4 Fat Storage and Adipose Tissue    4 Adipose Tissue and Obesity   6 What Does This Mean?    6 References   7 2 Variation  in Body Size and Obesity  9 Fat Distribution and Obesity   10 Fat Distribution and Diet   12 Fat Distribution and Physical Activity   12 Fat Distribution and Other Factors   12 Fat Distribution and Disease Risk   13 What Does This Mean?   13 References  14 3 G  enetics and Obesity 17 Epigenetics and Obesity   20 What Does This Mean?   21 References  22

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4 Non-dietary  Factors and Weight Gain 25 Hormonal Regulation of Body Weight   26 Non-hormonal Factors  28 Obesogens  31 What Does All This Mean?   35 References  36 5 D  iet and Obesity 41 Food Composition  43 Natural Diets and Obesity   44 Food Processing, Additives, and Obesity   45 Artificial Sweeteners  46 Dietary Fats and Processed Foods   46 Other Chemicals in Processed Foods   47 Ultraprocessed Food and Health   48 Precision Nutrition  48 What Does This Mean?   49 References  50 6 O  besity and Disease 55 Obesity and Diabetes   56 Obesity and Cardiovascular Disease   56 Obesity and Cancer   57 Obesity and Asthma   58 Obesity and Osteoarthritis   58 Obesity and Sleep Apnea   58 Obesity and Dementia   59 Obesity and Inflammation   59 Obesity and Pregnancy   60 Obesity and Sensory Loss   60 Obesity and Gallstones   60 Obesity and Mental Health   61 Obesity and Taste  61 Obesity and Smell   61 Overweight and Risk of Disease   62 What Does This Mean?   62 References  63

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7 Dieting,  Physical Activity, and Weight Loss 69 Weight Loss Diets   70 Calorie Counting  71 Low-Fat and Low-Carbohydrate Diets   71 High-Protein Diets  72 Fasting  73 Paleolithic and Mediterranean Diets   73 Genetics and Diets   73 Increased Physical Activity and Weight Loss   74 Lifestyle Intervention Programs   75 Commercial Weight Loss Programs and Weight Loss   75 Prevention of Weight Gain and Disease   76 Weight Regain  76 What Does This Mean?   77 References  78 8 D  rugs and Weight Loss 81 Efficacy and Side Effects of Drugs   83 Weight Loss Supplements   84 Natural Products and Weight Loss   84 Garcinia Cambogie  85 Irvingia Gabonensis  85 Green Tea  86 Spirulina  86 Chitosan  86 White Kidney Bean   86 Chromium  87 Green Coffee  87 Beta Glucans  87 Probiotic, Prebiotic, and Synbiotic Supplements   87 Intranasal Treatment of Obesity   88 Slimming Patches and Creams   89 Non-Systemic Agents  89 What Does This Mean?   89 References  90 9 S  urgery and Weight Loss 95 Liposuction and Lipectomy   96 Bariatric Surgery  96

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Non-surgical Procedures and Weight Loss   98 Cellulite Removal  98 What Does This Mean?   99 References  99 10 A  lternative Weight Loss Methods103 Acupuncture and Weight Loss  104 Ayurvedic Medicine  104 Tai Chi  105 Yoga 105 Pilates 106 Mindfulness 106 Hypnotherapy 107 Behavioral Modification  107 Weight Loss Devices  108 What Does This Mean?  109 References 109 E  pilogue: What Can We Do?113 I ndex117

About the Author

Alfred Poulos has a PhD from London University, a law degree from Adelaide University, and a professorship from Adelaide University, for his research in genetic diseases, fats, and fat metabolism. He held the position of Chief Medical Scientist at the Adelaide Women’s and Children’s Hospital in Adelaide, South Australia, for many years and has published over 150 papers in the international scientific and medical journals. He is a current member of the Human Research Ethics Committee of Alfred Health in Melbourne, reviewing medical and other health-related research projects. While Professor Poulos’ medical and scientific research has been wide and varied, it has chiefly focused on the role fats play in health and disease. His recent interests are in nutrition, and in the chemical pollutants present in our food, water, and the environment. This interest led to his publication of The Silent Threat (2005), a book that provides consumers with information on the source of many of these chemicals as well as their possible effects on our health and The Secret Life of Chemicals (Springer, 2021).

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1 Body Composition: What Are We Made of?

Summary • Our body contain complex mixtures of chemical substances. • Fat is a major component making up to a third of our body weight. • For those considered to be obese the fat content may be more than 40% of body weight. • Fat has many functions apart from energy storage. • Many of our vitamins are fats (e.g., vitamins A, D, E, and K). • Fat in the form of triglycerides is stored in adipocytes found in adipose tissue at different sites throughout the body. • Adipose tissue occurs in white, brown, and beige forms. • Adipose tissue also contains many different cell types including components of the immune system. The composition of adipose tissue at the different body sites may vary.It is probably no surprise to learn that perhaps as much as 45–75% of the body is made up of water the proportion depending on age or physiological status [1–3]. Protein and fat make up most of the rest while a small amount, around 6%, includes a variety of minerals including sodium, potassium, calcium, phosphorus, iron, magnesium, and small amounts of a mixture of other substances. Proteins are complex substances made up of chains of amino acids the actual number varying greatly depending on the protein and its function in the body. There are 20 or more different amino acids so each protein is a complex structure. There are literally thousands of unique proteins in the body each with a specific function.

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There are a great number of different carbohydrates in the body. The most common is glucose which occurs in the blood but also in glycogen which consists of chains of glucose molecules and is probably the human equivalent of starch. It is found in the liver and muscles where it is used as a reserve store of fuel for the body. Other simple carbohydrates found in the body include galactose, mannose, fucose, xylose, ribose, and lactose. The latter is the main carbohydrate in milk and is made up of glucose and galactose. More complex carbohydrates, containing additional chemical groups, include acetylgalactosamine, acetylglucosamine, and sialic acid. Many of these are found linked to proteins in connective tissue such as cartilage, bone, and lymph and, together with glycogen make up little more than 1% of the total body weight. Of course, another important component in our body is deoxyribonucleic acid or DNA in our genes which provides the chemical blueprint for making another human being is also present in minuscule amounts (less than 1%). It is worth noting that the DNA structure includes a carbohydrate and ribose. Body fat in men and women has been reported to be around 28% and 40% of body mass, respectively, indicating that women’s bodies contain a significantly greater fat content than men’s [4, 15, 16]. For those considered to be obese, the corresponding values are 26–28% for males and 39–41% for females [4]. According to the World Health Organisation 1.9 billion adults were overweight and 650 million were obese in 2016 [5]. In addition, the prevalence of overweight and obese children and adolescents increased fourfold from 1975 to 2001 [5].

What Are Fats? Fat is present in all of our body tissues with the brain, in particular, comprising nearly 60% fat [6]. It is worth having a brief look at the chemical structures in the body that are classed as “fats.” They are a large group of substances that are involved in processes as varied as reproduction, vision, and nerve impulses. There is indeed a staggering variety of fats in the human body. One group, the phospholipids which, as the name indicates, contain phosphorus, are integral components of the inner and outer membrane structures of all cells in the body. Sphingolipids are a group of fats that contain sphingosine, a complex structure made up of 18 carbon atoms mostly either linked to phosphorus or to various carbohydrates such as glucose or galactose. In addition to the phospholipids and sphingolipids there is a variety of fats that include cholesterol, which is made up of a series of rings of carbon atoms, as well as vitamin D which is derived from cholesterol.

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The chemical form in which fats are stored is termed “triglycerides.” These are made up of two components, one of which is water soluble and the other is water insoluble. The water-soluble part is the simple substance, glycerol, which exists naturally as a viscous liquid. Chemically bonded to the three carbon atoms in glycerol are the fatty bits, the fatty acids. There are many different fatty acids in nature, with chemical structure varying according to the number of carbon atoms. The most common fatty acids in nature are those made up of 12–20 carbon atoms joined to form a chain. Attached to the carbons are up to 40 or more hydrogen atoms and at least two oxygen atoms. Within each fatty acid structure, there is a further degree of complexity because at various sites along the carbon chain there may be a reduced number of hydrogen atoms attached to the carbon atoms leading to a chemical “kink” in the carbon chain (referred to as double bonds). There may be up to 6 of these double bonds (the most common are from 1 to 4). If there are 2 or more of these double bonds they are referred to as polyunsaturated fats. The position of the double bonds in the carbon chain determines whether a polyunsaturated fat is an omega-3 or omega-6 fat. Animal fats contain predominantly omega-6 fats while seafood is rich in omega-3 fats. There is yet another source of variation in the chemical structure of fatty acids, i.e., the cis and trans forms. This refers to the three-dimensional position in space of the two hydrogen atoms of adjoining carbon atoms in a double bond. If the two hydrogen atoms in the normal chemical representation of a double bond in the carbon chain of a fatty acid are next to each other in space, the double bond is referred to as cis, while if the hydrogen atoms are located opposite each other, they are considered to be trans fatty acids. Cis fatty acids are the most common in animals and plants while trans fats occur naturally in much smaller amounts. However, the amounts of trans fats are increased after a process referred to as hydrogenation which involves the addition of hydrogen to certain oils and fats. Hydrogenation is used as means of changing the physical characteristic of an oil, in particular, its “spreadability” in the case of margarines. Unfortunately, there is some concern over this process because there is some evidence that trans fatty acids may increase the risk of heart disease. Indeed, because of this increased risk there is legislation in some countries to decrease the levels of trans fats in food [17]. The net result of all of this is that the human body contains a great number of chemically distinct fatty acids. But fatty acids are not just found in triglycerides because they are components of a great variety of other fatty substances which are predominantly structural components of all tissues. There are fatty substances containing phosphorus (phospholipids), carbohydrates (glucose, galactose, mannose),

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and even sulfur. An organ that is particularly rich in many different types of fats is the brain [6]. The importance of these fats in the brain is clear from the many different inherited diseases affecting brain function that are caused by genetic abnormalities in the way specific fats are handled by the organ [14].

What Is the Function of Our Body Fats? Strange as it may seem many of us think of our body fat only as something unsightly, fat has a number of important functions in our bodies. Some are used to store energy, others are converted into hormone-like substances that are termed “eicosanoids,” while other fats facilitate the actions of hormones such as the sex hormones and insulin. And of course, there are a number of vitamins, including vitamins A, E, and K that are fats. Even cholesterol with its apparent link to heart disease is converted to another fat, vitamin D, which is involved in many processes in the body, in particular, bone growth and maintenance [27]. It is worth a few words about this “facilitation” process. Hormones are a type of chemical messenger that signals to different parts of our body inducing them to do or make something. In the case of the well-known hormone insulin the signal to muscles, brain, etc. is to take up and use blood sugar as a fuel. To do this, insulin binds to parts of a particular tissue which in turn generates a chemical signal instructing the tissue to take up and use glucose as a form of energy or fuel. Certain fats are a part of this signaling process. Finally, it is worth noting that cells, the key structural components of every tissue in the human body, are made of complex mixtures of fats and proteins. These components are cell membranes that regulate what enters and leaves the cell. Membranes are also found in the many different specialized structures within each individual cell within the body, often referred to as organelles, such as for example mitochondria, peroxisomes, and the nucleus. The latter contains the genetic material, i.e., the DNA, while the mitochondria are involved in energy production, and peroxisomes have a number of functions including the breakdown of fats.

Fat Storage and Adipose Tissue The fats that are used as reserve fuel in the body are stored as droplets in the cells of adipose tissue, referred to as adipocytes [26]. Analysis of adipose tissue has confirmed the presence of up to 13 different classes of fats including

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triglycerides, and there are differences in fat composition in the adipose tissue taken from different sites in the body [7]. In addition to adipocytes, adipose tissue also contains cells of the immune system, blood and lymph cells, and other cell types such as stem cells [8]. It is clear therefore that, because of its composition, adipose tissue is not just a fat storage site in the body. Indeed, there is a view that it has some of the properties of an endocrine organ, i.e., a hormone-secreting gland [8]. Adipose tissue has a wide distribution and is located at different sites of the body including the abdomen, the upper back, the gluteal and femoral regions of the legs, some of the joints, the bone marrow, and even behind the eye [9]. It is also located in proximity to internal organs such as the intestine, liver, and even the heart. There is a further layer of complexity because there are three types of adipose tissue—the more common or white, brown, and beige. It is perhaps even more complex than this because there have even been suggestions that the composition of the various fat depots may also be affected by their location [28]. While the white form serves as a reserve form of energy, it is thought that brown fat has thermogenic properties, i.e., it is able to convert stored fat into heat [10]. The function of the so-called beige form (also referred to as “brite”) seems to be intermediate between the white and brown adipose tissue and its amounts appear to decrease with age [11]. White adipose tissue, which is considered to be the fat accumulating and storage site, can be converted into an energy release form, i.e., brown adipose tissue, by a natural process referred to as “browning” [12]. Not surprisingly, there has been increasing interest in this process because it is thought to have potential in the treatment of obesity [13]. Because of the differences in function, it is not surprising that there are considerable differences in the chemical composition of the different types of adipocytes [19]. In particular, the fats in brown and beige adipocytes contain much higher amounts of cardiolipin, a complex fat found in significant amounts in the energy-producing organelles of all cells, the mitochondria. Analysis of brown and beige adipocytes has confirmed that they contain number of mitochondria which is not surprising considering that one of their primary functions is the generation of energy from fats as compared to white adipocytes whose primary function is energy storage [21]. Mitochondria, which have been mentioned earlier, are organelles, that are involved in the generation of chemical energy in the form of adenosine triphosphate (ATP). To add to the complexity, even white adipose tissue has been reported to contain some mitochondria but fewer than brown adipose tissue [24].

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Adipose Tissue and Obesity Because of its importance in energy storage, and in the production of various substances involved in the promotion of energy balance in the body, it is not surprising that changes that occur in adipose tissue as a consequence of obesity may have detrimental effects potentially increasing the risk of disease [18]. It is believed that obesity may increase the risk of dysfunction of adipocytes. For example, the breakdown of the main storage fat, triglycerides, an important function of adipose tissue, is decreased in obesity and its storage is increased [22]. Aging also results in an increased storage of triglycerides due to their decreased breakdown and can lead to an increase in body weight if uptake of triglycerides into adipocytes is not reduced [23]. There is a view that analysis of the fat composition of adipocytes from the different sites may increasingly be used to assist in the better diagnosis of disease states such as diabetes and cardiovascular diseases [20]. Obesity also affects the function of mitochondria, the components of most cells which play a key role in energy generation. It is believed that obesity has an effect on both the numbers of mitochondria in white adipose tissue as well their function. It has even been suggested that these changes may explain the downregulation of mitochondrial production as well as the apparent link between obesity and the increased risk of disease [24, 25].

What Does This Mean? It is clear that our bodies contain a complex mixture of chemical substances. While water is the major component of our bodies, fat is the next most common comprising up to a third of the body weight and increasing to more than 40% in those considered obese. Fat has always suffered as the dietary “bogeyman” because of its link with obesity. However, this view does not take into account their many, varied, and critical functions in the body which include not just energy storage in fat deposits throughout the body but many other functions such as energy production, facilitation of hormonal action, and hormone-like activities. In addition, some fats eg vitamins A, D, E, and K are essential nutrients that facilitate a number of key metabolic processes in the body. Even the much maligned cholesterol, which is also a fat, is required for the synthesis of vitamin D and some of the sex hormones. And triglycerides, stored in adipocytes located at different sites in the body, serve as the principal food in the human “larder.” Adipose tissue is not just a fat storage site but is

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made up of specialized cells, predominantly adipocytes, but also contains many different cell types including components of the immune system. To and there is evidence that the composition of the fat depots at various body sites may not be the same, To add to the complexity, adipose tissue occurs as white, brown and beige forms. White adipose tissue is the main site of storage and, via a process not well understood, referred to as “browning” can be converted into brown adipose tissue. It is believed that browning provides a means of removing excess fat through conversion into heat and is the subject of considerable research because of its potential for drug development. There is increasing evidence that the storage of fat in white adipose tissue is increased in obesity while its removal is decreased. It has been postulated that these changes may at least be partially explained by the reduction in the numbers and activity of mitochondria, those parts of the cell that are essential for both the breakdown of fats and for the production of chemical energy in the form of ATP. It is believed that these changes may in turn increase the risk of disease, in particular, cardiovascular disease.

References 1. Laja Garcia AL et al (2019, 1923) Influence of water intake and balance on body composition in healthy young adults from Spain. Nutrients 11(8) 2. Popkin BM et al (2010) Water, hydration and health. Nutr Rev 68:439–458 3. Garrow JS et al (2000) Human nutrition and dietetics, 10th edn, p 14 4. Li C et al (2009) Estimates of body composition with dual-energy X-ray absorptiometry in adults. Am J Clin Nutr 90:1457–1465 5. World Health Organisation. Obesity. https://www.who.int/health-­topics/ obesity#tab=tab_1 6. Chang CY et al (2009) Essential fatty acids and human brain. Rev Acta Neurol Taiwan 18:231–241 7. Al-Sari N et  al (2020) Lipidomics of human adipose tissue reveals diversity between body areas. PLoS One 15:e:0228521 8. Lenz M et al (2020) Adipose tissue in health and disease through the lens of its building blocks. Sci Rep 10:10433 9. Frank AP et  al (2019) Determinants of body fat distribution in humans may provide insight about obesity related health risks. J Lip Res 60:1710–1719 10. Ikeda K et al (2018) The common and distinct features of brown and beige adipocytes. Trends Endocrinol Metab 29:191–200 11. Zoico E et  al (2019) Brown and beige adipose tissue and aging. Rev Front Endocrinol 10:368

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12. Montanari T et al (2017) Factors involved in white-to-brown adipose tissue conversion. Obes Rev 18:495–513 13. Okla M et al (2017) Dietary factors promoting brown and beige fat development and thermogenesis. Rev Adv Nutr 8:473–483 14. Pollard AC et al (1980) Enzymological diagnosis of a group of lysosomal storage diseases. Review of 5-year experience of 1600 patient-sample referrals. Med J Aust 2:549–553 15. Flegal KM et al (2009) Comparisons of percentage body fat, body mass index, waist circumference, and waist-stature ratio in adults. Am J Clin Nutr 89:500–508 16. Schorr M et al (2018) Sex differences in body composition and association with cardiometabolic risk. Biol Sex Differ 9:28 17. Wilczek MM et  al (2017) Trans-fatty acids and cardiovascular disease: urgent need for legislation. Cardiology 138:254–258 18. Torres-Castillo N et al (2020) (2020) healthy obese subjects differ in chronotype, sleep habits, and adipose tissue fatty acid composition from their non-healthy counterparts. Nutrients 13:119 19. Leiria LO, Tseng YH (2020) Lipidomics of brown and white adipose tissue: implications for energy metabolism. Biochim Biophys Acta Mol Cell Biol Lipids 1865(10):158788 20. Lapid K, Graff JM (2017) Form(ul)ation of adipocytes by lipids. Adipocytes 6:176–186 21. Leiria LO, Tseng YH (1865) Lipidomics of brown and white adipose tissue: implications for energy metabolism. Biochim Biophys Acta Mol Cell Biol Lipids 10:158788 22. Arner P et al (2011) Dynamics of human adipose lipid turnover in health and metabolic disease. Nature 478(7367):110–113 23. Arner P, Rydén M (2022) Human white adipose tissue: a highly dynamic metabolic organ. J Intern Med 291:611–621 24. Heinonen S et  al (2020) White adipose tissue mitochondrial metabolism in health and in obesity. Obes Rev 21(2):e12958 25. Lahera V et al (2017) Role of mitochondrial dysfunction in hypertension and obesity. Curr Hypertens Rep 19(2):11 26. Konige M et al (2014) Role of adipose specific lipid droplet proteins in maintaining whole body energy homeostasis. Biochim Biophys Acta 1842(3):393–401 27. Umar M et al (2018) Role of vitamin D beyond the skeletal function: a review of the molecular and clinical studies. Int J Mol Sci 19:1618 28. Petrus P, Arner P (2020) The impact of dietary fatty acids on human adipose tissue. Proc Nutr Soc 79:42–46

2 Variation in Body Size and Obesity

Summary • There are large differences in body weight and shape. • Whether someone is above body weight is determined by the measurement of the body mass index (BMI). • BMI measurements have shown that a large proportion of the world's population is overweight. • A significant proportion of those overweight are considered obese. • Racial and socioeconomic factors appear to have an effect on BMI. • With increasing BMI there are corresponding differences in body fat distribution. • Hormonal influences, age, and diet are some of the factors that can affect fat distribution. • Increased fat distribution at certain sites, for example, visceral fat, is believed to increase the risk of disease. It is fairly clear that there are big differences in height and weight of people around us [1, 2]. There are a number of factors that have to be taken into account in any determination of whether someone is of normal weight, overweight or obese. Clearly, age is a factor because there is a natural increase in weight from birth to at some point in the late teenage years when growth in height, an important factor in body weight in childhood, ceases. There is no doubt that genetic factors play a key role in determining height and weight in children, as well as adults, but it is clear that other factors, particularly nutrition and disease also play a role [2–4]. These factors will be discussed in greater detail later.

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One way of determining whether someone is overweight and therefore likely to be carrying extra fat reserves for their height is to use what is referred to as the BMI or body mass index [1]. This is determined by dividing the weight in kilograms by the height squared. Adults whose BMI is 18.5–24.9 are considered of normal weight, while BMIs of 25–29.9 are considered overweight and those above 30 years are considered obese. The global standardized BMI in 1975 for children aged from 5 to 19 years was 17.2 and 16.8 (measured as kilograms per height in meters squared) for girls and boys, respectively. Measurements taken in 2016 showed an increase in both boys and girls to 18.6 and 18.5, respectively. This compares with much higher figures for women and men (18.5–24.9) [1]. The scale of the obesity epidemic even in children is clear from figures provided by the World Health Organisation which reported that more than 340 million children in the ages 5–19 years were overweight or obese in 2016, and 39 million children under the age of 5  years, were overweight or obese in 2020 [5]. The prevalence of overweight or obesity in children aged 5–19 years rose from 4% in 1975 to 18% in 2016. In 2016, 39% of adults were overweight and, of these, 13% were considered obese. There is clear evidence that obesity may commence early in life because obese children are thought to be up to five times more likely to become obese adults than those of normal weight [6]. Another factor that appears to affect the risk of developing obesity in childhood, is race or ethnicity. In a recent study carried out in the United States, the prevalence of obesity in children from an American Indian background was found to be 31.2% as compared to 22, 20.8, 15.9, and 12.8% prevalence for children from Hispanic, black, white, and Asian backgrounds, respectively [7]. Socioeconomic factors have also been reported to affect the risk of developing obesity [8]. Race also appears to be a factor in adults. According to the US Centre for Disease Control, the incidence of obesity for adults in the United States also varies according to race with a prevalence of 49.9, 45.6, 41.4, and 16.1% for non-Hispanic black adults, Hispanic adults, non-­ Hispanic white adults, and non-Hispanic Asian adults [9].

