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Handbook of Obesity Volume 2 of the Fifth Edition of the Handbook of Obesity spotlights clinical applications for the evaluation, diagnosis, prevention, and treatment of obesity. It covers the several major developments that occurred between the previous and new edition, including the effect of SARS-CoV-2 on people with obesity, the concept of “Precision Medicine,” and new medications approved by the U.S. FDA aiding patients with obesity weight loss of 15 to 20%. This volume is structured into 5 parts: • Part 1 provides insights from evolution on changes in diet and physical activity, and the implications and results for preventing obesity, healthcare costs associated with obesity, and the cost-effectiveness of obesity prevention and treatment. • Part 2 deals with the evaluation of overweight patients, approaches for classifying obesity and using this knowledge to evaluate patients, and addressing ethnic and racial considerations in evaluating patients with obesity. • Part 3 explains the impact of lifestyle in managing obesity, which includes behavioral management, diet, dietary composition, and meal timing, and the effects of physical activity and exercise in weight loss and weight loss maintenance. • Part 4 is focused on medications in the management of obesity. This includes drug selection, various classes of drugs, the combination of drugs affecting weight loss, the effect of herbal agents on weight loss and treatment of obesity in pediatric populations, genetic diseases causing obesity, and the role of drugs in treating dyslipidemias. • Part 5 discusses bariatric surgery, its history, procedures and effects in detail, and other surgical techniques including electric stimulation of the vagus nerve, gastric balloons, intestinal liners, and liposuction.
Handbook of Obesity – Volume 2 Clinical Applications Fifth Edition
Edited By
George A. Bray, MD Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana
Claude Bouchard, PhD Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana
Associate Editors
Peter T. Katzmarzyk, PhD Pennington Biomedical Research Center Louisiana State University Baton Rouge, Louisiana
John P. Kirwan, PhD Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Louisiana State University Baton Rouge, Louisiana
Leanne M. Redman, PhD Reproductive Endocrinology and Women’s Health Laboratory Pennington Biomedical Research Center Louisiana State University Baton Rouge, Louisiana
Philip R. Schauer, MD Metamor Institute Pennington Biomedical Research Center Louisiana State University Baton Rouge, Louisiana
Designed cover image: Shutterstock Fifth edition published 2024 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN CRC Press is an imprint of Taylor & Francis Group, LLC © 2024 selection and editorial matter, George A. Bray, Claude Bouchard, John Kirwan, Peter Katzmarzyk, Leanne Redman, Philip Schauer; individual chapters, the contributors This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/ opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact mpkbookspermissions@tandf.co.uk Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. ISBN: 9781032551081 (hbk) ISBN: 9781003432807 (ebk) DOI: 10.1201/9781003432807 Set ISBN: 9781032047126 (hbk) Set ISBN: 9781003437734 (ebk) Set DOI: 10.1201/9781003437734 Typeset in Times by Deanta Global Publishing Services, Chennai, India
This edition of the Handbook of Obesity is dedicated to Claude Bernard “Doc” Pennington, whose generous gift to Louisiana State University in 1980 made possible the initiation of the Pennington Biomedical Research Center, which has served all of the editors and associate editors of this book as an academic home and a site for internationally recognized research in nutrition and metabolic health.
Contents Preface xi About the Editors xiii Associate Editors xv Contributors xvii Introduction to Volume 2 xxiii
Part 1 Prevention and Economic Outcomes of Obesity
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1 Dietary Changes in Human Evolution: Implications for the Prevention of Obesity Peter Andrews and Richard Johnson
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2 Evolutionary Changes in Physical Activity, Diet, and Energy Expenditure: Implications for the Prevention of Obesity Herman Pontzer
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3 Prevention of Obesity in Adults Suzanne Phelan
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4 The Prevention of Obesity in Children and Adolescents Tim Lobstein and Louise Baur
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5 Re-engineering the Built Environment: Progress in Schools, Worksites, Neighborhoods, and Communities 39 Stephanie T. Broyles and Maura M. Kepper 6 The Economic Costs of Obesity Adam Biener, John Cawley, and Chad Meyerhoefer
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7 Cost-Effectiveness of Obesity Prevention and Treatment Jaithri Ananthapavan, Marj Moodie, and Victoria Brown
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8 Role of Government and Non-government Organizations in the Obesity Pandemic and Its Prevention Simon Barquera, Mariel White, Gabriela Argumedo, Carolina Batis, and Juan Rivera-Dommarco
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9 Role of Reimbursement in the Delivery of Treatment for Obesity in Adults and Children Chika Vera Anekwe, Veronica R. Johnson, Matthew J. Townsend, and Fatima Cody Stanford
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Part 2 Evaluation of the Patients with Overweight or Obesity
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10 Classification, Evaluation, and Staging of the Patient with Obesity Robert F. Kushner and Amanda Velazquez
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11 Indicators of Central Adiposity: A Critical Evaluation of Their Usefulness Ian J. Neeland, Jean-Pierre Després, André C. Carpentier, and Paul Poirier
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12 Genetic Obesity Syndromes I. Sadaf Farooqi and Stephen O’Rahilly
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viii Contents 13 Ethnic and Racial Considerations in the Evaluation of the Patient with Obesity Peter T. Katzmarzyk, Sean Wharton, Fatima Cody Stanford, and Daniel G. Aaron
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Part 3 L ifestyle in the Management of Obesity: Behavioral Modification, Diet, and Exercise 141 14 Best Practices: Obesity and the Primary Care Providers Christine Gallagher, Donna H. Ryan, and William Dietz
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15 In-Person Behavioral Approaches for Weight Management Jena S. Tronieri and Thomas A. Wadden
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16 Behavioral Interventions Delivered Remotely Christoph Höchsmann and Corby K. Martin
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17 Cultural Considerations in Behavioral Therapy for the Management of Obesity Robert L. Newton, Jr., Elva Arredondo, Patricia Dionicio, and Noe C. Crespo
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18 Diet Composition and Weight Loss: Is a Calorie a Calorie? Kevin D. Hall
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19 Circadian Rhythms and Weight Loss: Timed Food Intake Emily N.C. Manoogian, Nikko R. Gutierrez, Erika Padilla, and Michael J. Wilkinson
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20 Comparison of Modern-Millennial Diets Monica Dinu, Daniela Martini, Francesco Sofi, Mauro Serafini, Marisa Porrini, and Donato Angelino
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21 Dietary Energy Density and Its Contribution to Weight Control Faris M. Zuraikat and Barbara J. Rolls
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22 Dietary Patterns as a Basis for Diet Selection Catherine M. Champagne
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23 Physical Activity and Weight Loss: Volume, Intensity, and Mode John M. Jakicic and Renee J. Rogers
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24 Modifying Sedentary Behavior for the Prevention and Treatment of Obesity Bethany Barone Gibbs
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25 Preventing Weight Regain after Weight Loss Stephen D. Anton and Michael G. Perri
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26 Personalized and Precision Nutrition in the Management of Obesity: Can We Tailor the Treatment to the Patient? George Thom and Mike Lean
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Part 4 Medications in the Management of Obesity
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27 Drug-Associated Weight Gain and Clinical Alternatives Barbara Ameer and Michael A. Weintraub
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28 Mechanisms of Drug Action in Obesity M. Furkan