Fat Distribution and Obesity While BMI measurements are a useful means of determining whether someone is obese, they do not take into account the actual amount of fat stored in the body, nor do they provide information on where the fat is stored. The storage sites are important because there is increasing evidence that it is an

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important risk factor in diseases associated with obesity. As mentioned earlier, fat is stored in adipose tissue which is located at different sites throughout the body predominantly under the skin in the hips and thighs and around the waist, and also within the abdominal cavity, for example, within layers around the intestine, liver, pancreas, and the pericardium which is a layer surrounding the heart. The fat within the abdominal cavity is referred to as “visceral fat.” There are individual differences in where fat is stored in the body and what determines the storage sites can vary from person to person [10, 11]. There is also increasing evidence that not only does the distribution of fat vary, the composition of adipose tissue at the different sites throughout the body is not the same [12]. Women have more body fat than men with most fat stored in the hips and thighs as compared to greater storage in the abdominal area for men. In women, changes in physiological state, as occurs pre- and post-menopause, lead to a more “android” type of changes, i.e., increased amounts of visceral and upper body fat, although the changes are not as pronounced after menopause [13]. It is believed that there are hormonal factors that underlie these differences in fat distribution between the sexes [14, 15]. Aging also results in increases in body fat although in later old age the amounts of body fat may even decrease [16]. Because BMI measurements do not always provide information on how much, and where excess fat is stored, coupled with the view that some fat, such as visceral fat is more likely to increase the risk of disease, a variety of alternative measurements are being used. Some of these include waist-hip ratio, body adiposity index, and trunk-leg fat ratio measurements [17]. More accurate measurements of total body fat involve complicated and expensive methods such as underwater weighing and dual-energy X-ray absorption techniques. Bioelectrical impedance devices which measure body fat, muscle mass, and water have been used increasingly although there are concerns about the accuracy of these devices [18]. While fat storage is an important function of the main cell type in adipose tissue, fat is also stored in other cellular types. For example, the so-called ectopic fat, i.e., non-adipose tissue fat, is stored in many different cell types, including the heart, skeletal muscle, and even the pancreas, the insulin-­ releasing organ [19]. There is an increasing amount of abdominal fat with aging, as well as fat deposition in the heart, liver, and skeletal muscle [20].

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Fat Distribution and Diet Because of the health implications, both the amounts and the storage sites in the body, have been the subject of considerable research over the last few years. Apart from genetics, there are a number of other factors which can influence both amounts of body fat and its distribution. One of these is diet. While it is well known that the type of diet does have an effect on total body fat, it also has been shown to influence the sites of its distribution in the body. A recent study looked at fat distribution in individuals who had followed criteria for a healthy diet developed by researchers from the US Department of Agriculture and the US National Cancer Council [21]. According to these criteria, the quality of a diet can be given a score which is referred to as the HEI-2015 score and is a sum of the scores of the different components in a particular diet. Some of the dietary components affecting the score include total fruits, whole fruits, total protein, fat, and type of fat. There were indications that there were decreases in fat deposits in those parts of the body, in particular, in the abdomen, which are believed to contain the more potentially harmful fat deposits. Another recent study which examined the fat distribution of individuals who were on what was considered a healthy plant based diet, confirmed the reduction in the less healthy visceral fat [22].

Fat Distribution and Physical Activity In addition to its impact on the amount of body fat, increases in physical activity including standing, has also been found to reduce the amount of visceral fat, and increased sitting time increases the deposition of pericardial fat (fat around the heart) [23–25]. Increased distribution of fat in the trunk has also been shown in children and adolescents who sit for extended periods of time watching TV or videos [24].

Fat Distribution and Other Factors Food and physical activity are not the only factors that can influence fat distribution. There are reports that smoking can increase the deposition of fat in the trunk rather than the extremities [26, 27]. Another factor that can increase the deposits of so-called “central fat,” i.e., fat around the waist is alcohol, particularly, if consumption is excessive [28, 29]. A variety of drugs are known to

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cause weight gain including changes in fat distribution [30]. This will be discussed elsewhere in this book. Whether there are genetic factors that play a role in body fat distribution is not known. However, in a recent study it has been reported that the sites of fat distribution, which are now believed to play a role in the development of certain disease states may be under some degree of genetic influence [31].

Fat Distribution and Disease Risk The effects of obesity on health and well-being will be discussed in a later chapter of this book. However, in relation to fat distribution the so-called “obesity paradox” has received increasing attention because it appears to indicate that even normal-weight individuals may have an increased risk of cardiovascular disease and diabetes if there is increased distribution of visceral fat [32]. That is, according to this view, while the BMI is important, the actual site of fat deposition is key and does vary from person to person. Substantial fat deposits beneath skin around the buttocks and thighs may not look attractive but are not believed to have the same effects on health as visceral fat.

What Does This Mean? Any cursory examination of the people around us can confirm there are significant differences in height. Height is largely genetically determined although disease and nutrition do play a role. It is also apparent that there are also large differences in weight and body shape. Whether someone is above the normal weight for age and sex is determined using the basal metabolic index (BMI) which is a measure of the weight in kilograms divided by the height in meters squared. BMI measurements taken in most countries show clearly that a large proportion of the world population is overweight. There are indications that racial and socioeconomic factors can have an effect on the BMI.  A significant proportion of those who are overweight with an even higher BMI are considered to be obese. With increasing BMI there are marked differences as well in body shape which is influenced by fat storage depots at different sites throughout the body. The buttocks, waist, thighs, and even the face and neck are the most obvious sites. But there are many other sites in the body where fat is distributed. There are a number of factors that affect the amount of fat, and its distribution sites in the body. Clearly, diet is an important factor as is the amount of

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physical activity. Women naturally have larger amounts of body fat but its distribution changes with menopause which indicates there is a hormonal influence that may determine the location of fat deposits. There are also changes in fat distribution with age, smoking, and excessive alcohol consumption. It is clear that body shape is influenced by the differences in fat deposits around the body. While the main reason for many people wanting to change body shape is to improve their appearance, there is increasing evidence that there are significant health implications associated with a particular body shape which in turn influenced by the sites of fat deposits. From a health perspective, not all sites are the same. The sites of greatest concern are the so-­ called visceral fats which lie within the abdomen and close to important organs such as the intestine and even the heart because fat deposits in these parts of the body appear to increase the risk of cardiovascular disease and diabetes.

References 1. (2017) Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975-2016.: a pooled analysis of 2416 population based measurement studies in 128.9 million children, adolescents, and adults. Lancet 390:26327–22642 2. Robinson M et al (2015) Population genetic differentiation of height and body mass index across Europe. Nat Genet 47:1357–1362 3. Pigeyre M et al (2016) Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Rev Clin Sci (Lond) 130:943–986 4. Kyle UG et  al (2015) Growth failure and nutrition considerations in chronic childhood wasting diseases. Rev Nutr Clin Pract 30:227–238 5. World Health Organisation (2021) Obesity and overweight. https://www.who. int/news-­room/fact-­sheets/detail/obesity-­and-­overweight 6. Simmonds M et  al (2016) Predicting adult obesity from childhood obesity: a systematic review and meta-analysis. Obes Rev 17:95–107 7. Isong IA et  al (2018) Racial and ethnic disparities in early childhood obesity. Pediatrics 141(1)2001:e20170865 8. Benusic M, Cheskin LJ (2021) Obesity prevalence in large US cities: association with socioeconomic indicators, race/ethnicity and physical activity. J Public Health (Oxf ) 43:148–154 9. Centers for Disease Control and Prevention (2022) Adult obesity facts. https:// www.cdc.gov/obesity/data/adult.html

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10. Goossens GH (2017) The metabolic phenotype in obesity. Fat mass, body fat distribution, and adipose tissue function. Rev Obes Facts 10:207–215 11. Frank AP et  al (2019) Determinants of body fat distribution in humans may provide insight about obesity-related health risks. J Lipid Res 60:1710–1719 12. Kwok KHM et al (2016) Heterogeneity of white adipose tissue: molecular basis and clinical implications. Exp Mol Med (48)3:e215 13. Greendale GA et al (2021) Changes in regional fat distribution and anthropometric measures across menopause transition. J Clin Endocrinol 106:252–2534 14. Karastergiou K et al (2012) Sex differences in human adipose tissues – the biology of pear shape. Biol Sex Differ 3:13 15. Tchernof A et al (2018) Androgens and the regulation of adiposity and body fat distribution in humans. Compr Physiol 8:1253–1290 16. Al-Sofiani ME et al (2019) Body composition changes in diabetes and aging. Rev J Diabetes Complications 33:451–450 17. Bergman RN et  al (2011) A better index of body adiposity. Obesity (Silver Spring) 19:1083–1089 18. Ward LC (2019) Bioelectrical impedance analysis for body composition assessment: reflections on accuracy, clinical utility, and standardization. Rev Eur J Clin Nutr 73:194–199 19. Kozawa J, Shimomura I (2021) Ectopic fat accumulation in pancreas and heart. J Clin Med 10:1326 20. Kuk JL et al (2009) Age-related changes in total and regional fat distribution. Rev Ageing Res Rev 8:339–348 21. Xu F et al (2020) Relationships of physical activity and diet quality with body composition and fat distribution in US adults. Obesity (Silver Spring) 28:2431–2440 22. Ratjen I et al (2020) Adherence to a plant-based diet in relation to adipose tissue volumes and liver fat content. Am J Clin 112:354–363 23. Larsen BA et al (2014) Associations of physical activity and sedentary behavior with regional fat deposition. Med Sci Sports Exerc 46:520–528 24. Liao J et al (2021) Association of sedentary patterns with body fat distribution among US children and adolescents: a population- based study. Int J Obes 45:2048–2057 25. Ando S et al (2020) The association of daily physical activity behaviors with visceral fat. Obes Res Clin Pract 14:531–535 26. Wei C et al (2019) Associations of nicotine dependence and fat distribution in Chinese male adults: a cross sectional study in Lanxi, China. BMJ Open 9(3):e:022465 27. Canoy D et al (2005) Cigarette smoking and fat distribution in 21, 828 British men and women: a population-based study. Obes Res 13:1466–1475 28. Wannamethee SG et al (2005) Alcohol and adiposity: effects of quantity and type of drink and time relation with meals. Int J Obes 29:1436–1444

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29. Sayon-Orea C et al (2011) Alcohol consumption and body weight: a systematic review. Nutr Rev 69:419–431 30. Verhaegen AA, Van Gaal LF (2021) Drugs affecting body weight, body fat distribution, and metabolic function-mechanisms and possible therapeutic or preventative measures: an update. Rev Curr Obes Rep 10:1–13 31. Pulit SL et al (2019) Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum Mol Genet 28:166–174 32. Piché ME et al (2020) Obesity phenotypes, diabetes, and cardiovascular diseases. Circ Res 126(11):1477–1500

3 Genetics and Obesity

Summary • Studies with twins have demonstrated that genetic factors play a critical role in the development of obesity. • Obesity can develop as a result of mutations in certain genes that are involved in the hormonal control of food intake and utilization. • Minor structural changes of genes (polymorphisms) do not normally cause obesity but can increase the risk of obesity in combination with polymorphisms in other unrelated genes. • The risk of obesity may result from epigenetic changes which affect the methylation of DNA and subsequent expression of certain genes. • The inflammatory changes resulting from obesity may affect the expression of certain genes. It is clear that there are non-dietary factors that affect body size and fat distribution, such as age, sex, and physiological state, over which we have little control. There is, in addition, another factor which is not often considered and that is genetics. We all have 20,000 or more genes which are located on chromosomes, tiny structures found in the nucleus of most cells in the body, The chromosomes are composed of deoxyribonucleic acid or DNA. There are 23 pairs of chromosomes, making a total of 46 chromosomes. Twenty-two of these chromosomes are referred to as autosomes. In females, there are an additional two chromosomes, the X chromosomes, while males only have a single X chromosome but have, in addition, what is termed a Y chromosome. So females have XX and males XY chromosomes. We inherit two copies of each

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of these autosomes, one from the mother and one from the father. The genes determine whether we are male or female, the color of our eyes, skin, and hair, and many other characteristics including whether we are likely to develop one of the many different diseases that afflict humanity. It is even more complicated that this because each gene provides a blueprint for the production of an individual protein which in turn may be subject to certain changes in structure such as the cleavage to produce a smaller protein, or the addition of carbohydrate or fatty tags. Changes in the DNA structure of a gene can give rise to what is termed “mutations” which can lead to the production of a protein that is defective and is unable to carry out its normal function. This can lead to disease and even death. Cystic fibrosis and tyrosinemia are just two examples of many different genetic diseases. If the abnormality occurs on one of the X chromosomes then the result is an X-linked disease such as hemophilia. On the other hand, if the change in DNA is only slight or is insufficient to cause a major change in the activity of the resulting protein then it is referred to as a polymorphism. However, even though polymorphisms of genes by themselves are not normally sufficient to give rise to sufficiently abnormal proteins which in turn are harmful, they can interact with other genes to increase the risk of disease. One example of a polymorphism and its impact on health is the gene for a specific blood protein apolipoprotein E. Certain polymorphisms of the apolipoprotein E gene are thought to increase the risk of Alzheimer’s disease [1]. It is important to note, however, that this change in the DNA for lipoprotein E is not the cause of the disease but it is a factor in the increased risk. In a recent study, it was found that the risk factors for developing relatively common diseases such as coronary arterial disease, diabetes, atrial fibrillation, and inflammatory bowel disease are influenced by the structures of multiple genes [2]. It is worth noting that genetic polymorphisms are not always associated with a disease or risk of disease but contribute to many basic human characteristics such as facial shape, and skin and hair color [3, 4]. There is increasing evidence that many different genes are involved in another key human characteristic, height, although it is clear that there are many other factors such as disease and diet that are also involved [5, 6]. Genetic factors are also an important factor in determining body weight including the risk of obesity [7, 8]. Further evidence for the role of genes in body weight is indicated by twin studies which show that monozygotic twins, i.e., those that develop from a single ovum, and therefore contain the same genes as compared to dizygotic twins whose DNA is different, are more likely to become obese [9].

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The importance of genetics in the development of obesity is clear from research which indicates that the heritability is between 40 and 70% [10]. We now know that an abnormality in one of a number of different genes can give rise to obesity. Depending on the type of genetic abnormality, these diseases are referred to as monogenic (i.e., affecting a single gene) or polygenic (where there are changes in a number of different genes). It is even more complex than this because monogenic diseases are in turn divided into syndromic and non-syndromic conditions. Monogenic syndromic conditions can affect a number of organs. For example, one of these monogenic diseases, the Bardet-­ Biedl syndrome, is characterized by abnormalities in the retina of the eye and the kidneys, mental retardation, as well as obesity [11, 12]. To illustrate the complexity of the role of genetics in obesity, abnormalities in any one of 19 genes have been reported to give rise to this disease [13]. Genetic abnormalities in single genes affecting certain hormones can also cause obesity [11]. The role of these hormones in obesity will be discussed in greater detail later in this book. Three of the better-known gene products include the protein hormones leptin, ghrelin, and melanocortin. Leptin is a protein that is produced by adipose tissue. It is termed an “anorexigenic” agent. That is, it acts as an agent to suppress appetite. It is believed that it does this by acting in a certain part of the brain, the hypothalamus. It is thought that the levels of leptin are an indication of the amounts of energy stored as fat in the adipose tissue. A genetic abnormality of leptin is believed to give rise to obesity [14]. Genetic abnormalities in a receptor which binds another protein involved in appetite regulation, ghrelin, have also been reported to give rise to obesity [15]. Obesity is also thought to result from an abnormality of yet another protein linked to the regulation of appetite, the melanocortin receptor [16]. Recent studies have suggested that obesity may also develop as a result of polymorphisms in a great number of genes [17, 18]. In these cases while the changes or polymorphisms in individual genes may not be sufficient to have an impact on body weight, in combination with certain polymorphisms in other genes it can increase the risk of obesity. A more serious example of a polygenic disease is Prader-Willi syndrome. In addition to short stature and intellectual disability, individuals with this disease have a constant feeling of hunger which results in overeating and, eventually, obesity [12]. The genetic abnormality relates to a missing group of genes normally inherited from the father rather than polymorphisms of a number of genes.

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Epigenetics and Obesity As DNA provides the blueprint for the production of thousands of different proteins in the body, and as there are clearly major differences in the structure and function of the many different organs in the body it is clear that there has to be another way of ensuring that there is a tissue specificity for the manufacture of different proteins otherwise the same proteins would be manufactured in all cells of the body. Clearly, a mechanism for ensuring a degree of specificity in the different proteins produced by the different organs is needed. This mechanism, which is termed epigenetics, relies on the ability to turn on the synthesis of proteins specific to a particular organ while at the same time ensuring that proteins not required by the same organ are not synthesized or expressed. Like most of the processes that take place in the cells of our bodies, expression is under chemical control. There are a number of ways of doing this and they are mostly chemical in nature. Perhaps the most well known is methylation. Methylation refers to the addition of a methyl group to specific sites in the DNA. A methyl group is essentially a single carbon atom joined to three hydrogen atoms. Another method involves the chemical modification of histones, proteins around which the DNA is coiled. There is increasing evidence that a variety of chemicals, including drugs and pollutants can interfere with epigenetic modifications of DNA, and this in turn may increase the risk of disease [17, 19]. The importance of epigenetics in obesity is well illustrated by studies carried out with certain strains of mice which have shown that aberrant methylation of a particular gene involved in coat color leads to the production of the gene product, i.e., a specific protein associated with coat color, in other parts of the body and, in particular, in certain parts of the brain controlling appetite which in turn results in obesity [17]. It has become increasingly clear that, for example, the various processes required for the synthesis, breakdown, and storage of fats, as well as the hormonal signals controlling appetite involve a great number of individual genes which are also subject to epigenetic changes which in turn can affect the expression of the DNA and the synthesis of individual proteins involved in these various reactions. It is logical to assume that anything that interferes with this complex process may have an effect on hormonal signals to and from the brain, as well as fat synthesis, breakdown, and storage in the body. There are indications that epigenetic changes are dynamic, i.e., they respond to environmental factors [20, 21]. For example, studies carried out on women who were prenatally exposed to famine during the Dutch Hunger Winter

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during the Second World War showed a reduction in methylation of certain genes in the developing fetus which continued after birth [22, 23]. There is also evidence that a variety of environmental pollutants, including agricultural chemicals, air pollutants, fluorocarbons, smoking, and bisphenol A can influence methylation and hence the expression of genes [24–27]. Other research indicates that methylation of genes also may be affected by dietary factors and even speculation that epigenetic changes may result from the amount of physical activity [20, 28–30]. There is also a view that certain nutrients present in food and others released by the microbiome may even affect the critical interaction between the gut and brain and thereby modify behavior [28]. What is of considerable interest is the suggestion that changes in methylation of DNA may be the result of, rather than the cause, of obesity [31, 32]. Treatment of genetic disease is highly complex mostly involving gene transfer or gene editing. For those diseases which lead to obesity, such as, for example abnormalities in the melanocortin pathway, treatment has mostly involved the use of drugs. A recently developed drug, setmelanotide, is now being used to treat those genetic diseases that affect the melanocortin pathways in the brain. The chemical structure of setmelanotide has a structural similarity to a naturally occurring chemical (alpha melanocyte stimulating hormone). These conditions, such as the Bardet-Biedl Syndrome and the Leptin Receptor deficiency often lead to extreme hunger which in turn results in overeating and, ultimately, obesity [33].

What Does This Mean? There is little doubt that genetic factors play a critical role in the development of obesity. Studies carried out with identical twins provide support for this view. It is believed that heritability of obesity is as high as 40–70% or more. We now know that obesity can develop from major changes in single critical genes involved in hormonal control of food intake and utilization but these are rare. One example is the gene for leptin, a protein involved in the hormonal control of food intake. Examples of two other genes that take part in the regulation of food intake include the cell receptor for ghrelin, a protein that acts as an appetite suppressant and the receptor for melanocortin, which is also involved in the regulation of appetite. Obesity can also develop, together with other abnormalities, in certain diseases that are caused by changes in multiple genes on certain chromosomes. Minor structural changes in genes, referred to as polymorphisms, of certain individual genes do not normally

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cause obesity by themselves but can increase the risk of obesity in combination with changes in other, apparently unrelated genes. Another way our genes may affect the risk of obesity is through epigenetics which can affect their expression. This process involves chemical changes, in particular, methylation of genetic DNA, which in turn influences the expression of individual genes in different parts of the body. There is increasing evidence that obesity, perhaps as a consequence of the inflammatory changes which are a feature of the condition, can alter these methylation patterns, which in turn can affect the expression of certain genes and may explain the increased risk of diseases such as diabetes and cardiovascular diseases in obesity [20, 21].

References 1. Belloy ME et  al (2019) A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Rev Neuron 101:820–838 2. Khera AV et al (2018) Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet 50:1219–1224 3. Cha S et al (2018) Identification of five novel genetic loci related to facial morphology by genome-wide association studies. BMC Genomics 19:481 4. Sulem P et al (2007) Genetic determination of hair, eye and skin pigmentation in Europeans. Nat Genet 39:1443–1452 5. Guo MH et  al (2018) Insights and implications of genome-wide association studies of height. Rev J Clin Endocrinol Metab 103:3155–3168 6. Perkins JM et al (2016) Adult height, nutrition, and population health. Rev Nutr Rev 74:149–165 7. Nazareth M et al (2021) Association between parental and offspring BMI: results from EPAC1 Portugal 2012. Public Health Nutr 24:2797–2807 8. Goodarzi M (2018) Genetics of obesity: what genetic association studies have taught us about the biology of obesity and its complications. Rev Lancet Diabetes Endocrinol 6:223–236 9. Stunkard AJ et al (1986) A twin study of human obesity. JAMA 256:51–54 10. Loos RJF and Yeo GSH (2022) The genetics of obesity: from discovery to biology. Nat Rev Genet 23:120–133 11. Rohde K et al (2019) Genetics and epigenetics in obesity. Metabolism 92:37–50 12. Butler MG et  al (2019) Prader-will syndrome-clinical genetics, diagnosis and treatment approaches: an update. Rev Curr Pediatr Rev 15:207–244 13. Khan SA et al (2016) Genetics of human Bardet-Biedl syndrome, an updates. Rev Clin Genet 90:3–15

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14. Wasim M et al (2016) Role of leptin deficiency, inefficiency, and leptin receptors in obesity. Biochem Genet 54:565–572 15. Wang W, Tao YX (2016) Ghrelin receptor mutations and human obesity. Prog Mol Biol Transl Sci 140:131–150 16. Vázquez-Moreno M et al (2020) The Melanocortin 4 receptor p.Ile269Asn mutation is associated with childhood and adult obesity in Mexicans. J Clin Endocrinol Metab 105(4):dgz276 17. Mahmoud AM (2022) An overview of epigenetics in obesity: the role of lifestyle and therapeutic interventions. Int J Mol Sci 23:1341 18. Khera AV et  al (2019) Polygenic prediction of weight and obesity trajectories from birth to adulthood. Cell 177:587–596.e9 19. Efimova OA et  al (2020) Environmental epigenetics and genome flexibility: focus on 5-hydoxymethylcytosine. Int J Mol Sci 21:3223 20. Samblas M et  al (2019) DNA methylation markers in obesity, metabolic syndrome, and weight loss. Epigenetics 14:421–444 21. Ling C, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab 29:1028–1044 22. Heijmans BT et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105:17046–17049 23. Tobi EW et al (2014) DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun 26:5592 24. van der Plaat DA et al (2018) Occupational exposure to pesticides is associated with differential DNA methylation. Occup Environ Med 75:427–435 25. Mukherjee S et  al (2021) Air pollution-induced epigenetic changes: disease development and a possible link with hypersensitivity pneumonitis. Environ Sci Pollut Res Int 28:55981–56002 26. Kim S et  al (2021) Epigenetic changes by per- and polyfluoroalkyl substances (PFAS). Environ Pollut 279:116929 27. Joehanes R et  al (2016) Epigenetic signatures of cigarette smoking. Circ Cardiovasc Genet 9:436–447 28. Allison J et  al (2021) Targeting DNA methylation in the adult brain through diet. Nutrients 13:3979 29. Grazioli E et al (2017) Physical activity in the prevention of human diseases: role of epigenetic modifications. BMC Genomics 18(Suppl 8):802 30. Cuevas-Sierra A et al (2019) Diet, gut microbiota, and obesity: links with host genetics and epigenetics and potential applications. Adv Nutr 10(Suppl_1):S17–S30 31. Wahl S et al (2017) Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 541:81–86 32. Chen Y et al (2021) Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: an EWAS in multi-ethnic Asian individuals. Clin Epigenetics 13:195

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33. US Food and Drug Administration. FDA approves treatment for weight management in patients with Bardet-Biedl Syndrome aged 6 or older. https://www.fda. gov/drugs/news-­e vents-­h uman-­d rugs/fda-­a pproves-­t reatment-­w eight-­ management-­patients-­bardet-­biedl-­syndrome-­aged-­6-­or-­older#:~:text=The%20 U.S.%20Food%20and%20Drug,%2DBiedl%20Syndrome%20(BBS)

4 Non-dietary Factors and Weight Gain

Summary • There are many factors that regulate the intake and utilization of energy from food. • Hormones such as the male and female sex hormones, insulin, glucagon, and thyroxine play important roles. • Two other hormones, leptin and grehlin, have an even more direct effect in the regulation of body weight. • Non-hormonal factors, such as certain chemicals, referred to as obesogens, are now believed to interfere with these processes. • Chemicals produced by the microbiome, the microbial population of the gut, may be involved in the regulation of body weight. • Certain drugs are believed to contribute to the rising incidence of obesity. • The marketing of food which has resulted in the increasing consumption of ultraprocessed food is believed to be a factor in the increasing incidence of obesity. The regulation of body mass is a highly complex process and much more than energy going in (i.e., food) and going out. While the latter includes physical activity, energy is also required to drive the various processes that take place every minute of every day throughout our lifetimes. Some of these processes include food digestion, and brain, kidney, liver, heart, and skeletal muscle function. There are natural processes in our bodies that ensure that there is a balance between the amount of energy from food we take in, and our energy requirements. It is easy to see how anything that interferes with this balance

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can cause weight loss or gain. Perhaps the most important factors in the regulation of energy input and output are hormonal.

Hormonal Regulation of Body Weight Like many other processes that take place in our bodies, they are controlled by a number of hormones produced by different tissues and collectively referred to as the endocrine system. The best known of these hormones include insulin, produced by the pancreas, and thyroxine and tri-iodothyronine (referred to as T4 and T3), produced by the thyroid gland. Insulin has an indirect effect on obesity through its regulation of blood levels of the sugar glucose which is derived from food. Energy produced from glucose is used to drive the various metabolic processes that take place in the body. However, insulin also functions as an anabolic hormone, that is it also promotes the storage of energy, in the form of the complex sugar found in the liver, glycogen, but also the production of triglycerides, the fat stored in adipose tissue and mentioned in an earlier chapter of this book. In some type 2 diabetic patients, the apparent resistance to insulin, and the ability of the hormone to promote fat synthesis is thought to be a cause of their obesity [1–3]. Thyroxine also takes part in the regulation of energy from food. Its involvement in body mass is indicated by reports that higher than normal amounts of thyroxine (hyperthyroidism) can cause weight loss, while reduced amounts of thyroxine (hypothyroidism) can result in weight gain [4, 5]. Another protein involved in energy production in the body is the hormone glucagon which is generated by the pancreas, the organ that produces insulin. While the latter promotes the utilization of blood glucose, glucagon is involved in the generation of glucose, produced from the complex carbohydrate glycogen in the liver. A related protein, the glucagon-like protein (GLP-1) is generated in the gut and the brain. Upon release, it binds to specific receptors in the brain which are thought to be involved in the control of food intake [6]. Not surprisingly because of their potential effects on food intake, drugs such as liraglutide have been developed which can induce weight loss. This will be discussed further in a later chapter of this book. There are as well a number of other hormones which have more indirect effects on obesity. One of these hormones is the male sex hormone testosterone. Lower levels of testosterone appear to increase the amounts of body fat, particularly the more potentially harmful visceral fat [7, 8]. Testosterone supplements in obese men have been reported to cause weight loss [9]. As menopausal women are more likely to develop obesity than premenopausal women,

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and as their treatment with the female sex hormone estrogen can reduce the levels of visceral fat, it is believed that estrogens also play a role in the regulation of the amount and distribution of body fat in women [10]. Research over the last decade or so has revealed that there are other substances with hormone-like activities that regulate the production of energy from food and have a more direct effect on body weight. The three best known are leptin, ghrelin, and melanocortin. Leptin is a protein produced mainly by adipose tissue and its main function is the regulation of energy production from food. It produces its effects by binding to a special receptor [11–13]. Factors that promote its production and release include overeating and increased amounts of fat stored in the body while low fat reserves and fasting inhibit leptin production. It acts through its effects on special receptors in the brain and in other parts of the body. Because of its apparent ability to decrease food intake, there have been attempts to use leptin as means of weight reduction. However, treating normal obese individuals with leptin as a means of appetite suppression and weight reduction have been largely unsuccessful for reasons that are not fully understood [12, 13]. On the other hand, treatment of patients who are obese because of genetic abnormalities in either leptin or leptin receptor has been more successful [14–17]. Genetic abnormalities in the leptin receptor, a protein that binds leptin and transmits signals within cells, also cause obesity [18, 19]. The actions of leptin are regulated by other substances with hormone-like properties. After feeding, leptin stimulates the production of another protein in the brain, proopiomelanocortin (referred to as POMC), which in turn is converted into two proteins, alpha- and beta-melanocortin proteins. These two proteins bind to yet another protein in the brain, the melanocyte-4-­ receptor (MC4R) which is believed to be involved in the regulation of food intake [20]. The latter is clearly important in the regulation of body weight because a genetic abnormality can give rise to obesity [20]. Another protein involved in the regulation of energy production is ghrelin. It is produced mainly in the stomach and intestine and then travels to the brain where it binds to regions which stimulate appetite. It is for this reason it has been called the “hunger hormone.” It is believed that it contributes to promoting the drive to eat even when not hungry and this has led to its investigation as a potential target for overeating [21]. Decreased blood levels of ghrelin have been observed in obese individuals as compared to those with normal BMIs [22]. Increasing blood levels of ghrelin are also observed through dieting or food restriction and this may explain the long-term failure rate of dieting as a means of weight loss [23, 24].

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In addition to leptin and melanocortin the brain contains at least two other hormone-like substances which are involved in the regulation of food intake. These are the neurotransmitters, serotonin, and dopamine. It is thought that these substances play a role in the homeostatic and hedonic systems in the brain. The homeostatic system in the brain receives information from different parts of the body and regulates food intake, while the hedonic system is thought to be involved in the “motivational and rewarding aspects” of food intake. Studies in animals and humans have shown that the pathways in the brain involving serotonin and dopamine can affect eating behavior such as motivation to eat [25].

Non-hormonal Factors As hormonal regulation is such an important factor in the regulation of body mass it is not surprising that anything that interferes with this process is likely to either cause weight loss or gain. There are numerous other factors which either interfere with the hormonal processes, or disturb the natural balance which exists for ensuring that the energy in food is sufficient to cope with the energy requirements of the body but not excessive which can lead to excess fat storage and obesity.

Obesogens Because of the increasing prevalence of obesity and the concomitant exposure to a variety of environmental pollutants it is not surprising that there is a view that chemical exposure may be a factor in the development of obesity. The chemicals that are thought to contribute to the development of obesity have been termed “obesogens” and are believed to act as endocrine disruptors, i.e., they interfere with the hormonal regulation of weight. Obesogens are prevalent in our environment and have been identified in dust, water, processed foods (including food additives), food packaging, food and storage containers, cosmetics and personal care products, furniture and electronics, air pollution, solvents, disinfectants, pesticides, sunscreens, plastics and plasticizers, non-nutritive sweeteners, some antidepressants and antidiabetic drugs, and common household products [26, 27]. One view is that the obesogens increase the number of adipocytes (fat-storing cells) and may also increase the storage of fat in these cells. It is believed that exposure at certain times, for example,

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in utero or in the neonatal period, maybe more critical and could increase the risk of obesity. The organotin compounds are good illustrations of the potential of an environmental pollutant to affect fat storage, in particular, tributyltin. These substances, which consist of the metal tin joined to one or more butyl groups (containing four carbon atoms), have been used as a fungicide and an anti-­ fouling treatment. They have been detected in PVC plastics, seafood, and even house dust [28]. As yet there have been few studies linking obesity in humans with organotin exposure although they have been found to increase the storage of fat in various organs in offspring of exposed pregnant mice [28, 29]. As mentioned earlier, there are a variety of other endocrine chemical disruptors which can interfere with the functions of the endocrine system, including adipogenesis. Plastic components in particular, such as bisphenol A and phthalates, as well as fluorocarbons, which are used in lubricants, waterproofing agents, and sealants, are thought to be potential obesogens [26, 30–32]. Adipose tissue has also been confirmed as a site of storage of a potentially great number of environmental pollutants, the actual composition apparently varying according to the source of exposure [33, 34]. There is a view that adipose tissue also serves as a means of removing various fatty pollutants from circulation and thereby reducing their exposure to other important organs of the body. Release of some of the pollutants stored in adipose tissue into the circulation which occurs after weight loss may also be potentially harmful, particularly for brain function [35, 36]. It is worth noting that while studies have shown that a variety of individual environmental pollutants as well as other substances may have obesogenic properties, they almost always are present in the body as complex mixtures. There have been few studies in humans on possible obesogenic effects of mixtures of pollutants even though the phenomenon of synergism, where mixtures of substances may produce a greater effect than that predicted by adding the activity produced by each component. Is well known [37]. Synergistic effects involving two known obesogens, tributyl tin, and fluorocarbons, have been observed in animal studies [38].

Gut Microbiome Over the last few years the role of microbes in the gut, referred to as the microbiome, has assumed much greater importance. It is believed that gut microbes, which include bacteria, viruses, protozoa, and fungi, play an important role in the harvesting, storage, and expenditure of energy obtained from

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the diet [39]. The microbes are able to utilize components of food that are not digestible by the human host and convert them into a variety of different substances [40]. Some of these substances are able to produce effects not just in the gut but in different parts of our bodies [41]. The numbers and types of microbes are thought to vary at different sites within the gut. Diet and physical activity have been reported to affect the composition of the microbial population [41, 42]. There is some evidence that there are differences in the microbiome population between normal, overweight, and obese individuals and this has led to speculation that it may be a factor in the development of obesity [43]. This has led to further speculation that the use of probiotics or antibiotics could lead to changes in the composition of the microbiome and this in turn may affect body weight [44].

Disruption of Circadian Rhythm Humans, animals, and even plants are subjected to variations in light, temperature, and food availability throughout the day. This has led to the development of an internal timekeeping system or circadian clock, in humans and animals, located in the hypothalamus in the brain and with links to many other parts of the body. This system adapts to changes throughout the day and night. To meet this fluctuating demand in energy requirements which arise throughout the day, our circadian clock regulates some of the natural processes that take place in our bodies, such as fat synthesis. If there is a disruption in this system, as occurs, for example, by flying across time zones, in shift work, or in disturbed eating patterns, this can lead to an increased risk of obesity [45–48].

Time of Eating For many people their diet consists of three meals a day, breakfast, lunch and dinner, with perhaps some degree of snacking at different times between meals. There is now evidence that snacking times may influence the type of food consumed and this in turn may increase the risk of obesity. In a US study, it was reported that snacking in the morning often included relatively low-calorie fruits and vegetables while snacking in the evening included more obesogenic foods and higher calorie foods such as fast food, French fries, and soft drinks, and was associated with a higher BMI. It was concluded that evening snacking increased the risk of obesity [49].

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Disability and Obesity It has been estimated that almost 25% of the US population has a disability which has an impact on their lives and similar findings have been observed in other developed countries [50–52]. Disability can be divided broadly into two categories, physical and mental. Even within each category, there are many different types of physical and mental disabilities. It is even more complex than this because some individuals may have both physical and mental disabilities. A reduction in physical activity, which could be expected to occur in those with some sort of physical disability, could lead to weight gain and obesity. However, there are other factors that increase the risk of obesity in physically disabled people. Some of these include medications used, lack of healthy food choices, and chronic and intermittent pain. The link between physical disability and obesity has been confirmed in a study carried out on US adults which showed that the proportion of physically disabled individuals who were obese was significantly greater (up to two times) than those without a disability [50]. Similar findings have been reported in a number of other countries [52]. Intellectual disability has also been reported to increase the risk of obesity in children and older individuals [53–55]. Increased incidence of obesity has even been observed in athletes with intellectual disabilities [56].

Binge Eating and Obesity Binge eating and the related bulimia nervosa are psychopathological conditions which involve episodes of overeating for periods of time, and can lead to obesity. They demonstrate that there are factors other than our energy requirements that can influence the choice and how much food we consume [57].

Old Age and Obesity The incidence of obesity in the over 80s has been reported to be half that of those aged from 50 to 59 [58]. While this would appear to be surprising, on closer inspection it is worth noting that measurement of the BMI does not take into account the loss of muscle mass which is common in older individuals, the retention or even increase in body fat, and the loss of height which is a common feature of old age and an integral component of BMI measurements. The apparent increase in waist circumference reported for those aged

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50–70 years is a further indication that the amount of body fat is increased with age.

Food Marketing and Weight Gain Food choice is clearly an important factor in the amount of energy taken into the body. This in turn is influenced by many factors such as the sensory properties of the food, cultural differences, physiological status (hungry, thirst, presence, or absence of illness), allergies, age, cost, and neophobia. The latter is a measure of the avoidance of unfamiliar food [59]. In more recent times, however, the marketing of food through the media (e.g., television and social media) has assumed greater importance in determining diet, particularly, children and adolescents. In a recent report, it was estimated that some children and adolescents view advertisements on social media relating to food on average 30 and 189 times a week, respectively [60]. In many cases, the food advertised was mainly sugar-sweetened beverages or fast food and therefore likely to have a relatively high-calorie content. Yet another way the young are targeted with relatively high-calorie food and drink is through sport. In this case, targeting is carried out through sport sponsorships, athlete endorsements, and sports video games, It has been argued that endorsement by athletes sends mixed messages. On the one hand, physical activity is encouraged while on the other there is an encouragement of the consumption of unhealthy food that is likely to result in weight gain [61]. This is clearly the view of the World Health Organisation which has stated that consumers are exposed to the marketing of foods and non-alcoholic beverages that “contribute to unhealthy diets (such as fast food, sugar-sweetened beverages, and chocolate and confectionery) that uses a wide range of strategies likely to appeal to young audiences such as celebrity/sports endorsement, promotional characters and games.” According to his view marketing can undermine healthy diets and negatively shape food preferences and values [62]. There seems little doubt that marketing of food does influence choice, particularly in the more vulnerable in the community. Unfortunately, some of the food promoted by fast food outlets and supermarkets are high in calories and are likely to increase the risk of obesity unless there is a corresponding increase in energy output [62–65]. Food marketing predominantly promotes foods that contribute to unhealthy diets (such as “fast food,” sugar-sweetened beverages, and chocolate and confectionery) and uses a wide range of creative strategies likely to appeal to young audiences (such as celebrity/sports endorsements, promotional

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characters, and games). The findings of the consumer research studies included positive associations between the frequency of, or level of exposure to, food marketing and habitual consumption of marketed foods or less healthy foods.

Drugs and Weight Gain We live in an age when many of our health problems may be managed, perhaps even cured, by drugs. We now have pills for high blood pressure, high blood cholesterol, diabetes, infections, inflammation and inflammatory diseases, neurological conditions such as seizures, Parkinson’s disease and multiple sclerosis, and psychological and cognitive diseases. Unfortunately, many drugs have side effects so it would not be surprising if some did not affect the complex pathways in the brain and in adipose tissue that are involved in the maintenance of normal body weight. Perhaps the best-known drugs associated with an increased risk of weight gain are antipsychotics, those used to treat a variety of psychiatric conditions such as Tourette’s syndrome, autism, schizophrenia, anxiety disorder, bipolar disorder, depression, and attention deficit disorder [66–68]. Other drugs that may cause weight gain include insulin (for diabetes), beta-blockers (for heart failure), and antiretrovirals for hepatitis C [69–72]. And with the increasing recognition that obesity fulfils the criteria for a disease, it is also not surprising that drugs have been developed to treat this “disease” [37]. This will be discussed in a later chapter of this book.

Alcohol and Weight Gain While excessive alcohol consumption is a factor in weight gain, it is believed that moderate consumption is not [73–75]. However, it is a complex question because of the number of variables, such as the amount and type of alcohol, the frequency of consumption, and the corresponding effects on food choices and physical activity.

Altitude and Obesity There is increasing evidence that living at high altitudes is associated with a decreased risk of obesity [76]. It is likely that the combination of low amounts of oxygen in the tissues and increased physical activity, which are almost

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certainly features of living in this type of environment, are important factors in reducing the risk of obesity at higher altitudes.

Rural Environments and Obesity A higher prevalence of obesity has been observed in children and adults living in rural areas [77]. It is thought that the limited availability and choice of healthy foods are important factors and this in turn may relate to climate, transportation access, education, and remoteness [77].

Workplace and Obesity As 40 hours a week or more are spent at work, and travelling to and from work, and as the amount of physical activity and hence energy utilization varies greatly in the many different working environments, it is not surprising that there have been studies researching the impact of the workplace on the risk of obesity. Studies suggest that working conditions may contribute to the development of obesity [48]. Long working hours, shift schedules, excessive sitting, as well as technological innovations which decrease energy expenditure, are all thought to be factors in the link between obesity and the workplace [78, 79]. As the principal cause of obesity is thought to be due to an imbalance between energy taken in as food and the energy expended through the various physical activities carried out in the workplace it would not be unexpected that certain occupations may show an increased risk of obesity. In many instances the working environment may include prolonged periods of physical inactivity—sitting at a desk at work or in a motor vehicle, train or bus getting to work—is not uncommon which really means that energy expended may be limited. If food consumed at work is high in calories, particularly if certain ultraprocessed foods are chosen because of their convenience, it would not be surprising if energy taken in as food is greater than that required to drive the various processes in the body. Over a period of time it could be expected that this energy imbalance could result in weight gain. It is worth noting that there have been studies showing that the working environment does increase the risk of certain diseases. For example, in a large study carried out by the International Labour Organisation (ILO) it was found that exposure to chemicals in different workplaces increased the risk of certain disease states [80]. It was also found that exposure to certain physical

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agents such as, for example, noise and radiation also increased the risk of disease. Although obesity is not included in the various ILO lists, in view of the changes in body fat distribution and the inflammatory changes, it would appear to fulfil at least some of the criteria of disease. According to the US Centre for Disease Control, the five professions whose workers have the greatest incidence of obesity include truck drivers, protective services (police, firefighters, emergency responders), cleaning and building services, mechanics and repairers, and health services (excluding doctors and nurses) [81]. Long-distance truck drivers, in particular, have been reported to have a high incidence of obesity, more than double the rest of the population [82]. In another study, more than 50% of nurses were found to be overweight [83]. While there are many factors which contribute to the higher incidence of obesity in nurses, such as, for example, shift work, there are indications that exposure to certain chemicals, for example, endocrine disrupting chemicals such as the phthalates which are present in gloves, face masks, and medical devices, and which are thought to have obesogenic properties may be involved [84, 85]. Another example of workplace chemical exposure and obesity has been reported in Thai farmers [86]. In this particular case it was thought that the pesticides used acted as obesogens.

What Does All This Mean? Research has shown that there are many factors which affect the delicate balance between the energy taken up as food and that which is used to drive the body. As hormones, such as insulin, glucagon, the glucagon-like protein, the thyroid hormone, and others such as leptin and ghrelin, and even the sex hormones, appear to play key roles in the regulation of food intake and the deposition of body fat, it is not surprising that any change in their activities such as occurs in different physiological states (e.g., menopause and aging), or even disturbance of the circadian system, can increase the risk of obesity. One area of increasing concern is the presence of chemical substances, referred to as obesogens, which have also been reported to have the ability to increase the risk of obesity. Our food, water, and air now contain myriad chemicals and little is really known about the impact they may have individually, or combined with complex mixtures of other chemicals, on the complex hormonal systems which determine our body weight. Some chemicals, even in relatively small amounts, can have an impact, as is apparent from the effects of a number of pharmaceuticals that can both increase and decrease body weight.

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It has become increasingly clear that motivation to eat more than is required to satisfy basic energy needs, as well as the choice of food, or drink, can be influenced by external factors, such as marketing through the media, or through psychopathological disease states such as bulimia or binge eating, and this can lead to weight gain and even obesity. The effects of marketing, particularly on children and young adults, are likely to be profound. Reduced physical activity, as can occur from physical injury, mental or physical disability, or even change to a least physically active work environment, can also lead to weight gain unless there is a corresponding reduction in food intake. The recognition recently of yet another factor, the gut microbiome, with its ability to produce a variety of products from food some of which may affect fat distribution and storage in the body illustrates the complexity of the processes involved in normal weight maintenance.

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71. Pischon T, Sharma AM (2001) Use of beta-blockers in obesity hypertension: potential role of weight gain. Obes Rev 2:275–280 72. Shah S et al (2021) Are new antiretroviral treatments increasing the risk of weight gain? Drugs 81:299–315 73. Traversy G, Chaput JP (2015) Alcohol consumption and obesity: an update. Curr Obes Rep 4:122–130 74. Sayon-Orea C et al (2011) Alcohol consumption and body weight: a systematic review. Nutr Rev 69:419–431 75. Fong M et  al. ‘Joining the dots’: individual, sociocultural and environmental links between alcohol consumption, dietary intake and body weight-a narrative review. Nutrients 13 76. Merrill RM (2020) Explaining the inverse association between altitude and obesity. J Obes 31:1946723 77. Lenardson JD et  al (2015) Rural and remote food environments and obesity. Curr Obes Rep 4:46–53 78. Schulte PA et al (2007) Work, obesity, and occupational safety and health. Am J Public Health 97:428–436 79. Shrestha N et al (2016) The impact of obesity in the workplace: a review of contributing factors, consequences and potential solutions. Curr Obes Rep 5:344–360 80. ILO list of Occupational Diseases (2010). https://www.ilo.org/wcmsp5/groups/ public/%2D%2D-­ed_protect/%2D%2D-­protrav/%2D%2D-­safework/documents/publication/wcms_125137.pdf 81. Hosier F (2014) Top 10 occupations prone to obesity. Safety News Alerts. https:// www.safetynewsalert.com/top-­10-­occupations-­prone-­to-­obesity/ 82. Sieber WK et  al (2014) Obesity and other risk factors: the national survey of U.S. long-haul truck driver health and injury. Am J Ind Med 57(6):615–626 83. Miller SK et  al (2008) Overweight and obesity in nurses, advanced practice nurses, and nurse educators. J Am Acad Nurse Pract 20(5):259–265 84. Kolena B, Hlisníková H, Kečkéšová Ľ, Šidlovská M, Trnovec T, Petrovičová I (2022) Risk of abdominal obesity associated with phthalate exposure of nurses. Toxics 10(3):143. https://doi.org/10.3390/toxics10030143 85. Zhang Q et al (2020) Association between shift work and obesity among nurses: a systematic review and meta-analysis. Int J Nurs Stud 112:103757 86. Noppakun K, Juntarawijit C (2021) Association between pesticide exposure and obesity: a cross-sectional study of 20,295 farmers in Thailand. F1000Res 10:445

5 Diet and Obesity

Summary • The human diet has changed greatly since the Paleolithic era when most food consumed was derived from animals and plants that were available locally. • The late twentieth and early twenty-first century has seen the rapid growth of ultraprocessed food with its variety of chemical additives. • Apparently coinciding with the increased consumption of ultraprocessed food there has been a rapid growth in the incidence of obesity. • Little is known about the effects of the variety of chemicals on the complex hormonal systems that regulate body weight. • It is likely that our bodies differ greatly in their ability to handle nutrients and chemical additives in food and this may be a factor in the development of obesity. • Because of these differences, it is worthwhile seeking advice from health professionals before undertaking a personalized weight loss program. Before examining the role of diet in the development of obesity it is worth reviewing what is known about the basic energy requirements of humans. Energy is required to drive the body. Unless the levels of physical activity are very high, most energy used by the body is the resting energy expenditure, i.e., the energy required by the body at rest which is used to drive the various processes in the body, e.g., heart, lungs, and liver. Energy is also required to maintain the body temperature. The energy required when the body is completely at rest is referred to as the basal metabolic rate (BMR). The BMR is not

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the same for everyone and has been found to vary according to many factors such as age, sex, ethnicity, and body composition, in particular, the fat-free mass [1]. Even climate is believed to influence BMI [2]. There are also indications that genetic factors may also contribute to the differences observed in BMR [3]. In addition to the energy requirements for the BMR additional energy is required for the various physical activities that are a normal part of life. For example, even sitting requires up to 20% more energy than the BMR while the energy requirements for walking at a normal pace are up to 3 times greater and heavy manual work may be 6 times or more [4]. This energy, and the energy required to drive multiple activities throughout the day has to come from food or drink. Scientists have worked out a way of measuring the energy we use for various activities. However, to do this, they had to devise a unit of energy that would be used for the purpose. The two units of energy that are most commonly used are calories (Cal) and kilojoules (kJ) where one Cal is the amount of energy required to raise the temperature of 1 g of water (just a fraction of a teaspoon) by one degree Centigrade. To convert Cal to kJ you multiply by 4.18 so, for example, 2000 cal is 8360 kJ. There is little doubt that what is taken up as food is one of the two most important factors in weight gain. While the amount of energy expended in the form of physical activity is also important, for most people the easiest way to regulate their body weight is through diet. We do not need to be dietitians or doctors to know that what goes into the mouth can be altered in some mysterious way and then deposited as fat throughout our bodies. So if we change the amount we eat, or what we eat, we may be able to prevent weight gain and obesity. Or to put it another, more scientific way, if the energy content of our food is less than the combined energy of our BMR and our physical activity, we lose weight. On the other hand, if the energy in our food is greater than our energy requirements, we gain weight. It is worth noting that any observable changes in our body weight occur over a period of time. One question which is clearly important is how much food energy is required per day. There are many factors that determine how much energy is needed to get through the day and these include age, sex, amount of physical activity, breastfeeding, and pregnancy. The recommended daily energy requirements for women and men are around 2000–2200 and 2600–2800 Cal, respectively, although there are clearly many factors that can affect this [5, 6]. The calorie requirements are different for children and relate to age. For example, the energy requirements for 2–3 year old and 11–12 years old children are thought to be around 1000–1400 and 1800–2000 Cal per day,

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respectively [7]. Another factor that has to be considered is pregnancy because extra energy is required for the growth of the fetus. Extra energy from food is recommended during the second and third trimesters (350 and 450 cal per day) [7].

Food Composition Before examining any contribution of the energy in food to body weight it is worth looking at the components of a normal diet. Apart from water, which is the major component of fresh foods and can vary from more than 80% in most fruits and vegetables and 60–70% in meat, all food contains protein and fat. Carbohydrate is largely absent from meat but present in most fruits and vegetables, and grains such as flour. The carbohydrate content may approach 50% in some white breads. It is more complicated than this because carbohydrates can vary in chemical structure from relatively simple sugars such as fructose and glucose, to complex carbohydrates, for example, glycogen found in animals and made up of chains of glucose molecules, and starch and cellulose, also consisting of chains of glucose molecules, and found in plants. To add to the complexity as far as food is concerned, while cellulose in plants can be degraded by sheep, cattle, and other animals, mostly through the microbes in their intestines, and released as energy, humans lack the ability to do this. Food from a variety of sources, including, for example, fruits, seeds, tubers, oats, barley, and legumes, contains fiber. The latter is complex and includes a number of chemical entities including bran, cellulose, hemicellulose, lignin, dextran, pectin, beta-glucan, inulin, resistant starch, and beta-mannan [8]. Some of the components of fiber, including inulin, dextran, resistant starch, and pectin can be fermented by microorganisms in the human intestine, while others, for example, those containing cellulose and hemicellulose, are poorly degraded [8]. Similarly, there is a great variety of fats, mentioned in an earlier chapter of this book, and most, particularly triglycerides, can be used as energy sources. The third major component is protein and it too is complex because it occurs as chains of a mixture of up to 20 different amino acids. Of course, there are small amounts of many other components, for example, metals (e.g., sodium, calcium, and magnesium), phosphate, vitamins, DNA in genetic material, and a variety of other substances some of which provide little energy but may take part in the multitude of chemical reactions occurring in plant and animal tissues.

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Natural Diets and Obesity There has been much discussion on whether, and how, the changes in the human diet which have occurred over the preceding millennia have affected human health and in particular the incidence of obesity and diseases such as diabetes. For many scientists, the most basic human diet is the diet of humans who lived in the Paleolithic era—the paleo diet. This diet depended on what was available locally. It consisted of plant foods such as tubers, nuts, seeds, and animal foods such as small game animals and seafood. Insects, including some of their products such as honey and honeycomb were also thought to be a part of the paleo diet [9]. According to the mismatch and evolutionary discordance theories, as the human diet changed with the development of agriculture and modern foods, our genes may not have evolved sufficiently to cope with the significant dietary changes that have occurred since Paleolithic times [10, 11]. There have been substantial changes in diet, particularly in the last century with the inclusion of larger amounts of sugar, salt, a variety of different fats, and a bewildering array of additives to enhance flavor, appearance, and to ensure stability. And of course dietary fruits and vegetables often contain traces of fertilizers and pesticides which were not a part of the early Paleolithic diet [12, 13]. One way of examining the link between diet and weight is through a study of populations who live a subsistence-style lifestyle more closely aligned to the Paleolithic way of life. A group that has been studied recently is the Tsimane, a forager-gatherer population who live in the Bolivian Amazon region and are found to have a very low incidence of obesity. Similar findings have been reported in the Hadza, a group of hunter-gatherers who live in northern Tanzania [14, 15]. However, it is worth noting that there is another factor which also reduces the risk of obesity in present-day hunter-­ gatherer populations and that is the increased level of physical activity which, because of their way of life, is likely to be greater than those who live more modern lifestyles. There is some evidence that changes to a more “modern diet” may have affected the health of some of the indigenous populations whose way of life has changed considerably over the last century. For example, the incidence of obesity in the Inuit who live in Greenland increased markedly from 1963 to 1998 [16]. There have been similar findings in aboriginal people in Canada, Australia, and Mexico [17–19]. It is worth noting that changes in diet and reductions in physical activity leading to obesity are not a human problem alone but appears to also affect animals. For example, the incidence of obesity in human pets such as cats and dogs, and zoo animals such as elephants, has also risen [20, 21].

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Modern diets are many and varied. While most diets include animal foods, a significant proportion of the population adheres to either vegetarian or vegan diets. These latter diets are thought to be more environmentally sustainable and have been reported to reduce the risk of obesity [22–24]. The Mediterranean diet, which includes a high intake of fruit, vegetables, nuts, cereals, whole grains, and olive oil, a moderate consumption of fish and poultry and a low consumption of meat and dairy, is another natural diet thought to reduce the risk of obesity [25, 26]. Modern Asian diets, previously thought to be less obesogenic than Western diets, have been found to be as energy dense as Western diets [27]. There is increasing evidence that, as the incidence of obesity is high in most developed and developing countries, and as its incidence appears to have increased over the last century, there are factors in the modern diet that have contributed to this change.

Food Processing, Additives, and Obesity The processing of food involves the treatment to convert basic food into food products. The NOVA system of food classification divides our food into four categories [28]. According to this system, those foods which are subjected to such as basic processes as milling, grinding, heating, and drying and do not contain any added sugar, salt, oils, fats, or other added substances, are included in Group 1 [28]. Group 2 foods are mostly prepared from Group 1 foods by simple processes such as pressing, refining, milling, and drying and include basic ingredients such as oils, butter, sugar, and salt. They are mostly added to Group 1 foods and include stews, soups, salads, and bread. Group 3 includes processed foods such as bottled or canned fruit and vegetables, cheeses, and yoghurt. Food that is ultraprocessed is included in Group 4 and includes soft drinks, packaged sweets, and savory dishes. In addition to oils, salt, and sugar added to these foods, Group 4 may contain a variety of additives such as hydrogenated fats, hydrolyzed proteins, antioxidants, artificial colors, and flavors. It is worth noting that, in addition to the chemicals that are deliberately added to ultraprocessed food, some of the chemicals present in the containers in which some of the foods are stored can be released into food. There may thus be a mixture of foreign chemicals in processed foods. There are traces of some foreign chemicals even in fresh, unprocessed foods, such as fruits or vegetables, but these are mostly traces of pesticides that are used during cultivation, or other pollutants in the soil and water used to grow the food.

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Artificial Sweeteners Perhaps the most commonly used chemicals in ultraprocessed foods are the sweeteners. Although sugar (sucrose) is the main sugar used there are many other nutritive sweeteners including honey, corn syrup, fructose, glucose, mannitol, and xylitol. These all generate calories and therefore energy. Non-­ nutritive sweeteners such as aspartame, stevia, sucralose, saccharin, and cyclamate either produce no energy or small amounts of energy, and are increasingly used instead of sugar because while they provide sweetness to food, and particularly to drinks, they produce few calories. Saccharin which is 200–700 times sweeter than sugar is one of the oldest sweeteners. While their presence in sweets and soft drinks is not surprising it is even found in products such as mouthwash, toothpaste, and even some medications [29]. Despite their few calories, there is little evidence that non-nutritive sweeteners reduce the risk of obesity [30, 31]. There are indications that some of these sweeteners do have some biological effects because there have been reports of their ability to change the composition of the microbiome [31].

Dietary Fats and Processed Foods The other major component of all food, including processed food, is the fats and in particular the fatty acids which are present in most. While the so-called cis fats are the most common naturally occurring fats some natural foods may also contain small amounts of trans fats. Depending on the treatment and storage conditions both cis and trans fats can degrade leading to the generation of products that are believed to increase the risk of cardiovascular disease [32–34]. While potentially harmful breakdown products are formed even in home cooking, these products are greatly increased with repeated frying as often occurs in fast food [35]. Also, because of cost factors, oils that are used in processed foods are not necessarily the healthiest but are chosen mainly because of cost and stability to repeated frying. It is not unusual, despite repeated frying of fast food, for oil used for frying to be changed weekly. Whatever breakdown products are formed will almost certainly depend on the oil used, the container in which the oil is heated, the temperature, and the nature of the fried food. These breakdown products are almost certainly present in much smaller amounts in home cooked food using oils that have not been repeatedly reheated. It is also unlikely that home cooked food using fresh

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oils contains the complex mixture of metals that have been reported to be present in oils that have been reheated [35].

Other Chemicals in Processed Foods Other chemicals are added to prevent spoilage of the food caused by bacterial or fungal contamination. These include such chemicals as benzoate, propionate, and sorbate. A variety of chemicals with different functions such as emulsifying agents, thickeners, coloring, flavoring, and anticaking agents are also used. The diversity of added chemicals is clear from an examination of food labels of products on supermarket shelves or refrigerators. For example, the label of a well-known brand of apple cake shows the presence of emulsifiers, “natural flavour,” antioxidants, citric acid, “natural colour,” thickener, and raising agents. Another good example of the variety of additives in what is really a simple food is the ordinary hot cross bun found in a local supermarket. Apart from “natural flavour,” the label shows the presence of additives 322 (lecithin), 476 (polyglycerol polyricinoleate), 440 (vegetable gum/pectin), 330 (citric acid), 202 (potassium sorbate), 471 and 475 (mono- and diglycerides), and 415 (xanthan gum). These various additives may be synthesized chemically or extracted from natural sources. While most of the synthetic flavoring and flavor enhancers used in processed food are believed to be harmless, some have been shown to be potentially harmful and banned by the US Food and Drug Administration [36]. These include benzophenone, ethyl acrylate, eugenyl methyl ether, myrcene, and pulegone. Data from toxicology studies in animals indicate that, at much higher doses, they may cause cancer [36]. Little is really known of the combined or synergistic effects of these chemicals, and the many other chemicals added to ultraprocessed foods. The use of chemicals in food processing, in addition to the increasing globalization of trade, eventually led to the establishment of the Codex Alimentarius Commission by the combined actions of the World Health Organisation and the United Nations. Its role was to protect the health of consumers and to develop standards based on sound scientific principles. Individual countries have adopted the principles outlined in the Codex. The number of chemicals added to foods is not insignificant as is clear from the US Substance Added to Food inventory which lists 4000 substances [37]. Similarly, Food Standards Australia and the European Union list a great number of additives [38, 39]. In addition to the additives, some of the many other chemicals that are present in food packaging can also find their way into food.

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The US FDA has provided an inventory of a great number of these substances [40].

Ultraprocessed Food and Health It is clear that ultraprocessed foods, which include fast food, often contain a mixture of additives of limited nutritional value that may not normally be present in untreated fresh food or present in much smaller amounts. Little is really known of the health effects of the continued ingestion of these complex mixtures. Based on animal studies, there are suggestions that some individual food additives may have obesogenic properties but little is really known of the combined effects of the complex mixtures that are frequently present in ultraprocessed foods [41–43]. There are indications as well that, as well as increasing the risk of obesity, ultraprocessed food consumption may also increase the risk of cardiovascular disease, metabolic syndrome, diabetes, and even depression [33, 44–47]. Whether it is simply due to excess calories in the foods consumed, or to the number and variety of other chemicals added to the food and their effects on the various hormonal pathways that regulate food consumption, or to a combination of these factors, remains unclear. More recently there has been speculation concerning the possible role of ultraprocessed food on the microbiome and its possible effects on the development of obesity [48].

Precision Nutrition The importance of genetic factors in the development of obesity has been discussed earlier in this book. There is no doubt that our genes, and the corresponding gene products, do play a central role in many aspects of our lives including the control of appetite, generation of energy from the food we eat, and any subsequent storage of fat in adipose tissue. We know that there are differences in our abilities to handle drugs which are determined by slight differences in the structure of our genes so it is not surprising that there may also be similar differences in the way we handle the various food components. Good examples of genetic differences in the way certain components of food are handled by our bodies include lactose intolerance and coeliac disease. Lactose is an important carbohydrate component of milk which is degraded by a specific protein, lactase. The levels of lactase decline significantly for most people after the weaning phase and result in a condition referred to as lactose intolerance, characterized by intestinal discomfort after the consumption of

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milk. Some individuals are able to maintain the ability to digest lactose throughout life due to slight differences in their lactase gene [49]. Similarly, gluten is a protein found in wheat, rye, and barley in relatively high amounts and therefore in a number of foods, and particularly breads and cereals [50]. Coeliac disease results from slight genetic differences in the way the body handles the breakdown products formed from gluten [51]. It is worth noting that food intolerances and allergies, which are the body’s response to a component or breakdown product of food are also caused by slight genetic differences. They are not uncommon because some studies have shown that they may affect, for example, almost 8% of children in some countries [52]. According to the USDA, 90% of allergic food reactions are caused by eight foods: milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, and soybeans [53]. This is yet another example of how relatively small genetic differences can have a significant effect on how our bodies handle even normal food components. Whether some of these differences contribute to the development of obesity, at least in some individuals, is not known. Because of the differences in our genes, the degree of obesity, possible pre-­ existing conditions such as diabetes and cardiovascular disease, and the risk of deficiencies of key minerals and vitamins as a consequence of dieting, it is believed that it may be worthwhile seeking advice from healthcare professionals such doctors and nutritionists prior to embarking on a weight loss program [54].

What Does This Mean? The human diet has changed from the Paleolithic diet which consisted of plants and animals that were able to be gathered locally. Further changes in the diet occurred with the development of agriculture. However, the late twentieth and early twenty first century has seen the growth of ultraprocessed food, a food that often contains a variety of chemical additives that are not normally present in the food. There are hundreds of these additives that are now available to the food industry. Some of these are also added to fast food, a rapidly growing market. Apparently coinciding with the growth in processed and fast food is the obesity epidemic which has affected people from developing and developed nations. It is tempting to speculate the changes in diet that have occurred have played some part in the development of obesity. There are some indications that this may be so from studies that been carried out on indigenous populations that have seen a rise in obesity apparently linked to changes in lifestyle including diet. While lifestyle changes, in

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particular reductions in physical activity are thought to have contributed to the development of obesity, the role of processed food often containing many different chemical substances not normally present in the food is rarely considered. Little is known of the effects of the multitude of chemical additives on the hormonal systems, and well as the microbiome, which influence body weight. What we do know is that our bodies differ greatly in how we handle many of the components of food. The way we cope as individuals to some of the components is food may be yet another factor is the development of obesity. Because of these differences, the possible impact of dietary changes on our health and wellbeing, and the likelihood of weight regain, it is worthwhile for anyone considering undertaking a weight loss program, particularly those wanting to lose significant amounts of weight, to seek advice from specialist doctors or nutritionists/dietitians before undertaking a personalized program.

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46. Lane MM et al (2021) Ultraprocessed food and chronic noncommunicable diseases. A systematic review and meta-analysis of 43 observational studies. Obes Rev 22(3):e13146 47. Moradi S et al (2021) Ultra-processed Food consumption and adult diabetes risk. A systematic review and dose-response meta-analysis. Nutrients 13(12):4410 48. Cuevas-Sierra A et  al (2021) Gut microbiota differences according to ultra-­ processed food consumption in a Spanish population. Nutrients 13(8):2710 49. Anguita-Ruiz A et al (2020) Genetics of lactose intolerance: an updated review and online interactive world maps of phenotype and genotype frequencies. Nutrients 12(9):2689 50. Aboulaghras S et al (2022) Pathophysiology and immunogenetics of celiac disease. Clin Chim Acta 528:74–83 51. Johansson E, Mersha TB (2021) Genetics of food allergy. Immunol Allergy Clin N Am 41(2):301–319 52. Demirdag Y, Bahna S (2020) The role of genetics in food allergy. Expert Rev Clin Immunol 18(4):401–411 53. US Department of Agriculture (2021) Allergy. https://www.usda.gov/media/ blog/archive/tag/allergyttps://www.usda.gov/media/blog/archive/tag/allergy 54. Cachero K et al (2021) Efficacy and safety of clinically managed weight loss programs: a systematic review and meta-analysis protocol. Syst Rev 10:197

6 Obesity and Disease

Summary • Societal pressure to conform to a particular body size and shape is a major reason for embarking on weight loss programs. • Obesity is more than just body shape because there is increasing evidence that it increases the risk of a variety of disease states in particular cardiovascular disease and diabetes. • Some of the other conditions believed to be associated with obesity include sleep apnea, certain cancers, osteoarthritis, asthma, and dementia. • The apparent link between obesity and sensory loss and in particular changes in taste and smell perceptions is surprising. • There is increasing evidence that the greater risk of disease is due to the inflammatory changes which occur in obesity. There is little doubt that an important factor in what drives people to want to lose weight is the societal pressure to conform to a stereotypical body type. While health is a consideration for some, there appears to be a limited understanding of why putting on that extra weight may be potentially harmful. One of the reasons for this is that any health effects of the extra 5–10 kg or more of body weight are not immediate but develop over time. Another reason could be that changes in diet—particularly if it involves doing without, or eating less of, favorite foods—are not that easy. Unfortunately, there is evidence that carrying excess body fat can increase the risk of many different disease states. Indeed there is a view, mentioned elsewhere in this book, that obesity itself may fulfil some of the criteria of a disease [1, 2]. However, as is

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common in many areas of medical research, it is not that simple because there may be a number of factors that can influence the development and severity of an obesity-related disease. The principal diseases that appear to be linked to obesity include diabetes, cardiovascular disease, cancer, asthma, osteoarthritis, sleep apnea, and possibly dementia.

Obesity and Diabetes Diabetes results from an inability to process glucose, a major source of energy in the body [3]. The utilization of glucose is regulated by insulin, a protein produced by the pancreas. There are three forms of diabetes type 1, type 2, and gestational diabetes. Type 1 diabetes is due to the reduced production of insulin by the beta cells of the pancreas thought to be caused by the destruction of the function of the gland by the immune system [3]. While it was previously believed that individuals with type 1 diabetes were mostly lean, there is increasing evidence that up to 50% or more are either overweight or obese [4]. Type 2 diabetes results from the gradual development of a resistance of the body to insulin. Obesity is thought to be one of the risk factors in the development of type 2 diabetes [5]. The cause of gestational diabetes, which develops during pregnancy but mostly disappears after birth is not known although obesity prior to, and during pregnancy, is thought to contribute to the development of the disease [6]. Diabetes is a potentially serious condition with effects on the heart, blood vessels, eyes, nerves, and kidneys. It is believed that the excess fat that is deposited in the liver and pancreas in obesity interferes with the utilization of glucose. As obesity may be a factor in the development of type 2 diabetes, it is not surprising that the impact on weight loss strategies has been studied. Weight loss can lead to a reversal of the insulin resistance in type 2 diabetes provided weight regain is prevented [7–9]. Bariatric surgery for weight loss of obese type 1 patients leads to improvements in the regulation of blood glucose but there is limited information on long-term effects of weight loss [10].

Obesity and Cardiovascular Disease Cardiovascular disease refers to a group of disorders affecting the function of the heart muscle and blood vessels supplying the heart, brain, and other parts of the body. The risk of cardiovascular disease in individuals with elevated

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BMIs and/or obesity has been found to be greatly increased [11]. The increased risk of cardiovascular disease appears to be related to a number of factors. There is a direct mechanical effect of increased weight on the chest wall due to excess visceral and epicardial fat deposits which affect heart function. Obesity leads to an increase in the cardiac afterload which is the pressure required to pump blood to the different parts of the body [12]. Other risk factors for heart disease in obesity include the abnormal production of triglycerides and LDL cholesterol [13, 14]. In particular, there is also increasing evidence of a link between visceral adiposity and cardiovascular disease [11]. In addition, the degree and duration of obesity seem to be important factors in the development of cardiovascular disease. However, for reasons that are not understood, individuals with heart failure that are overweight or obese have improved survival as compared to those with normal weight. This phenomenon has been referred to as the “obesity paradox” [15]. However, bariatric surgery for the removal of fat appears to result in a reduction in the number of cardiovascular deaths [11, 16, 17].

Obesity and Cancer There is some evidence that the risk of many different cancers is increased in obesity. Some of these include endometrial, esophageal, stomach, brain, kidney, colon, postmenopausal breast, ovaries, gallbladder, and thyroid cancers [18, 19]. It is thought that the link between obesity and cancer may be due to inflammatory changes, as well as the higher than normal levels of some of the hormones including the sex hormones, insulin, and insulin-like growth factor [19, 20]. One theory that has been proposed is that the hormone-like substances, the adipokines, which are produced by the fat cells may be involved in the promotion of cancer [21]. As there are indications that obesity increases the risk of some cancers an obvious question is whether weight loss can reduce the risk of cancer and there is some evidence that it may [22, 23]. There are also indications that bariatric surgery for the removal of excess weight may also reduce the risk of a number of cancers and particularly post-menopausal breast cancer, endometrial and colon cancers [24]. However, there are also reports that the incidence of at least one form of cancer, esophageal cancer, may increase after bariatric surgery but it is not clear whether this is due to the surgical procedure [25].

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Obesity and Asthma Asthma is a disease affecting lung function leading to breathing difficulties that can vary from moderate to severe. Obesity is considered to be a risk factor for asthma [26–28]. It is believed that asthma which develops in the obese may lead to a more severe form of the disease which does not respond as well to normal treatment [27]. The link between asthma and obesity is not understood although there have been suggestions that changes in the immune system which are thought to occur in obesity may be involved [27]. There are reports that weight loss, including surgically induced weight loss, may improve lung function in obese individuals [28–30].

Obesity and Osteoarthritis Osteoarthritis results in pain and discomfort in the joints at different parts of the body including hands, back, knees, and hips. It is due to the gradual deterioration of the cartilage that cushions the ends of bones. While it occurs increasingly with age, there is now considerable evidence that the risk of osteoarthritis is increased in obesity [31–33]. It is thought that obesity leads to the increased production of inflammatory factors which act on the cartilage and this in turn leads to a deterioration of the cartilage followed by joint pain. There are studies which appear to show that the degree of disability is greater in the more obese and that weight loss in these individuals may actually lead to an increase in their disability [32].

Obesity and Sleep Apnea Sleep apnea is a disease characterized by abnormalities in breathing during sleep. It is believed that around one billion people are affected and its prevalence is increased in obesity [34–36]. It is potentially a serious condition because it is considered to be an independent risk factor for cardiovascular disease [34]. There is some evidence that weight loss through diet and exercise may reduce the severity of the condition [37].

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Obesity and Dementia Dementia is a condition characterized by impaired brain functions such as memory, judgement, thinking, reasoning, and social skills as well as changes in behavior. There are many different types of dementia and they include Alzheimer’s disease, frontotemporal, Lewy body, vascular, and mixed dementia but they mostly involve damage or loss of function of nerve cells in the brain [38]. Dementia is also associated with certain inherited diseases such as Huntington’s disease as well as other conditions of unknown etiology including Creutzfeldt Jakob and Parkinson’s diseases, and even brain injuries may cause dementia. While age is a major factor there is a view that obesity may be a modifiable risk factor [39–42]. Two other risk factors, often associated with obesity, include hypertension and reduced physical activity [42]. The cause of the relationship between obesity and dementia is not known but it has been suggested that inflammatory changes associated with obesity may be involved [39]. Bariatric surgery for the removal of fat has been reported to lead to improvements in cognition in severely obese individuals [43]. However, it is clear that the relationship between body mass and dementia is complex because there are even reports that a lower BMI and losing weight after the age of 65 years may actually increase the risk of dementia [44, 45].

Obesity and Inflammation As obesity has been shown to increase the risk of various disease states, it has become apparent that fat deposits at various sites throughout the body are more than just simply storage sites for fat that may be used at some time in the future. As mentioned earlier in this book, recent research has shown that in addition to its role as a reserve store of energy, adipose tissue contains a variety of substances that can be secreted and produce effects at different sites throughout the body. These substances belong to one of two different classes, adipokines and cytokines [46]. The adipokines are involved in the utilization of fat and carbohydrates, while cytokines take part in various inflammatory processes in different parts of the body. Because of the presence of these substances and their secretion into the circulation, there is a view that adipose tissue is an endocrine organ, i.e., a gland that produces hormonal substances that travel to different sites in the body. It is now believed that obesity leads to changes within the adipose tissue which in turn leads to the production and release of increased amounts of inflammatory substances. According to this view, the substances released by adipose tissue in obesity may have adverse

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effects on some organs in the body, such as the heart and the pancreas, and may explain the increased risk of disease [46].

Obesity and Pregnancy Obesity in women is linked to effects on menstrual periods and ovulation which in turn affects fertility [47]. Often blood insulin is increased and this in turn is believed to lead to increased production of androgens, the male sex hormones normally produced in small amounts in women. These changes are thought to be a factor in menstruation abnormalities. Overweight women are thought to be more prone to developing diabetes and cardiovascular disease during their pregnancy [48, 49]. Also, there is a greater risk of prematurity, injury, fetal anomalies, or even death of children born to obese mothers and an apparent link between obesity in the mother and an increased risk of obesity in their offspring [48, 50–53]. There are suggestions that maternal obesity may cause changes in the expression of some genes in the developing fetus, referred to as epigenetic alterations, and these changes may explain the increased risk of certain diseases later in life [54, 55].

Obesity and Sensory Loss Sensory loss is caused by the inability of the brain to properly process information received via touch, hearing, taste, smell, and vision. As there are significant hormonal and inflammatory changes occurring in obesity, it is perhaps not surprising that there have been studies looking at the impact of excess body weight on the function of our eyes and ears, two of the body’s major sensory organs, There are a number of reports which appear to show that there are changes in visual and aural functions in obesity [56–61]. Perhaps even more surprising is the apparent change in taste which has been reported to occur after weight gain and is likely to have an impact on the choice of food during any attempt to lose weight [62, 63].

Obesity and Gallstones The gall bladder is a small organ situated close to the liver. Its principal function is the production of bile which assists in the breakdown of fats by the liver. Gallstones develop within the gallbladder or bile duct which links the

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gallbladder to the liver. Depending on their composition, there are main types—cholesterol and bilirubin gallstones. Obesity is one of a number of factors which increase the risk of developing gallstones [64–67]. It is believed that the metabolic changes which occur in obesity are a factor in the development of gallstones.

Obesity and Mental Health Even in those individuals who are obese without medical conditions often associated with obesity, e.g., cardiovascular disease and diabetes, there is a slight increase in the risk of associated mental health problems. The risk is increased in the obese who have other medical conditions [68]. Studies carried out on postmenopausal women have also confirmed the association between obesity and mental health problems, and in particular sleep disorders, anxiety, and depression [69].

Obesity and Taste Another important function of the brain is taste. Receptor cells in the tongue transmit messages to the brain which identifies the food as bitter, sweet, sour, savory, salty, etc. [70]. Because of the apparently increased consumption of sweet food in overweight or obese individuals. It has been proposed that obesity may result in changes in taste perception and this may have an impact on the amount and type of food consumed [71]. There are indications that weight loss after bariatric surgery may result in changes in taste perception [72].

Obesity and Smell Yet another function of the brain is smell. In recent studies, it has been found that individuals with obesity have a reduction in the ability to identify odors [73, 74]. It has been suggested that this contributes to the delay in achieving fulness which in turn may explain the higher intake of high-energy food and drinks in obesity [74]. It has even been suggested that olfactory dysfunction may be a factor in the development of obesity [74].

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Overweight and Risk of Disease While the evidence linking obesity with various disease states is persuasive what is not so clear cut is the impact of being overweight rather than obese on the risk of disease. However, a Swedish study carried out on a group of women whose BMI varied from normal values to those with BMIs in the severe obesity range found a significant increase in the risk of myocardial infarction, stroke, and cardiovascular disease in overweight women with a markedly increased risk in the obese women [75]. In another study which reviewed the impact of weight gain on males and females, it was found that an increase in body weight of as little as 5 kg was associated with an increased risk of cardiovascular disease [76]. An increased risk of diabetes, another condition that has been found to be associated with obesity, has also been reported for individuals who are overweight [77]. The risk of sleep apnea, some cancers, osteoarthritis, incident arthritis, asthma, and cardiovascular disease has also been observed in overweight individuals [66, 76, 78, 79]. The reason for increased risk of disease in overweight individuals is not known although the sites of fat deposits may play a role. For example, there is some evidence that increases in visceral fat may lead to an elevation in ambulatory blood pressure and this in turn may increase the risk of cardiovascular disease [80].

What Does This Mean? For many people, particularly the young, the main reason for embarking on weight loss programs is the societal pressure to conform to a particular body size and shape. For older persons, there is also the perception that carrying too much weight may not be very good for their health. Indeed there has been debate as to whether obesity is a disease because the fat deposits appear to be more than sites for the storage of body fat. There is evidence that weight gain leading to obesity is indeed bad for our health because there is an increased risk of a variety of disease states, some of which, for example, cardiovascular disease, diabetes, and certain cancers, are potentially harmful and even lethal. It is now believed that the increased fat deposits in the obese state are not completely harmless because these deposits, in particular those in certain parts of the body, for example, visceral fat, can act as glands releasing a variety of active, and potentially harmful substances into the circulatory system. From there they are carried throughout the body. Some of these products may have adverse effects on vital organs and this in

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turn can lead to disease. The incidence of a variety of disease states linked to obesity is remarkable but not surprising considering the hormonal and inflammatory changes which have been reported to occur with obesity. The possible link of obesity with mental disease is of particular interest. What is particularly alarming is the changes in taste which have been reported to occur in the obese state because this has implications for the choice of food with dieting, a key factor in any attempt to lose weight through the introduction of dietary changes.

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7 Dieting, Physical Activity, and Weight Loss

Summary • Dieting is the most common method of weight loss, often in combination with increased physical activity. • The number and variety of diets are extensive due to the complexity of food itself which varies greatly in energy content and composition. • Protein, carbohydrate, and fat are the main components of most food and each of these is a complex mixture. • In addition to the major components, food also contains a variety of other components such as metals, vitamins, and antioxidants. • Dietary weight loss programs can produce significant losses in body weight but may require significant behavioral changes. • There appear to be compensatory mechanisms that can lead to an increase in energy intake and subsequent weight regain after weight loss. It will become apparent that there are a number of factors that determine whether someone gains weight or not. However, for most people who want to lose weight almost invariably the solution is to change their diet and in particular to reduce the number of calories consumed. It is perhaps not surprising because we do not need to be dietitians or doctors to know that what goes in the mouth can be altered in some mysterious way and then deposited as fat in different parts of our bodies. And if what we consume is the key to weight gain, it follows that if we want to lose weight we have to choose a diet that is different from the one that has led to our weight gain or, at the very least, eat less. And there are, of course, plenty of diets to choose from, as there are

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promoters and dietary gurus who espouse the benefits of this or that diet. Indeed, a search of the phrase “weight loss diets” in the Internet brings up more than 200 million hits. But it is really not that simple because diets vary greatly and weight loss diets certainly reflect this. So, when we go on a weight loss diet it is important to remember that the diet we choose may be quite different from our existing diet which may have been a part of our way of life for many years. It is therefore not that surprising that changes in diet, particularly as part of weight loss programs are difficult to maintain for extended periods of time. It is even more onerous for those individuals who have allergies, intolerances, or ethical reasons and are therefore more limited in their food choices.

Weight Loss Diets The three main components of our diet—fat, protein, and carbohydrate—are our principal source of energy. As the amino acids that makeup proteins are critical to a number of cellular functions and so are more difficult to limit, most diets for weight loss involve the reduction in the intake of carbohydrate and/or fat. And as the energy produced from fat is more than double that from carbohydrate or protein (9 vs. 4 calories per gram) it is not surprising that diets that limit fat intake are popular. There are a great number of diets that have been proposed for those wanting to lose weight. Mostly they involve: Calorie counting or restriction Low fat High fat/low carbohydrate Low carbohydrate/high protein Fasting—intermittent, total Paleo diet Mediterranean diet If the numbers of basic diets are relatively few, how do we explain the staggering number of diets available to consumers? Often there may be a claim involving a dietary component with beneficial properties—e.g., grapefruit, green tea, and fiber. Some of the many other diets are given the names of individuals or organizations who promoted or developed the diet (Dean Ornish, Atkins, CSIRO Total Wellbeing). Others include the name or product formed from one of one of the key components (Protein Power, ketogenic), or commercial weight loss programs (Weight Watchers, Jenny Craig).

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With so many diets, as well as claims about the efficacy of the diet, it is perhaps not surprising that there is considerable confusion as to the most appropriate diet for someone who wants to lose weight.

Calorie Counting Calorie or kilojoule counting diets work on the principle that we need a certain amount of energy for growth and/or maintenance and if the energy input exceeds this amount we will put on weight. For example, if the average 21–25 year old male and female require 2400–3000 and 2000–2400 calories per day, respectively, then intake of energy from food less than this over a period of time should result in weight loss [1]. However, it has been argued that while these types of diets will result in weight loss it is difficult to choose a healthy diet based purely on calories because the nutritional quality of food does not always relate to the calorie content [2]. According to this view calorie counting as a means of weight loss without recognition of the nutritional value of a food may result in deficiencies of key nutrients [3, 4]. Of course, this applies to all diets irrespective of whether they are low-fat, low-­ carbohydrate, or low-protein diets. There is also considerable debate as to what constitutes the ideal proportions of calories from protein, fat, and carbohydrate in a low-calorie diet. Despite the potential for nutrient deficiency, studies have shown that calorie restriction diets are effective in inducing weight loss and, moreover, there are indications that they may ameliorate some of the factors involved in the development of diseases such as diabetes, cancer, and cardiovascular disease [5, 6].

Low-Fat and Low-Carbohydrate Diets There are obvious advantages in low-fat diets because, in addition to the high-­ calorie content of fat as compared to proteins and carbohydrate, cholesterol, and saturated fats have been linked to coronary disease and are therefore restriction of fat in the diet as part of a weight loss program is thought to have some health benefits [7]. It is worth noting, however, that certain vitamins A, D, E, and K are fats and excessive restrictions of fat intake can lead to a deficiency of these vitamins. Low-carbohydrate diets, which include the Atkins diet, are also effective in weight loss programs [8, 9]. There are also indications that there may be remission of diabetes although there is some debate as to what constitutes

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diabetes [10]. It is even more complicated than this because not all foods have the same effect on the amounts of sugar in the blood, a key factor in diabetes, which has led to the development of special diets aimed at controlling blood sugar levels, best illustrated by the Zone and low glycemic index diets. These work on the principle that whereas starchy foods such as potatoes and bread have the ability to rapidly increase the amounts of glucose in the blood, a property referred to as a high glycemic index (GI), the carbohydrates in non-­ starchy foods such as cauliflower, broccoli, and beans, have a low GI and thus a limited effect on blood glucose levels. The GI value for a food is determined by comparing the amount of glucose in the blood after eating a particular food with that obtained by drinking a glucose solution. In the GI scale glucose is considered to have a value of 100 and most other foods have values below 100. High GI foods have values in excess of 70 while low GI is normally below 55. It has been believed that a diet low in high GI carbohydrates is more efficient in the promotion of weight loss although more recent research has suggested that there is little evidence that low GI diets are superior to high GI diets in the prevention of obesity [11]. Low-carbohydrate diets form the basis for yet another diet, the so-called ketogenic diet. The word ketogenic refers to products of the breakdown of fats, ketones. The ketogenic diet is characterized by very low levels of carbohydrate, often less than 50 g per day, with moderate amounts of protein and high levels of fat. There is some evidence that ketogenic diets may decrease appetite and increase the breakdown of body fats [12]. The diet has been found to be effective in achieving weight loss but there have been reports of an increase in LDL cholesterol levels, considered a marker for an increased risk of cardiovascular disease [13]. It is worth noting that short-term side effects, referred to as the “keto flu,” have been noted some of which include fatigue, headache, nausea, and dizziness [14].

High-Protein Diets There is some evidence that the consumption of higher-than-recommended levels of dietary protein can reduce body weight via a reduction in body fat while preserving fat-free body mass. This effect has been observed in low-­ calorie and normal diets [15]. There is limited understanding of the mechanism although it has been suggested that the high-dietary protein may increase thermogenesis, i.e., the production of body heat [15]. In addition, dietary protein is believed to increase satiety, or the feeling of fullness, and energy expenditure [16].

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Fasting Another way of limiting food, and therefore energy intake, is by fasting. There are two types of fasting—intermittent and total. The former involves dietary restrictions on some of the days every week, alternate days, or some days in a week [17]. There are a number of variations some of which include a 16 h fast followed by feeding over an 8-h period, or a 20-h fast followed by a 4-h feeding period [18]. Total fasting is clearly an efficient way of achieving weight loss as shown by a report involving hunger strikers who fasted for 43 days. This study showed that the average weight loss at the end of this period was 18% [19]. In a less drastic study, the effects of total fasting in obese individuals were compared with those on a low kCal diet (300 kCal). After 28 days, it was observed that weight loss was around a third greater for those on a total fasting diet [20]. While total fasting as a means of weight loss clearly works most weight loss programs involve some form of intermittent fasting. A recent review of a number of trials that have been carried out over the last few years has shown that this method of weight loss is effective with losses of body weight varying from 0.8 to 13% [21]. There are indications as well that these types of diets may result in an improved regulation of blood sugar levels which are increased in diabetes although there are concerns that these diets could result in hypoglycemia (low blood sugar) in diabetics who are taking insulin [21].

Paleolithic and Mediterranean Diets It is perhaps not surprising that the Paleolithic diet, which is believed to be more closely aligned to the diets of our early ancestors with its emphasis on natural foods, has also been considered as a means of achieving weight loss. There are reports that around 9–10% weight loss can be achieved in a 6–12  month period [22]. Similarly, the traditional and low-carbohydrate Mediterranean diets have been shown to produce weight losses of 8.7% and 10.3%, respectively [22].

Genetics and Diets Until relatively recently it has been assumed that, as far as weight loss strategies are concerned, the same dietary changes will produce the same effects on everyone. However, recent research has shown that the risk of obesity arising

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from different diets may be influenced by genetic factors. That is there is an interaction between the components of a particular diet and certain genes carried by an individual and this may determine the risk of obesity [23–25].

Increased Physical Activity and Weight Loss A number of years ago there was an active television campaign on television to encourage physical activity. The central figure in the campaign was an imaginary figure—his name was Norm and he was a true couch potato who barely had the energy to use the remote to change a television channel. While television Norm was an imaginary figure, there seems ample evidence that there are plenty of real-life Norms around. If the energy we use to drive the different parts of our bodies such as the heart, brain, and kidney, and the many different physical activities such as walking, running, housework, and playing golf or tennis is less than the amount of energy we take from food, then it is no surprise that we will put on weight. While dieting is a key element in weight loss, most strategies involve “lifestyle” changes which almost always include regular exercise. Exercise is considered as an important component of any weight loss program and there is ample evidence to support this view [26]. However, the limitations of exercise alone are clear from even a cursory look at the number of calories utilized on a treadmill where, for those of average weight, fewer than 200 calories may be used in a half hour of moderate exercise. To put this into perspective, this represents roughly the number of calories in a couple of glasses of wine, a small bag of peanuts, or a piece of cake. It is, therefore, worth remembering that regular, prolonged, and vigorous exercise regimes burn relatively few calories and a greater effect is observed when diet and exercise are combined [27]. There is a further factor that has to be considered in any program involving physical exercise and weight loss. It is well known that there are individual differences in loss of body weight in any program which includes an exercise component. This is not surprising because there are many factors that could contribute to any variability in weight loss. Some of these include age, sex, diet, differences in cardiac and lung function, and physiological changes (e.g., menopause and pregnancy). There is increasing evidence that genetic factors contribute to the variability in weight loss in response to an increase in physical activity as part of any weight loss program [28, 29]. This is not surprising because the breakdown of body fat is a highly complex process involving many different proteins taking part in processes such as the regulation of energy expenditure and appetite, the development of adipose tissue and heat

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production, which in turn are the products of a multitude of individual genes [28–30].

Lifestyle Intervention Programs Most weight loss strategies involve some lifestyle changes. Mostly these involve the introduction of dietary changes and increases in the amount and type of physical activity. While the changes may be introduced by the individual wanting to lose weight, in many instances any weight loss program may require significant behavioral changes to improve adherence to dietary and other changes and this may involve a third party, for example, a dietitian, clinician, physical therapist, exercise physiologist, or gym instructor. There is evidence that behavioral treatment strategies are effective in improving adherence to lifestyle changes and this in turn is thought to lead to better weight loss outcomes [31].

 ommercial Weight Loss Programs C and Weight Loss There are a number of commercial organizations that provide programs for those who want to lose weight. Some examples include Jenny Craig, Weight Watchers, Slimming World, and Rosemary Conley. The programs mostly include dietary strategies and support groups. In addition to regular meetings where members can get together to discuss progress and difficulties they are having with diets, and weigh-ins, members may also be able to discuss programs with specialist nutritionists and dietitians. Physical activity is also encouraged as part of many of the programs. The dietary aspects of the programs include elements of the various strategies mentioned earlier. Certainly, the programs do contribute to weight loss in the early stages, for example, Weight Watchers participants have been reported to have lost an average of 5.9 kg at 9 months and there are indications that some weight loss is retained even a year after the commencement of the diets [32, 33]. There has been general acceptance by the medical profession of weight loss programs providing there is peer-reviewed evidence of their efficacy and safety, i.e., information published in medical/scientific journals about the particular program [32].

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Prevention of Weight Gain and Disease In addition to its importance for the average healthy individual not wanting to put on weight, the prevention of weight gain is an important component of treatment for a variety of conditions including diabetes, hypertension, breast cancer, psoriasis, and even pregnancy [34]. In these situations, advice from medical professionals such as doctors and dietitians should be sought. Advice provided in these situations could include information relating to dietary fat composition (saturated, polyunsaturated, trans fats), micronutrients (e.g., vitamins), and macronutrient distributions (fat, protein, and carbohydrate). Studies have shown individualized treatment directed by nutritionists can achieve weight loss and is likely to reduce the risk of dietary deficiencies. In addition, LDL cholesterol and HbA1c, chemical markers for increased risks for heart disease and diabetes, respectively, are not increased.

Weight Regain There is little doubt that loss of weight can be achieved through dieting and/ or increased physical activity. It has also been shown that risk factors for certain disease states, for example, cardiovascular disease, can be reduced after weight loss [35, 36]. However, it is not easy to maintain diets long term and, after an initial loss of weight, there is often an increase in body weight. The current view is that changes in the hormonal systems involved in the regulation of food intake and which occur with dieting and subsequent weight loss may favor weight gain [37–40]. It has been argued that future weight regains after effective weight loss programs is not necessarily due to loss of motivation to continue a particular weight-control strategy but may relate to effects on existing hormonal mechanisms which respond to changes in body weight by stimulating food intake and depressing energy expenditure [38]. It is important to remember that these hormonal systems that led to weight gain may have developed over a considerable period of time and research is needed to better understand what appears to be compensatory mechanisms for maintaining the additional body weight [38, 41, 42]. Further research is needed to understand how factors such as degree of obesity, sex, age, and diseases such as diabetes and cardiovascular disease affect the ease and degree of weight loss as well as the factors involved in subsequent weight gain.

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What Does This Mean? Dieting, which involves restrictions on the amount and type of food, is the most commonly used method to lose weight. However, while on the surface at least the process should be relatively straightforward because it simply involves restricting the intake of food, it is much more complex because both the number and composition, of the various diets available to the average person are extensive. A good reason for this apparent complexity is the nature of food itself which, while it contains the three main sources of energy, i.e., fat, protein, and carbohydrate, also contains a number of other components, for example, vitamins, metals, and antioxidants whose intake may also be restricted and the implications this may have on health and wellbeing. While the main components of a diet are protein, carbohydrate, and fat it is not so simple because of the complexity of these principal ingredients. For example, proteins are made of a great number of amino acids and their proportions in individual foods vary greatly. Similarly, not all carbohydrates are the same and their ability to increase blood sugar varies greatly. And the composition of dietary fats is just as complex with the added complication that the consumption of excess amounts of some, for example, the saturated, trans fats, and cholesterol have been linked to an increased risk of heart disease. There is little doubt that weight loss can be achieved through dieting alone or, preferably, in combination with increased physical activity. What makes drawing any firm conclusions from the many reported weight loss trials is the heterogeneity of the populations taking part in these trials because those undertaking weight loss programs may vary in the degree of obesity, age, sex, physiological state, and pre-existing conditions such as obesity and cardiovascular disease. To add to the complexity of any weight loss program using dietary change is the view that there may be genetic factors that determine the choice of food. While dietary weight loss programs are certainly effective and can produce significant losses in body weight, what appears to be much more difficult is the maintenance of the lower weight. For reasons that are not understood there are compensatory hormonal mechanisms which can lead to increases in appetite and this can lead to an increase in energy intake.

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References 1. USDA.  Dietary Guidelines for Americans. https://www.dietaryguidelines.gov/ sites/default/files/2020-­12/Dietary_Guidelines_for_Americans_2020-­2025.pdf 2. Fernandes AC et al (2019) Perspective: public health nutrition policies should focus on healthy eating, not on calorie counting, even to decrease obesity. Adv Nutr 10:549–556 3. Nowalk MP, Wing RR (1985) Changes in nutrient intake of hypertensives during a behavioral weight-control program. Addict Behav 10(35):7–63 4. Engel MG et al (2018) Micronutrient gaps in three commercial weight-loss diet plans. Nutrients 10(1):108. https://doi.org/10.3390/nu10010108 5. Most J et  al (2017) Calorie restriction in humans: an update. Ageing Res Rev 39:36–45 6. Vidoni C et  al (2021) Calorie restriction for cancer prevention and therapy: mechanisms, expectations, and efficacy. J Cancer Prev 26:224–236 7. Seid H, Rosenbaum M (2019) Low carbohydrate and low-fat diets: what we don’t know and why we should know it. Nutrients 11:2749 8. Gardner CD et al (2018) Effect of low-fat vs low-carbohydrate diet on 12-month weight loss in overweight adults and the association with genotype pattern or insulin secretion: the DIETFITS randomized clinical trial. JAMA 319:667–679 9. Johnston BC et  al (2014) Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. JAMA 312:923–933 10. Goldenberg JZ et al (2021) Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data. BMJ 372:m4743 11. Gaesser GA et al (2021) Does glycemic index matter for weight loss and obesity prevention? Examination of the evidence on “fast” compared with “slow” carbs. Adv Nutr 12:2076–2084 12. Kim JY (2021) Optimal diet strategies for weight loss and weight loss maintenance. J Obes Metab Syndr 30:20–31 13. O'Neill B, Raggi P (2020) The ketogenic diet: pros and cons. Atherosclerosis 292:119–126 14. Batch JT et  al (2020) Advantages and disadvantages of the ketogenic diet: a review article. Cureus 12(8):e9639 15. Moon J, Koh G (2020) Clinical evidence and mechanisms of high-protein diet-­ induced weight loss. J Obes Metab Syndr 29:166–173 16. Moon J, Koh G. Clinical evidence and mechanisms of high-protein diet-induced weight loss. J Obes Metab Syndr 29:166–173 17. Johnstone A (2015) Fasting for weight loss: an effective strategy or latest dieting trend? Int J Obes 39:727–733 18. Malinowski B et  al (2019) Intermittent fasting in cardiovascular disorders-an overview. Nutrients 11:673

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19. Faintuch J et  al (2001) Refeeding procedures after 43 days of total fasting. Nutrition 17:100–104 20. Rabast U, Hahn A, Reiners C, Ehl M (1981) Thyroid hormone changes in obese subjects during fasting and a very-low-calorie diet. Int J Obes 5:305–311 21. Welton S et  al (2020) Intermittent fasting and weight loss: systematic review. Can Fam Physician 66:117–125 22. Anton SD et al (2017) Effects of popular diets without specific calorie targets on weight loss outcomes: systematic review of findings from clinical trials. Nutrients 9:822 23. Heianza Y, Qi L (2017) Gene-diet interaction and precision nutrition in obesity. Int J Mol Sci 18:787 24. Voruganti VS (2023) Precision nutrition: recent advances in obesity. Physiology (Bethesda) 38(1):42 25. San-Cristobal R et al (2020) Contribution of macronutrients to obesity: implications for precision nutrition. Nat Rev Endocrinol 16(6):305–320 26. Berge J et al (2021) Effect of aerobic exercise intensity on energy expenditure and weight loss in severe obesity-a randomized controlled trial. Obesity (Silver Spring) 29:359–369 27. Foster-Schubert KE et al (2012) Effect of diet and exercise, alone or combined, on weight and body composition in overweight-to-obese menopausal women. Obesity (Silver Spring) 20:1628–1638 28. Mazur II et al (2020) PPARGC1A gene polymorphism is associated with exercise-­ induced fat loss. Mol Biol Rep 47:7451–7457 29. Leońska-Duniec A et al (2016) Genetic variants influencing effectiveness of exercise training programmes in obesity - an overview of human studies. Biol Sport 33:207–214 30. Bouchard C et al (2011) Genomics and genetics in the biology of adaptation to exercise. Compr Physiol 1(3:1603–1648 31. Burgess E et  al (2017) Behavioural treatment strategies improve adherence to lifestyle intervention programmes in adults with obesity: a systematic review and meta-analysis. Clin Obes 7(2):105–114 32. Laudenslager M et al (2021) Commercial weight loss programs in the management of obesity: an update. Curr Obes Rep 10:90–99 33. Wee CC (2015) The role of commercial weight-loss programs. Ann Intern Med 162:522–523 34. Williams LT, Barnes K, Ball L, Ross LJ, Sladdin I, Mitchell LJ (2019) How effective are dietitians in weight management? A systematic review and meta-analysis of randomized controlled trials. Healthcare (Basel) 7(1):20. https://doi. org/10.3390/healthcare7010020 35. Yokose C et  al (2020) Effects of low-fat, Mediterranean, or low-carbohydrate weight loss diets on serum urate and Cardiometabolic risk factors: a secondary analysis of the dietary intervention randomized controlled trial (DIRECT). Diabetes Care 43:2812–2820

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36. Ma C (2017) Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-­analysis. BMJ 359:j4849 37. Greenway FL (2015) Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes 39:1188–1196 38. Busetto L et al (2021) Mechanisms of weight regain. Eur J Intern Med 93:3–7 39. MacLean PS et al (2015) The role for adipose tissue in weight regain after weight loss. Obes Rev 16:45–54 40. Most J, Redman LM (2020) Impact of calorie restriction on energy metabolism in humans. Exp Gerontol 133:110875 41. Hall KD, Kahan S (2018) Maintenance of lost weight and long-term management of obesity. Med Clin North Am 102(1):183–197. https://doi.org/10.1016/j. mcna.2017.08.012 42. Blomain ES (2013) Mechanisms of weight regain following weight loss. ISRN Obes 210524. https://doi.org/10.1155/2013/210524

8 Drugs and Weight Loss

Summary • Drugs to treat the “disease” of obesity are constantly being developed. • Weight loss drugs show some efficacy in contributing to weight loss. • It is unclear whether drug administration has to continue indefinitely otherwise weight regain may develop. • Some weight loss drugs have been withdrawn due to unexpected side effects. • Supplements often derived from natural sources are being increasingly used for weight loss but their efficacy remains unclear. • Probiotic, prebiotic, and symbiotic supplements are also being used for weight loss but their efficacy is not known. • Newer forms of weight loss treatment involving transdermal and intranasal administration of drugs have been developed. • Yet another form of weight loss treatment, the use of non-systemic agents which induce a feeling of fulness have also been developed. We live in an age when many of our health problems may be managed, perhaps even cured, by drugs. We now have drugs for asthma, high blood pressure, high blood cholesterol, bacterial infections, and even for the treatment of viral infections such as HIV and more recently COVID-19. As obesity is increasingly being considered a “disease,” and with so much obesity in the developed world, it is perhaps not surprising that enterprising pharmaceutical and biotech companies have joined the weight loss bandwagon. There may be a need for pharmaceutical intervention in the truly obese, especially those who have the sorts of genetic diseases mentioned earlier, but whether drugs should be used by ordinary people for losing a few kilos is open to debate. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. Poulos, Obesity in the 21st Century, https://doi.org/10.1007/978-3-031-39168-2_8

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Researchers now know that there are many potential steps in the pathway that lead to the deposition of fat in our bodies. Theoretically, at least drugs could be used to target one or more of these steps. If all went according to plan it is possible that we could achieve some degree of weight loss by interfering with one or more of these steps with a drug. After all, that is how most drugs that are used to treat diseases such as asthma, cancer and cardiovascular disease. So how would drugs for treating obesity work? They could act by: • • • • •

Suppressing appetite which would in turn restrict food intake. Restricting the uptake of high-energy foods such as fats. Reducing the conversion of food to fat. Burning fat more efficiently. Converting excess calories to heat.

There are now a number of drugs available to consumers. Some of those currently in use include the following [1–3]: Orlistat—Also known as Xenical and Alli. This drug works by inhibiting the absorption of fats. There are indications that the drug may inhibit the uptake of the fatty vitamins (vitamins A, D, E, and K) and so there are suggestions that vitamin supplements may be required. Phentermine/Topiramate—This drug combination, marketed as Qsymia which affects appetite was, until recently, the most widely used anti-obesity drug. Its mechanism of action is not known although there are indications that it acts as an appetite suppressor, possibly through its effects on biochemical pathways in the brain. It has been suggested that Topiramate may reduce energy intake [4]. Naltrexone/bupropion—This drug combination is thought to act on chemical pathways in the brain. It is interesting to note that naltrexone is considered an opioid antagonist, i.e., it reacts with the receptors in the brain which bind opioids and has been used to treat drug addiction. Bupropion is also thought to act via certain neurotransmitters in the brain (serotonin and norepinephrine). Liraglutide promotes the action of GLP-1, a naturally occurring protein that facilitates the release of insulin from the pancreas and therefore is believed to be involved in the regulation of blood sugar. GLP-1 is also thought to slow the emptying of the stomach and intestine and reduce appetite by acting on pathways in the brain. Further information on GLP-1 is mentioned in Chap. 5. Semaglutide also promotes the action of GLP-1 and has been shown to be an effective weight-loss drug [5].

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Rimonabant works by suppressing appetite. It does this by blocking the actions of hormone-like substances made in the brain, referred to as endocannabinoids which increase appetite. Substances present in marijuana, termed “cannabinoids” are also able to bind these same proteins and are one explanation for the stimulation of appetite by cannabinoids [6]. Lorcaserin (also known as Belviq) is thought to act on pathways in the brain involving a receptor for the neurotransmitter serotonin. While it has been shown to have some benefit in weight loss it was withdrawn in February 2020 because there were indications of a possibly increased risk of cancer [7]. Chromium picolinate is really a combination drug/supplement. The metal chromium is a trace component of many of the foods we eat and is thought to be involved in the utilization of our body’s key fuel, glucose. Picolinic acid is formed naturally from tryptophan. The latter can be converted in the body into 5-hydroxy tryptophan, also known as the neurotransmitter, serotonin [8]. Some studies show that chromium picolinate can induce weight loss although others report little effect [8, 9].

Efficacy and Side Effects of Drugs Depending on the drug used some degree of weight loss may be achieved. In addition, there are indications that cardiovascular function, as determined by blood pressure measurements, may improve [10]. However, it is worth mentioning that while all drugs undergo trials in different animal species followed by rigorous testing in humans to assess both efficacy and safety before they are released, adverse effects are not unknown. Side effects for individual drugs depend on a number of factors including age, pre-existing disease states, medications used for treating these diseases, and genetic factors. It could be expected that the same would apply to anti-obesity drugs. Indeed two of the drugs used in the United States, Qsymia and Belviq, have been banned by the European Union because of concerns about side effects but not in the United States. Another drug that showed initial promise for weight loss, lorcaserin, has been reported to increase the risk of cancer and has been withdrawn [7]. Semaglutide, may cause symptoms such as diarrhea, vomiting, and nausea [5]. Another drug, rimonabant has been withdrawn from the European market because it has displayed serious side effects such as anxiety, depression, and even suicidal thoughts [6]. Finally, while a number of drugs are effective in inducing weight loss, once treatment is discontinued weight regain has been observed in many indicating that either the drug treatment has to be continued or other weight loss strategies may be required [11].

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Weight Loss Supplements Many of us take herbal or dietary supplements because of the belief that these will help us to treat or prevent certain diseases. Fish oils we take for arthritis (and other diseases), St. John’s Wort for depression, calcium for our bones, and zinc to boost our immune system are just a few of the many supplements that are now available to us. It is really not a giant leap to take a supplement to “cure” or prevent yet another disease—that is obesity. And, in fact, there may even be a belief that all we have to do to cure our obesity is to take a supplement. It certainly is a lot less work than dieting or exercising. But if it were only that simple. There are two possible options for those who want to lose weight the easy way by taking pill-drugs or supplements. The latter choice is simple because visits to doctors and prescriptions are not required. Supplements have one big commercial advantage over drugs and that is, unlike drugs, there is no real requirement for them to have undergone clinical trials and shown to be effective before they are marketed. All that is normally required to satisfy regulatory authorities such as the United States Federal Drug Administration Authority (FDA) is that they are safe and any claims made are truthful and not misleading [12]. With this regulatory loophole, together with the desire of many people for a simple way of losing weight, it is therefore not surprising that there have been clever marketing campaigns through the internet and social media. According to the FDA weight loss supplements come in a variety of forms—capsules, tablets, liquids, powders, and bars [12]. Unlike drugs which normally contain the active ingredient and few other components, in some cases weight loss supplements may contain dozens of ingredients, perhaps as many as 90 [12, 13]. While there may be some research on the individual active ingredients there is really limited information about the effects of complex mixtures, again unlike the research that is required before a pharmaceutical is granted approval.

Natural Products and Weight Loss The term “natural product” implies a chemical substance that is normally found in nature, mostly in plants and animals. Simple examples of this include sugar, alcohol, acetic acid (in vinegar), lactose (in milk), vitamin C (in fruits and vegetables), and vitamin D (in cod liver oil). These products are distinguished from those made by humankind, i.e., pesticides, drugs, and flame retardants to name just a few. There are a few fairly important points to be

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made about natural products. Firstly, there is a widespread belief that, because something is “natural” it is safe. While this may be true for some there are many examples of natural products that are anything but safe. Strychnine (from certain plants), tetradoxin (from certain marine animals), aflatoxin (from certain molds), curare (from certain marine mammals), and botulinum (from some bacteria) are just a few examples of natural products that are poisonous. Secondly, natural products are not normally found pure but are present in plants or animals together with many other substances [14]. They can be isolated as pure substances from complex mixtures but do this is often slow, laborious, and expensive. Finally, many natural products can be made in a laboratory but, depending on the natural product, the process may be complicated and expensive. Because of these difficulties, many of the natural products that are used as supplements may be extracts and therefore complex mixtures containing the desired product together with many other chemical substances. A good example of this is fish oil which has been used over many years as a possible treatment for arthritis and, more recently, as a means of reducing liver and adipose tissue fat [15]. It is normally considered that there are two active components (EPA and DHA) but fish oil itself may contain upward of 100 different fatty substances and the exact composition may vary according to the source and treatment. There are potentially a number of ways supplements may induce weight loss. These could include effects on appetite, absorption, and breakdown of food nutrients, synthesis of fats, energy expenditure, and generation of heat from fat [16]. Just a few examples of the many supplements mostly derived from natural products that are now available are shown below.

Garcinia Cambogie Extracts of the fruit Garcia cambogie whose rind contains hydroxycitric acid are thought to inhibit the synthesis and storage of fat. Minor decreases in weight have been observed in some studies but not in others [17–19]. There are some concerns about the safety of supplements containing Garcinia [19].

Irvingia Gabonensis Extracts from the fruit of the deciduous tree Irvingia gabonensis may promote weight loss via their ability to inhibit the synthesis of fats and increase their breakdown [20]. While there are indications that Irvingia supplements may

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induce some weight loss it has been suggested that many of the studies carried out to test their efficacy are not convincing [20, 21].

Green Tea Green tea and many other plant products contain substances termed “polyphenols.” It is thought that polyphenols in green tea, and in particular the catechins, may be able to assist in weight loss [22–25]. It is not clear how the active ingredients in green tea produce their effect but one suggestion is that they may increase thermogenesis, i.e., the conversion of excess calories to heat rather than fat. Another suggestion is that they may reduce the levels of the hormone ghrelin [22].

Spirulina Spirulina is a blue-green algae containing a number of different antioxidants including tocopherol, phycocyanins, and beta-carotene, as well as a variety of other substances [26]. There are indications that Spirulina extracts may induce weight loss although there are different types of Spirulina and it is not known which type is the most effective [27].

Chitosan Chitosan, derived from chitin, a polysaccharide present in crustaceans, insects, and molluscs has been used as a weight loss supplement. Small reductions in body weight have been observed. There are indications that chitosan may also reduce some cardiovascular risk factors [28]. The mechanism for weight loss is not known although a possible inhibition of fat absorption has been suggested [16].

White Kidney Bean Extracts of the white kidney bean (Phaseolus vulgaris) have been used in a number of studies involving weight loss. The bean contains a substance that blocks the activity of alpha-amylase, a protein involved in the breakdown of

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starch and other complex carbohydrates that may be present in food. Small reductions in body weight (around 2–3 kg) have been reported [29].

Chromium Chromium is a naturally occurring metal found in trace amounts in the body and in many different foods. It is thought to affect various pathways in the body that are involved in the regulation of food intake perhaps through its effects on neurotransmitters in the brain [8, 30]. There have been reports that one form of chromium, chromium picolinate, may induce weight loss but this has been disputed [31].

Green Coffee Extracts from unroasted green coffee beans have been used for weight loss. Studies have found that extracts can produce some degree of weight loss. It is believed that one of the active components is chlorogenic acid which is thought to increase the breakdown of fat [30].

Beta Glucans These are complex substances found as soluble fiber in cereal grains and mushrooms. They are polysaccharides made up of chains of glucose molecules. They have been reported to increase the feeling of fulness. There is limited evidence that they may be useful as weight loss supplements [30]. It is worth noting that the evidence for the ability of the various supplements to induce some degree of weight loss is thought to be either insufficient or not considered high quality. According to one recent review chitosan and green tea show some promise as weight loss supplements but further studies are needed [30].

Probiotic, Prebiotic, and Synbiotic Supplements There is yet another group of natural products that are being used increasingly for weight loss. As mentioned earlier, gut bacteria, or what is referred to as the microbiome, appear to play a role in obesity. It is therefore not surprising that

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supplements containing probiotics, i.e., bacterial strains, are increasingly being used for this purpose. Two of the common strains include Lactobacillus and Bifidobacterium [32]. Other supplements, termed prebiotics, provide a source of food for the gut bacteria, while what is termed “synbiotics” include a mixture of probiotics and prebiotics, i.e., the bacterial strains as well as their food have also been used as supplements [33, 34]. There are indications that probiotic supplements can induce some degree of weight loss although their mechanism of action is not understood. It has been suggested that they may limit food intake through their effects on the secretion of hormones, neurotransmitters, and inflammatory factors [35]. While probiotics show some degree of promise in weight loss or reductions in BMI, there are concerns about the lack of regulation of probiotic supplements. Factors such as shelf life, microbial populations, formulation, treatment period, type of diet, patient age, and health status, are clearly important and need further research before probiotic supplements are used for weight loss [34–36]. According to a recent review of the evidence, it was concluded that the efficacy of most of the dietary supplements, including those mentioned, is not supported by what is believed to be high-quality evidence [16]. The evidence for the efficacy of green tea and white kidney beans is thought to be supported by “moderate quality evidence.”

Intranasal Treatment of Obesity Until recently treatments for most disease states have involved the oral administration or intramuscular or intravenous injections of a particular drug. More recently Intranasal administration of certain drugs has been developed as a means of bypassing the blood–brain barrier which can restrict the entry of drugs, including anti-obesity drugs, into the brain. In recent studies, oxytocin, a hormone produced by certain parts of the brain and released by the pituitary gland, was administered as a spray into each nostril a number of times a day. There were indications that this treatment did induce some degree of weight loss [11, 37, 38]. In another study, intranasal administration of insulin in normal weight and obese individuals was found to decrease appetite which suggested that this may be yet another means of weight management [39].

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Slimming Patches and Creams Working on the assumption that even taking a pill once or more a day is apparently too onerous, it is not entirely unexpected that a simpler method of drug or supplement administration involving skin patches containing weight loss agents was developed [40]. Slimming patches are now available to treat obesity [40, 41]. A variety of natural products including green tea, bitter orange, ephedra, acai berry, Japanese mint, and flaxseed oil have been reported to be present in the patches. There really is limited evidence that these patches can promote weight loss despite the claims made by manufacturers and vendors that kilograms can be lost in as little as 4 weeks. Yet another form of transdermal delivery of a drug involves an application of an agent to the skin which is present in a cream. One of these “creams” contains caffeine, normally associated with coffee and tea, and xanthene. The latter is an organic substance, and many of its derivatives occur as dyes. Another cream contains caffeine and an extract from the lotus plant. While these extracts may be useful in treating cellulite, once again there is little evidence of any substantial weight loss after application of the cream [42, 43].

Non-Systemic Agents Presumably because of concerns about the side effects of drugs taken orally or applied to the skin, what have been referred to as “non systemic agents” have been developed. The best known are Plenity and Gelesis, superabsorbent hydrogels that expand in the stomach and intestine providing a feeling of fulness [44, 45]. According to the US FDA, there is low adverse risk profile and there is a modest weight loss benefit [46].

What Does This Mean? As obesity is being increasingly considered to be a disease, it is not surprising that drugs to treat the “disease” have been, and are increasingly being developed. And yet while obesity may fulfil some of the criteria of disease it is clearly a complex condition that also appears to increase the risk of developing other disease states such as diabetes and cardiovascular disease. A number of drugs have been developed and show some efficacy in achieving some degree of weight loss, at least for short-term studies, but it is unclear whether drug

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treatment has to be continued indefinitely otherwise weight regain may develop. Supplements are an alternative to drugs because they are easy to purchase and, according to the manufacturers they are safe and effective. Unlike drugs, they do not have to undergo rigorous and time-consuming clinical trials carried out with both normal and obese individuals which assess the efficacy and safety before they can be purchased. Many of the weight loss supplements are derived from natural sources. Another group of supplements includes the probiotic, prebiotic, and synbiotics. Despite the claims made by manufacturers, there is really little evidence that most supplements, which include an array of natural products as well as probiotic and prebiotics, are both safe and effective in the long term, particularly, for those who have underlying other conditions such as diabetes and cardiovascular disease. Newer forms of drug administration, which include intranasal uptake of certain agents thereby bypassing the restrictions imposed by the blood–brain barrier, and transdermal delivery via skin creams have also been used. In yet another form of treatment for obesity non-systemic agents, which are taken orally and expand in size in the stomach inducing a feeling of fulness, have also been developed.

References 1. Son JW, Kim S (2020) Comprehensive review of current and upcoming anti-­ obesity drugs. Diabetes Metab J 44:802–818 2. Tak YJ, Lee SY (2021) Long-term efficacy and safety of anti-obesity treatment: where do we stand? Curr Obes Rep 10:14–30 3. Aaseth J et al (2021) Diets and drugs for weight loss and health in obesity – an update. Biomed Pharmacother 140:111789 4. Fox CK et al (2015) Topiramate for weight reduction in adolescents with severe obesity. Clin Pediatr (Phila) 54(1):19–24 5. O'Neil PM et al (2018) Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-­ blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 392(10148):637–649 6. Nguyen T et al (2019) Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: current approaches for therapeutics development. Curr Top Med Chem 19(16):1418–1435 7. de Andrade ML et al (2021) Is lorcaserin really associated with increased risk of cancer? A systematic review and meta-analysis. Obes Rev 22(3):e13170

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8. Willoughby D et al (2018) Body composition changes in weight loss: strategies and supplementation for maintaining lean body mass, a brief review. Nutrients 10:1876 9. Tian H et al (2013) Chromium picolinate supplementation for overweight or obese adults. Cochrane Database Syst Rev 11:CD010063 10. Horvath K et  al (2008) Long-term effects of weight-reducing interventions in hypertensive patients: systematic review and meta-analysis. Arch Intern Med 168:571–580 11. Hong SM et  al (2021) Oxytocin: a potential therapeutic for obesity. J Obes Metab Syndr 30(2):115–123 12. FDA.  Dietary supplements for weight loss. https://ods.od.nih.gov/factsheets/ WeightLoss-­HealthProfessional/ 13. Sharpe PA et al (2006) Availability of weight-loss supplements: results of an audit of retail outlets in a southeastern city. J Am Diet Assoc 106:2045–2051 14. Wharton S et al (2020) The safety and effectiveness of commonly-marketed natural supplements for weight loss in populations with obesity: a critical review of the literature from 2006 to 2016. Crit Rev Food Sci Nutr 60:1614–1630 15. Parker HM et al (2019) Effect of fish oil supplementation on hepatic and visceral fat in overweight men: a randomized controlled trial. Nutrients 11:475 16. Watanabe M et  al (2020) Current evidence to propose different food supplements for weight loss: a comprehensive review. Nutrients 12:2873 17. Batsis JA et al (2021) A systematic review of dietary supplements and alternative therapies for weight loss. Obesity (Silver Spring) 29:1102–1113 18. Maunder A et al (2020) Effectiveness of herbal medicines for weight loss: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab 22:891–903 19. Andueza N et al (2021) Risks associated with the use of Garcinia as a nutritional complement to lose weight. Nutrients 13:450 20. Onakpoya I et al (2013) The efficacy of Irvingia gabonensis supplementation in the management of overweight and obesity: a systematic review of randomized controlled trials. J Diet Supp 10:29–38 21. Lee J et al (2020) The effects of Irvingia gabonensis seed extract supplementation on anthropometric and cardiovascular outcomes: a systematic review and meta-­ analysis. J Am Coll Nutr 39:388–396 22. Chen IJ et al (2016) Therapeutic effect of high-dose green tea extract on weight reduction: a randomized, double-blind, placebo-controlled clinical trial. Clin Nutr 35:592–599 23. Dinh TC et al (2019) The effects of green tea on lipid metabolism and its potential applications for obesity and related metabolic disorders – an existing update. Diabetes Metab Syndr 13:1667–1673 24. Ohishi T et al (2021) The beneficial effects of principal polyphenols from green tea, coffee, wine, and curry on obesity. Molecules 26:453

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25. Yang CS et al (2016) 20 mechanisms of body weight reduction and metabolic syndrome alleviation by tea. Mol Nutr Food Res 60(1):160–174. https://doi. org/10.1002/mnfr.201500428 26. DiNicolantonio JJ et al (2020) Effects of spirulina on weight loss and blood lipids: a review. Open Heart 7(1):e001003 27. Lua PL et al (2021) Complementary and alternative therapies for weight loss: a narrative review. J Evid Based Integr Med 26:2515690X211043738 28. Moraru C et al (2018) A meta-analysis on randomised controlled clinical trials evaluating the effect of the dietary supplement chitosan on weight loss, lipid parameters and blood pressure. Medicina (Kaunas) 54:109 29. Nolan R et al (2020) It’s no has bean: a review of the effects of white kidney bean extract on body composition and metabolic health. Nutrients 12:1398 30. Bonetti G et al (2022) Dietary supplements for obesity. J Prev Med Hyg 63(2 Suppl 3):E160-E168.43 31. Wharton S, Bonder R, Jeffery A, Christensen RA et  al (2020) The safety and effectiveness of commonly-marketed natural supplements for weight loss in populations with obesity: a critical review of the literature from 2006 to 2016. Crit Rev Food Sci Nutr 60(10):1614–1630 32. US National Institutes of Health. Office of Dietary Supplements. Dietary Supplements for Weight Loss. https://ods.od.nih.gov/factsheets/ WeightLoss-­HealthProfessional/ 33. Perna S et al (2021) Is probiotic supplementation useful for the management of body weight and other anthropometric measures in adults affected by overweight and obesity with metabolic related diseases? A systematic review and meta-­ analysis. Nutrients 13:666 34. Markowiak P, Śliżewska K. Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients 9:1021 35. Aoun A et al (2020) The influence of the gut microbiome on obesity in adults and the role of probiotics, prebiotics, and synbiotics for weight loss. Prev Nutr Food Sci 25:113–123 36. Perna S et al (2020) Is probiotic supplementation useful for the management of body weight and other anthropometric measures in adults affected by overweight and obesity with metabolic related diseases? A systematic review and meta-­ analysis. Nutrients 13:666 37. Espinoza SE et al (2021) Intranasal oxytocin improves lean muscle mass and lowers LDL cholesterol in older adults with sarcopenic obesity: a pilot randomized controlled trial. J Am Med Dir Assoc 22(9):1877 38. Barengolts E (2016) Oxytocin - an emerging treatment for obesity and dysglycemia  - review of randomized controlled trials and cohort studies. Endocr Pract 22(7):885–894 39. Schneider E et al (2022) The effect of intranasal insulin on appetite and mood in women with and without obesity: an experimental medicine study. Int J Obes 46(7):1319–1327

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40. Li Z et al (2021) Transdermal drug delivery systems and their use in obesity treatment. Int J Mol Sci 22:12754 41. Boyer D (2021) Weight patches: how they work and the research behind their effectiveness. https://www.farrinstitute.org/do-­weight-­loss-­patches-­really-­work/ 42. Byun SY et al (2015) Efficacy of slimming cream containing 3.5% water-soluble caffeine and Xanthenes for the treatment of cellulite: clinical study and literature review. Ann Dermatol 27:243–249 43. Escudier B et al (2011) Benefit of a topical slimming cream in conjunction with dietary advice. Int J Cosmet Sci 33:334–337 44. Pass A et al (2021) Oral superabsorbent hydrogel (Plenity) for weight management. Ann Pharmacother 55(9):1146–1152 45. Greenway FL et al (2019) A randomized, double-blind, placebo-controlled study of Gelesis100: a novel nonsystemic oral hydrogel for weight loss. Obesity (Silver Spring) 27(2):205–216 46. FDA. De novo classification request for Plenity. https://www.accessdata.fda.gov/ cdrh_docs/reviews/DEN180060.pdf

9 Surgery and Weight Loss

Summary • Surgical methods for weight loss have been developed to treat obesity. • Lipectomy and liposuction are the simplest and often involve the removal of fat often around the waist and other more easily accessible areas. • Bariatric surgery is a more complex form of surgery mostly involving gastrointestinal surgery. • Like other surgical procedures, there are risks of complications, particularly in individuals with pre-existing conditions such as diabetes and cardiovascular disease. • Lower-risk procedures using endoscopy rather than surgery have been developed as an alternative form of treatment. • As in other forms of weight loss treatment there is a risk of weight regain. When diet, exercise, drugs, and supplements fail, the only option remaining for those wanting to lose body weight is surgery. It is generally used for those who are more than a few kilos overweight and who have tried other options without much success. A decision to opt for surgery is not taken lightly because there is always a risk of complications arising from surgery [1]. The two main types of surgery for weight loss include actual removal of fat from specific parts of the body (liposuction and lipectomy) and bariatric surgery which involves making changes to the stomach or small intestine.

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Liposuction and Lipectomy An obvious way to lose weight is to physically remove the offending fat. Liposuction and lipectomy are the two most common methods. Liposuction removes fat from specific areas of the body, such as the abdomen, thighs, buttocks, hips, arms, and neck. The removal of fat using liposuction involves the injection of a sterile saline solution into fatty parts of the body and then removing fat and saline under vacuum. There were earlier reports of complications from liposuction which included bleeding, infections, and pulmonary embolism, which were believed to be mainly due to lack of surgical experience [2]. More recent reports indicate that complications associated with liposuction procedures are relatively uncommon and include contour deformities, surgical wound infections, and edema [3]. Lipectomy surgically removes fat from different parts of the body, and particularly from the abdominal area. There may be an increased risk of bleeding, scarring, and infection after the surgery.

Bariatric Surgery Bariatric surgery refers to surgical procedures carried out at different sites of the digestive system which are designed to induce weight loss. The stomach is the main site of surgery and there are a number of procedures that have been used for this purpose. One of the most common is gastric banding or lap banding which involves reducing the amount the stomach can hold by placing a collar or band around the upper part of the organ. It is a relatively simple procedure that results in a reduction of the size of the stomach and, as a consequence, the patient appears to feel full more quickly. In effect, the operation is a non-drug appetite suppressant. The procedure is effective for many people, and it has the added benefit that it is reversible. Earlier studies carried out on large numbers of individuals who had gastric banding showed that there was significant weight loss which lasted up to 8 years after the procedure [4]. However, complications, some of which included inflammation of the esophagus, and migration, leakage, and erosion of the gastric band, may result in the need for further operations [4–7]. Weight regain over a period of time is observed in many patients. An alternative procedure, termed “gastric sleeve” involves the surgical removal of perhaps as much as three-quarters of the stomach. It is also effective, but even more invasive as a large chunk of the stomach is removed, and

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is not reversible. While it may be effective in weight loss there are some complications including bone loss. The latter has been observed even though the diets are supplemented with vitamin D and calcium, two dietary factors that are important to bone health [8]. Yet another procedure, gastric bypass, involves forming a pouch of a small portion of the upper stomach, bypassing the duodenum (the part of the intestine connected to the stomach), and connecting the stomach pouch to a lower part of the intestine. A comprehensive study of bariatric surgery has shown that the various procedures are clearly effective in achieving weight loss because according to a review of more than 160,000 bariatric surgery operations carried out on obese males and females with an average BMI of 46, a reduction in BMI of 12–17 was observed for up to 5 years after the different surgeries [5]. In addition, various studies have shown that there is a significant remission of the comorbidities (e.g., diabetes and hypertension). However, the review also showed that complications were associated with the different types of bariatric surgery (around 17%), requiring a significant reoperation rate (7%). Some of the complications observed using the different procedures included bleeding, vomiting, reflux, and gastrointestinal symptoms [5]. Another significant complication that has been reported after bariatric surgery is peritonitis, due to the inflammation of the peritoneum, a tissue layer that surrounds the abdominal organs [9]. While significant weight loss can occur after bariatric surgery there is increasing evidence that there may be other changes which may need to be considered. For example, bariatric surgery, in particular the bypass procedures, can induce alterations in the microbial composition of the microbiome which in turn lead to changes in the composition of the bacterial products formed, and absorbed, from the intestinal tract into the body [10, 11]. At present it is not known whether these changes, in the long term, will have an impact on future health and wellbeing. Vitamin D deficiency with secondary hypothyroidism has been reported to occur in obesity and may be aggravated after bariatric surgery [8, 12]. It has been suggested that supplementation with vitamin D before and after surgery may reduce the risk of fractures [12]. Iron has been reported to be deficient in obesity and there are indications that bariatric surgery may accentuate the deficiency [13]. Vitamin B12 has also been found to be affected. Stomach surgery in particular may reduce the amount of acid produced, a key factor in the release and uptake of the vitamin [14]. There are concerns also for a possible vitamin B1 deficiency because it can affect the function of the nervous system although its prevalence after bariatric surgery is thought to be low [15]. Finally, weight regain over time has been observed in a significant proportion of individuals after bariatric surgery [16–18].

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Non-surgical Procedures and Weight Loss Because of the financial costs associated with the various bariatric methods for weight loss, as well as the risk of complications, alternative non-surgical procedures have been developed [13, 14, 19, 20]. For example, in contrast to decreasing the size of the stomach by surgical removal, endoscopic sleeve gastroscopy involves the partitioning of a large part of the stomach by sewing together rather than removal of tissue. This process is referred to as endoscopy because it involves the use of an endoscopic device, which is a long flexible tube with a camera and tools attached at the end. As no incisions are required the process is not considered “surgery,” that is there are no incisions unlike gastric sleeves where perhaps as much as 80% of the stomach is actually removed. Further benefits of the procedure include a quicker recovery and fewer complications than the more conventional surgical methods. In addition, significant weight loss has been observed [20]. Another nonsurgical method reduces the size of the stomach by inserting balloons filled with a fluid, mostly saline and a pigment (methylene blue), gas, or a combination of both [21]. The Obalon system also uses a balloon but in this case, the balloon is packaged with a gelatin capsule and attached to a catheter. After swallowing, the gelatin is dissolved releasing the balloon which in turn is inflated via the catheter [14]. Yet another method, referred to as aspiration therapy involves the insertion of a tube into the stomach which in turn is connected to a button on surface of the skin. After a meal, the device permits the removal of up to 30% of the calories ingested [20, 22]. There have even been reports of the use of botulinum toxin injections into parts of the stomach and indications that this treatment may be effective in achieving a degree of weight loss [21, 23, 24]. These various methods, and no doubt many others will be developed in the future, appear to be effective and, as compared to surgical methods, risks are limited [20].

Cellulite Removal Cellulite, a condition characterized by the lumpy appearance of the skin predominantly in lower body areas such as the abdomen, thighs, and pelvis. It differs from generalized obesity because of the differences in body fat distribution and in the structure of the adipocytes (the fat storage cells) [25]. It is not fully understood but is thought to result from the protrusion of underlying fat

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cells into the overlying skin causing an “orange peel” like dimpling. Because of the higher prevalence in women than men it is believed that the female sex hormones may be a factor in its development [26]. Liposuction has been used to treat the condition but its efficacy is doubtful [26]. Subcision, involving the insertion of a needle under the skin to release the fibrous cords which are a feature of the condition has been found to be effective [25, 27]. The use of topic creams, mentioned elsewhere in this book has had limited success. Lasers, as well as light, radiofrequency, and acoustic waves have been used to treat the condition also with varying degrees of success [25].

What Does This Mean? There is little doubt that surgical methods have played an important role in weight loss over the last few years perhaps because it is easier, and less time consuming, to remove offending fat in this way rather than to rely on dietary changes and increased physical activity which can take long periods of time. While surgery is effective it has been used mostly for obese individuals with high BMIs. There are a great number of these medications now available. Moreover, there is always the risk of complications particularly when procedures are carried out on individuals who have other pre-existing conditions such as diabetes and cardiovascular disease. This has led to the development of a number of alternative, and lower-risk procedures, carried out using endoscopy rather than surgery. These have been found to be effective at achieving some degree of weight loss and risks are reduced. However, there is a risk of weight regain even after surgical and endoscopic treatments for obesity.

References 1. Dindo D et al (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213 2. Lehnhardt M et al (2008) Major and lethal complications of liposuction: a review of 72 cases in Germany between 1998 and 2002. Plast Reconstr Surg 121:396e–403e 3. Wu S et al (2020) Concepts, safety, and techniques in body-contouring surgery. Cleve Clin J Med 87:367–375 4. Mittermair RP et al (2009) Results and complications after Swedish adjustable gastric banding-10 years experience. Obes Surg 19:636

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5. Chang SH et al (2014) The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003-2012. JAMA Surg 149:275–287 6. Chisholm J et al (2011) Gastric band erosion in 63 cases: endoscopic removal and rebanding evaluated. Obes Surg 21:1676–1681 7. Kassir R et al (2016) Complications of bariatric surgery: presentation and emergency management. Int J Surg 27:77–81 8. Brzozowska MM et al (2021) Roux-en-Y gastric bypass and gastric sleeve surgery result in long term bone loss. Int J Obes 45:235–246 9. Lazzati A et al (2021) Postoperative care fragmentation in bariatric surgery and risk of mortality: a nationwide study. Surg Obes Relat Dis 17(7):1327–1333 10. Mika A et al (2022) The impact of the interplay of the intestinal microbiome and diet on the metabolomic and health outcomes of bariatric surgery. Obes Rev 23:e13455 11. Ciobârcă D et al (2020) Bariatric surgery in obesity: effects on gut microbiota and micronutrient status. Nutrients 12:235 12. Borges JLC et  al (2018) Obesity, bariatric surgery, and vitamin D.  J Clin Densitom 21:157–162 13. Bjørklund G et al (2021) Iron deficiency in obesity and after bariatric surgery. Biomol Ther 11:613 14. Glass J et al (2019) New era: endoscopic treatment options in obesity-a paradigm shift. World J Gastroenterol 25:4567–4579 15. Al Mansoori A et al (2021) The effects of bariatric surgery on vitamin B status and mental health. Nutrients 13(4):1383 16. Velapati SR et al (2018) Weight regain after bariatric surgery: prevalence, etiology, and treatment. Curr Nutr Rep 7:29–334 17. El Ansari W, Elhag W (2021) Weight regain and insufficient weight loss after bariatric surgery: definitions, prevalence, mechanisms, predictors, prevention and management strategies, and knowledge gaps-a scoping review. Obes Surg 31:1755–1766 18. Baig SJ et al (2019) Indian bariatric surgery outcome reporting (IBSOR) group. Weight regain after bariatric surgery-a multicentre study of 9617 patients from Indian bariatric surgery outcome reporting group. Obes Surg 29:1583–1592 19. Hedjoudje A et al (2020) Efficacy and safety of endoscopic sleeve gastroplasty: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 18:1043–1053 20. Král J et al (2021) Endoscopic treatment of obesity and nutritional aspects of bariatric endoscopy. Nutrients 13:4268 21. Bang CS et al (2015) Effect of intragastric injection of botulinum toxin A for the treatment of obesity: a meta-analysis and meta-regression. Gastrointest Endosc 81:1141–1149 22. Thompson CC et  al (2021) Aspiration therapy for the treatment of obesity: 4-year results of a multicenter randomized controlled trial. Surg Obes Relat Dis 15:1348–1354

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23. Yen YA et al (2022) Intragastric injection of botulinum toxin a for weight loss: a systematic review and meta-analysis of randomized controlled trials. J Gastroenterol Hepatol 37:983–992 24. Chang PC et al (2020) Intragastric botulinum toxin a injection is an effective obesity therapy for patients with BMI > 40 kg/m2: a systematic review and meta-­ analysis. Obes Surg 30:4081–4090 25. Sadick N (2018) Treatment for cellulite. Int J Womens Dermatol 5:68–72 26. Bass LS, Kaminer MS (2020) Insights into the pathophysiology of cellulite: a review. Dermatol Surg 46(Suppl 1):S77–S85 27. Dadkhahfar S et al (2020) Subcision: indications, adverse reactions, and pearls. J Cosmet Dermatol 19:1029–1038

10 Alternative Weight Loss Methods

Summary • There has been an increasing interest in the use of alternative, and unconventional, methods to treat obesity. • These methods include traditional practices such yoga, Tai Chi, ayurvedic medicine, and acupuncture. • Less traditional methods such as Pilates, mindfulness, hypnotherapy, and hypnotherapy have also been used. • Devices such as the Hypoxi Vacunaut equipment and the Maestro Rechargeable system have also been used. • There is limited evidence for long-term effects on weight loss of less traditional methods without some dietary and lifestyle changes. It is to be expected that, as the numbers of individuals with obesity increase and as many of the more conventional and properly researched methods used to lose weight may be perceived as time consuming, onerous, ineffective, or even risky, alternatives will be sought, mostly from the Internet. Even a cursory Internet search for weight loss methods will reveal literally thousands. While some of these may be based on properly conducted research and published in reputable medical or scientific journals rather than on websites, in many cases there is only limited information on the efficacy of the method which is being promoted. Included in any Internet search for weight loss are traditional methods, often from different cultures, and using quite different techniques from those used in Western medicine. It is worth examining a few of these methods which are based on traditional methods.

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Acupuncture and Weight Loss Acupuncture is a traditional Chinese practice which involves the insertion of needles in specific parts of the body. It is believed that the needles stimulate certain nerves in the body which are involved in the regulation of energy and metabolism. It is claimed that acupuncture can help with weight loss by regulating hormone production, improving the metabolism, optimizing digestion, reducing inflammation, suppressing the appetite, lessening water retention, and optimizing other bodily functions that are related to obesity and weight loss [1]. To add to the complexity of assessment of any study of the effects of acupuncture on obesity, it is worth noting that there are different forms of acupuncture—auricular, body, and electro-acupuncture. Electroacupuncture includes the passage of a small electric current between acupuncture needles at different body sites, while auricular acupuncture involves the use of needles at specific points around the ear, and for body acupuncture the needles pierce the skin at different body sites. These different forms of acupuncture, together with the great variability in age, sex, ethnicity, body weight, diets, exercise, and comorbidities of individuals undergoing treatment make it extremely difficult to draw any firm conclusions on any effects on obesity. Despite the complexity, in a recent review of a number of studies it was concluded that acupuncture may produce small changes in body weight, waist circumference, and BMI [2]. However, in another review it was concluded that, compared to exercise alone, the combination of exercise and acupuncture produced little change in body weight or BMI which really raises some doubts as to the efficacy of acupuncture in the treatment of obesity particularly if it does not include another weight loss strategy such as diet or exercise [3].

Ayurvedic Medicine Ayurvedic medicine is an ancient health and wellbeing system that was developed in India. Several Ayurvedic medicines which are have been exploiting for the treatment and management of various diseases in human beings [4]. More recently, because of their biological effects, some of these medicines, which are mostly derived from leaves, roots, flowers, or bark of plants, are being considered to be potentially useful in the treatment of obesity. One of the components of extracts taken from some of these plants, curcumin, is

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believed to show some promise for the treatment of obesity because of its effects on the proliferation of fat-storing cells (adipocytes), although as yet there are few studies on the effects of Ayurvedic medicines alone on obese individuals [5–8]. However, a recent study indicated that some degree of weight loss could be achieved using a combination of yoga and Ayurvedic medicine [9]. The potential of Ayurvedic medicine alone needs to be explored further with modern scientific validation methods.

Tai Chi Tai Chi is an ancient Chinese form of exercise that is performed slowly and accompanied by deep breathing. It is composed of many different styles, some of which may focus on the maintenance of health while others relate to martial arts. It involves a series of movements performed in a slow, focused manner and accompanied by deep breathing. Each posture flows into the next without pause, ensuring that the body is in constant motion. It is considered to be low impact placing minimal stress on the joints and muscles. Because it combines exercise and awareness it is not surprising that it has been considered as a possible means of controlling body weight. In one study of Tai Chi practitioners it was found that they had a lower amount of fat in various parts of the body [10]. The effects of Tai Chi on body mass and waist circumference have also been observed in normal individuals who were assigned to a Tai Chi exercise program [11]. Of considerable interest in a study of the effects of Tai Chi on body weight was the observation that HDL cholesterol, the blood cholesterol which has been linked to possible heart disease, was found to be reduced [12].

Yoga According to the Indian Government, yoga is a 5000-year-old tradition that combines physical, mental, and spiritual pursuits to achieve harmony of the body and mind [13]. As its focus is the bringing of harmony between and body it is not surprising that it has been explored as a means of treating obesity which, according to one point of view, is a result of a lack of balance between the mind and body which leads to overeating [14]. A survey of yoga practitioners showed that around 5% were considered obese as compared to 37.5% of the normal population [15]. While diet was thought to be a factor—a significant numbers were vegans or vegetarians—an overall greater

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than normal physical activity was also considered to be important. Trials carried out on normal subjects, which included dietary and behavioral changes as well as exercises, have shown small reductions in body weight [16, 17]. It is likely therefore that any weight loss associated with the practice of yoga is more than just the result of the many different poses that are part of the discipline and may indeed result from an increase in mind–body harmony.

Pilates Pilates is a type of exercise and body conditioning that was developed in the early twentieth century by Joseph Pilates. It was originally developed as a means of assisting dancers in their recovery from injury. Its exercises include movements and ideas from a variety of other disciplines including dance, yoga, martial arts, and gymnastics. In addition, it includes other elements such as centering, breathing, and flowing movements [18]. In one review of studies carried out on the effects of Pilates on body weight, it was concluded that Pilates significantly reduces body weight in overweight and obese individuals as well, providing the program is continued for more than 10 weeks [18]. However, these conclusions were not supported in another review [19]. It has been suggested that training intensity and diet control are important factors in determining the effect of Pilates on body weight [18].

Mindfulness As psychological factors such as mood and stress are believed to have an impact on food intake, it is not surprising that strategies have been developed to try to better regulate food consumption based on actual rather than perceived dietary needs. According to this view, dysfunctional food cues, such as advertising, boredom, anger and anxiety, promote weight gain, and if there is a better awareness of these cues, through training in mindfulness, can lead to better weight control [19]. Studies have shown that increased mindfulness can result in a degree of weight loss but there are many factors, such as the type of mindfulness practiced, whether the individual taking part in the trial has a pre-existing condition and the nature of that condition, as well as other factors such as diet and amount of physical activity [19, 20].

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Hypnotherapy Hypnotherapy, which is a treatment using hypnosis to treat obesity, is yet another alternative method that has been used. The inclusion of hypnotherapy as part of a weight loss strategy has been reported to result in small reductions in body weight. There were suggestions that hypnosis more than once a day may be more effective [1, 21].

Behavioral Modification Changes in our way of life which have occurred in the last century in transport, food choices, occupation, and leisure activities, are considered to be a major factor in the dramatic increase in the number of individuals who are overweight or obese. It is clear also that, as compared to earlier periods of time there are more external cues or signals to which our brains respond and which makes us want to eat more than we really need. Research carried out over many years has identified some of these cues which include plate and bowl size, labels, lights, colors, shapes, smells, watching TV, and food and drink advertisements that can affect what, and how much, we eat [22, 23]. It has been suggested that “mindless eating”—eating that is influenced by environmental factors rather than hunger—can increase food consumption. It is therefore not surprising that the choices we make in our daily lives are Important components of any weight loss program. Unfortunately, there is some evidence that obesity is associated with deficits in what has been termed executive function which includes elements such as working memory, planning, and decision-making [24]. These deficits may lead to behavioral changes affecting the choices we make and this in turn can increase the risk of obesity. Therefore, lifestyle changes that could promote weight loss are needed although difficult to achieve. As the most effective way of regulating weight is through dietary and physical activity changes, and as this involves a change in the way we live our lives, the use of a strategy for lifestyle changes based on what has been termed a “commitment device” has been suggested. The “device” is actually a pledge or a promise of a particular behavior which in the case of weight maintenance would involve dietary and/or physical activity changes to a particular lifestyle. There may be soft or hard commitments to the lifestyle change which, if breached, could lead to financial or other consequences [25]. The involvement of a health provider, or peers, is believed to increase the likely adherence to the pledge. There are indications that these

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devices do achieve some degree of weight loss, at least over the short term, particularly in group settings when health professionals or peers are involved.

Weight Loss Devices If dietary and physical activity changes are too difficult to maintain, and drugs and supplements are not effective, then another technique that has been explored is to use a device to remove excess amounts of body fat. One of these devices, Vacunaut, marketed by Hypoxi, consists of an airtight vacuum suit that covers certain high-fat areas of the body, for example, the thighs and waist. It is claimed that, with increasing pressure, fat is released from the fat deposits close to the suit, and released and “burned off” by muscular activity. While it is claimed by Hypoxi that their device works, we have been unable to find any reference to studies in credible scientific and medical journals which confirm the benefits of the procedure. Furthermore, a search of the medical/ scientific literature indicates that a German scientist apparently reported to have supported the technique (Drs CM Bamberger) did not confirm that studies had been published showing the efficacy of the technique [26]. Despite this, there are numerous websites claiming the many benefits of the procedure. Research has shown that communication of the brain with the intestinal tract is important in food ingestion and body weight regulation and this has been mentioned earlier. As the vagus nerve connects the brain with the abdomen via various organs including the heart and is believed to play a key role in gut–grain communication it is perhaps not surprising that attempts have been made to induce weight loss via this nerve [27]. Some support for the role of the vagus in the regulation of body weight has been observed in the weight loss of patients with epilepsy and depression undergoing vagal nerve stimulation [28]. The Maestro Rechargeable System includes a device placed under the skin near the ribs which produces a signal blocking the effects of the vagus nerve. The device is believed to reduce food intake by delaying the processing of food and emptying of the stomach [29, 30]. Studies using this device on obese subjects have shown that a moderate degree of weight loss can be achieved while complications related to the procedure were shown to be relatively minor and therefore may be a useful alternative to bariatric surgery. A related product, the vBlok, has also been shown to be effective in achieving weight loss with relatively minor side effects [31].

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What Does This Mean? If the usual methods of weight loss focusing mainly on dietary changes and increased physical exercise are too onerous for some, it is not surprising that there is an increasing interest in alternative methods that are based on traditional practices such as yoga, Tai Chi, acupuncture, and ayurvedic medicine. And if these are not effective then less traditional methods such as Pilates, mindfulness, hypnotherapy, or even behavioral modification, may be tried. The variety of traditional, and non-traditional methods will no doubt continue to grow. Depending on the method used, treatment may involve the use of traditional medicines mostly derived from natural sources, or meditation, certain physical activities, breathing exercises, dietary changes and even, in the case of acupuncture, the insertion of needles into the skin. While many of these techniques have been used, in some cases, for centuries, they mostly rely on psychological factors which in turn may affect energy intake. There is really limited evidence that they can, without dietary changes they can lead to weight loss, These methods often involve the use of traditional medicines mostly derived from natural sources. There are even devices that can be employed as part of a weight loss program. While there is some indication that weight loss may be achieved using these techniques there is really limited evidence that they can induce a substantial degree of weight loss without the inclusion of some dietary changes at least in the long term.

References 1. Lua PL et al (2021) Complementary and alternative therapies for weight loss: a narrative review. J Evid Based Integr Med 26:2515690X211043738 2. Yao J et al (2019) Acupuncture and weight loss in Asians: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 98:e16815 3. Zhong YM et al (2020) Acupuncture versus sham acupuncture for simple obesity: a systematic review and meta-analysis. Postgrad Med J 96:221–227 4. NIH.  National Centre for Complementary and Integrative Health (2019) Ayurvedic Medicine in Depth. https://www.nccih.nih.gov/health/ ayurvedic-­medicine-­in-­depth 5. Kasprzak-Drozd K et al (2022) Curcumin and weight loss: does it work? Int J Mol Sci 23:639 6. Akaberi M et  al (2021) Turmeric and curcumin: from traditional to modern medicine. Adv Exp Med Biol 129:15–39

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7. Zhao Y (2017) The beneficial effects of quercetin, curcumin, and resveratrol in obesity. Oxidative Med Cell Longev 2017:1459497 8. Jin T et  al (2017) Curcumin and other dietary polyphenols: potential mechanisms of metabolic actions and therapy for diabetes and obesity. Am J Physiol Endocrinol Metab 314(3):E201–E205 9. Rioux J, Howerter A (2019) Outcomes from a whole-systems ayurvedic medicine and yoga therapy treatment for obesity pilot study. J Altern Complement Med 25(S1):S124–S137 10. Stagi S et al (2020) Lower percentage of fat mass among Tai Chi Chuan practitioners. Int J Environ Res Public Health 17:1232 11. Dechamps A, Gatta B, Bourdel-Marchasson I, Tabarin A, Roger P et al (2009) Pilot study of a 10-week multidisciplinary Tai Chi intervention in sedentary obese women. Clin J Sport Med 19:49–53 12. Siu PM et al (2021) Effects of tai chi or conventional exercise on central obesity in middle-aged and older adults : a three-group randomized controlled trial. Ann Intern Med 174(1050–1057):13 13. Ministry of External Affairs. Government of India (2022) The origin of the international day of yoga 14. American Psychological Association (2013). Mind body health: Obesity 15. Ross A et al (2013) National survey of yoga practitioners: mental and physical health benefits. Complement Ther Med 21:313–323 16. Jakicic JM et al (2021) Feasibility of integration of yoga in a behavioral weight-­ loss intervention: a randomized trial. Obesity (Silver Spring) 29:512–520 17. Anheyer D et al (2021) Yoga in women with abdominal obesity - do lifestyle factors mediate the effect? Secondary analysis of a RCT.  Complement Ther Med 60:102741 18. Yi W et al (2021) Pilates for overweight and obese adults: a meta-analysis. Front Physiol 12:643455 19. Pellegrini M et al (2021) The use of self-help strategies in obesity treatment. A narrative review focused on hypnosis and mindfulness. Curr Obes Rep 10:351–364 20. Carrière K et al (2018) Mindfulness-based interventions for weight loss: a systematic review and meta-analysis. Obes Rev 19:164–177 21. Bo S et al (2018) Effects of self-conditioning techniques (self-hypnosis) in promoting weight loss in patients with severe obesity: a randomized controlled trial. Obesity (Silver Spring) 26(9):1422–1429 22. Wansink B (2010) From mindless eating to mindlessly eating better. Physiol Behav 100:454–463 23. Cohen DA. Obesity and the built environment: changes in environmental cues cause energy imbalances. Int J Obes (Lond) 32 Suppl 7(07):S137–42 24. Yang Y et al (2018) Executive function performance in obesity and overweight individuals: a meta-analysis and review. Neurosci Biobehav Rev 84:225–244

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25. Coupe N et  al (2019) The effect of commitment-making on weight loss and behaviour change in adults with obesity/overweight; a systematic review. BMC Public Health 19(1):816 26. https://circulate.net.au/science/ 27. Berthoud HR et al (2021) Gut-brain communication and obesity: understanding functions of the vagus nerve. J Clin Invest 131:e143770 28. de Lartigue G (2016) Role of the vagus nerve in the development and treatment of diet-induced obesity. J Physiol 594:5791–5815 29. FDA.  January 2015. Summary of safety and effectiveness data. Maestro Rechargeable System. https://www.accessdata.fda.gov/cdrh_docs/pdf13/ p130019b.pdf 30. Hwang SS et al (2016) Update on bariatric surgical procedures and an introduction to the implantable weight loss device: the maestro rechargeable system. Med Devices (Auckl) 9:291–299 31. Apovian CM et al (2017) Two-year outcomes of vagal nerve blocking (vBloc) for the treatment of obesity in the ReCharge trial. Obes Surg 27:169–176



Epilogue: What Can We Do?

There is little doubt that the incidence of obesity has increased dramatically over the last century. According to the World Health Organisation, more than a quarter of the world population is either overweight or obese. In some of the developed countries such as the United States prevalence of obesity is even greater than this (40%). As Inhabitants of some remote communities, such as the hunter/forager Tsimane and Hadza communities with completely different diets and lifestyles have much lower levels of obesity, it has led to speculation that these changes are a major factor in the rapid growth in obesity in the developed world, a theory that has been supported by the rapid growth of obesity in some communities, such as the Aboriginal communities in Australia, Canada, and Mexico. This has led to the evolutionary mismatch and discordance theories that have speculated that the modern way of life with its major dietary changes, corresponding reductions in physical activity, and increasing exposure to a great variety of chemicals added to our food, may be a factor driving the increases in body weight. As our genes are an important factor in both the utilization of food as a source of energy, and its storage, it is reasonable to speculate that, for many of us, the natural changes in our genes, referred to as mutations and polymorphisms, and which have occurred over long periods of time, have been unable to cope with the different world we live in. There is little doubt that our genetic makeup plays an important role in the development of obesity. This is clear from studies with identical twins and from studies with individuals whose severe obesity is linked to mutations in

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certain genes. More recently an increased risk of obesity has been observed in those with apparently minor changes, or polymorphisms, in a number of genes. In addition, there are indications that the expression of certain genes, that is the mechanism for the generation of a protein from a specific gene by a process referred to as methylation, may be affected by dietary factors or even chemical pollutants, and this could also contribute to the development of obesity. As we better understand the link between our genes and body weight it is likely that we may able to better predict our likelihood of developing obesity. For many young people, to look like the latest film star, supermodel, or glamorous royal, or to make oneself more desirable to the opposite sex seems to have become a major reason why many people—particularly young women—decide to lose weight. Certainly, body image is a powerful motivator but there are also very good health reasons why people should want to lose weight. Research has increasingly shown that the extra weight is carried in the form of fat depots in different parts of the body, not just around the waist but around some of the key organs of the body, including within the abdominal cavity and even around the heart. These particular fat depots, referred to as visceral fat, may not be as unsightly as the fat deposits around the waist, thighs, and buttocks but they are believed to increase the risk of disease. Fat depots are not completely inert but release a variety of chemicals that can have powerful effects on the body. Indeed it has been speculated that obesity is an inflammatory condition, perhaps even a disease in its own right, and may explain why the risks of diseases such as diabetes, cardiovascular disease, and perhaps even some forms of cancer, are increased. There are even indications of an increased risk of other diseases such as asthma, sleep apnea, and dementia, and even effects on body functions such as taste and smell. It is perhaps not fully appreciated that the regulation of food uptake and utilization, as well as storage of fat in different parts of the body, is a complicated process controlled by a number of hormones. While there is little doubt that obesity is caused by an intake of energy provided by food that is greater than the energy required to drive the many functions of the body at rest, as well as the many physical activities that are the normal part of daily life, it has become increasingly clear that there are many factors that contribute to the imbalance of energy in and energy out. Apart from the genetic factors already mentioned, our food often contains high amounts of sugar and oils which increase the energy content of a food and, at the same time, its appeal. In addition, some foods, particularly ultraprocessed foods may contain a variety of chemicals added to the food to improve the taste, appearance, and stability. The number of potential chemical additives in ultraprocessed foods is truly

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astounding as any visit to government websites can show. Perhaps the greatest concern is the limited information available on the potential impact of these mixtures of chemicals, some of which may have never been part of human diet, on the various hormonal systems that regulate food intake and utilization. There are legitimate reasons for concern because certain chemical entities, referred to as obesogens, have been reported to increase the risk of obesity in animals. More recently there have also been concerns regarding the potential effects of dietary components, particularly in ultraprocessed food, on the microbial population in the gut, i.e., the microbiome, and the possible impact this may have on the regulation of body weight. While, apart from diet, there are many factors that determine our body weight—and some of these can be influenced by our age, sex, and physiological state such as puberty, menopause, and old age—there are weight loss methods that have been shown to be effective. These mostly involve a combination of dietary restrictions and increased physical activity. In addition, alternative traditional methods such as acupuncture, yoga, Pilates, Tai Chi, and Ayurvedic medicine, or nutritional supplements or probiotics have been used with varying degrees of success. More recently anti-obesity drugs have been developed and even weight loss devices. When all else fails, many people resort to bariatric surgery. There is no doubt that some of the weight loss methods are effective, at least in the short term. However, weight regain is common whichever weight loss method is used indicating that dietary and lifestyle changes introduced as part of any weight loss program must be maintained. There is increasing evidence that weight regain may reflect physiological changes which have occurred in the obese state. According to this view, reductions in body weight, particularly after long periods of carrying additional weight, may induce compensatory mechanisms for maintaining the pre-­ weight loss body weight. It is important to remember that the hormonal systems that lead to weight gain may have developed over a considerable period of time and research is needed to better understand what appears to be compensatory mechanisms for maintaining the additional body weight. Further research is also needed to understand how factors such as the degree of obesity, sex, age, and diseases such as diabetes and cardiovascular disease affect the ease and degree of weight loss as well as the factors involved in subsequent weight gain. At present, without a better understanding of why some of us put on weight more easily than others apparently on a similar diet, we are mostly reliant on dietary restrictions, or even fasting, as a means of losing weight. However, we should be aware that there are many factors that contribute to weight gain just

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as there many different weight loss diets. What research has shown is that our genetic “blueprint” probably plays a much greater role in energy regulation and in the maintenance of body weight, than has been believed. It is tempting to speculate that, in the future, genetic analysis may provide individual, and more effective, ways of regulating our body weight.

Index

A

Acupuncture and weight loss, 104 Adipocytes brown and beige, 5, 7 browning, 5, 7 mitochondrial content, 6 and storage of fats, 4–5 triglyceride storage, 6 Adipose tissue body distribution of, 5, 11 cellular composition of, 5 immune cells in, 5, 7 in obesity, 6, 7, 11, 19, 26, 27, 29, 59 triglyceride content of, 5, 6 types of, 5 Age body fat content and, 6, 11, 31–32 Alcohol and weight gain, 12, 33 Altitude and risk of obesity, 33–34 Alzheimer’s disease and risk with obesity, 59 Apolipoprotein E and Alzheimer’s disease, 18

Artificial sweeteners as obesogens, 28, 46 Asthma increased risk with obesity, 58, 62 Australian aborigines obesity and change of diet in, 44 Ayurvedic medicine and weight loss, 104–105, 109, 115 B

Bardet Biedl syndrome genetic disease and obesity, 19, 21 Bariatric surgery weight loss and, 56, 57, 59, 61, 96–97, 108, 115 Basal metabolic rate (BMR) factors contributing to, 41–42 Binge eating and obesity, 31, 36 Bioelectrical impedance device for measurement of body fat, 11 BMI, see Body mass index (BMI) Body fat distribution of, 10–13, 27, 35, 98

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118 Index

Body mass index (BMI) and weight loss, 10, 13, 27, 59, 88, 97, 99, 104 Body weight and BMI, 10, 13, 62 and obesity, v–vii, 10, 18, 35, 56, 62, 76 Browning of adipocytes, 6, 7 C

Cancer obesity risk for, 56–57 Carbohydrates in fibre, 43 food sources of, 43, 77 Cardiovascular disease and risk in obesity, 49, 56–58, 62, 76 Celiac disease and gluten intolerance, 49 Cellulite treatment for, 98–99 Cholesterol and cardiovascular disease, 57, 72 Chromosomes mutations of genes on, 18 polymorphisms of genes on, 18, 21 Circadian rhythm and risk of obesity, 30 Cis trans fatty acids, 3, 46 hydrogenation and, 4 Climate influence on risk of obesity, 34 Coeliac disease and gluten intolerance, 48 Commercial weight loss programs, 70, 75

D

Dementia and obesity, 59 Diabetes obesity and risk of, 56, 61 Diet chemical additives, 49 and food intolerances, 48, 49 Mediterranean diet, 45, 70, 73 Paleolithic diet, 44, 49, 73 precision nutrition, 48–49 ultraprocessed foods and obesity, 47 vegetarian/vegan, 45, 105 Disability risk of obesity and, 31 DNA chromosomes and, 17, 18 methylation of, 20–22 Dopamine and effects on eating behaviour, 28 Drugs and weight gain, 13, 33 and weight loss, 26, 81–90, 108 E

Eicosanoids, 4 Endoscopy weight loss and, 98, 99 Environmental pollutants as obesogens, 28, 29 synergistic effects of, 29 Epigenetics and effects of obesity on methylation of DNA, 20 and methylation of DNA, 20, 22 Estrogen and regulation and distribution of body fat in women, 27 Ethnicity risk of obesity, 10 Evolutionary discordance theory and risk of obesity, 44

 Index  F

Fast food increasing incidence of obesity with, 30 Fat structure and function of, 2–4 Fat distribution body sites for, 11–13 Fatty acids saturated and trans and risk of disease, 3 variation in chemical structure of, 3 Food additives and risk of obesity, 28, 47–48 Food allergies, 32, 49, 70 Food composition, 43 Food marketing and risk of obesity, 32 Food processing and risk of diseases, 46

Glycogen and source of blood glucose, 26 storage in liver, 2, 26 H

Hadza incidence of obesity of, 44, 113 Hormonal factors and control of food intake, 21 Hunter gatherers diet and incidence of obesity in, 44 Hydrogenation of fats, 3 and trans fats, 3 Hypnosis effects on weight loss, 107 I

G

Gallstones and increased risk with obesity, 60–61 Gastric bypass treatment for obesity with, 97 Gastric sleeve treatment for obesity using, 96, 98 Genetic abnormalities monogenic and polygenic, 19 and obesity, 19, 27 Genetics and obesity, 17–22 Ghrelin blood levels in obesity and dieting of, 27 effects on energy production of, 27 Glucagon-like protein (GLP-1) control of food intake and, 26 Gluten coeliac disease and, 49

119

Indigenous communities diet and obesity, v, 49–50 Inflammation and obesity, 59–60 Insulin and diabetes, 33, 56, 73 and utilisation of glucose, 26, 56 Intranasal administration and oxytocin treatment for obesity, 88 Inuit incidence of obesity of, 44 L

Lactose and intolerance, 48 presence in milk, 2, 48, 84 Leptin appetite suppression and, 27 and regulation of energy production, 27

120 Index

Lipectomy weight loss and, 96 Liposuction weight loss and, 96 Liraglutide and weight loss treatment, 26 M

Melanocortin effect on body weight of, 27, 28 leptin stimulation and, 27 Menopause fat distribution in, 11, 14 Mental health effect of obesity on, 61 Microbiome and development of obesity, 29–30, 48 diet and physical activity effects on, 30 probiotics for, 30, 87–88 Mindfulness and weight loss, 106, 109 Mismatch theory, 113 Mitochondria energy production in adipocytes by, 5 Monogenic causes of obesity, 19 diseases resulting in obesity, 19 Mutation of genes and obesity, 18, 113

Obesogens chemical structures of, 28 and risk of obesity, 29 Old age and fat distribution, 11 Organotin and increased storage of fat, 29 Osteoarthritis and increased risk in obesity, 58 P

Paleolithic diet composition of, 49 and incidence of obesity, 44 Phospholipids structure and function of, 2, 3 Physical activity effect on weight maintenance and loss, 69–77 Pilates and weight loss strategy, 106 Polygenic diseases and obesity, 19 Polymorphisms of genes and obesity, 18–19 Probiotic supplements for weight loss, 87–88 Proopiomelanocortin (POMC), 27 R

Rural environments effects on body weight in, 34

N

NOVA system dietary classification using, 45 O

Obesity paradox, 13, 57

S

Sensory loss with obesity, 60 Sleep apnoea effects of body weight in, 60 Slimming patches and treatment for obesity, 89

 Index 

Smoking and body weight, 12 Supplements for weight loss, 84, 87, 90 Surgeon General, v Surgery and treatment for obesity, 96–97 and weight loss, 95–99 T

Tai Chi and weight loss, 105

121

Taste effect of obesity on, 61 Triglycerides chemical structure of, 3 storage in adipocytes of, 6 U

Ultraprocessed food artificial sweeteners in, 46 effect on microbiome of, 48, 115 risk of obesity and, 48 synergistic effects of chemicals in, 47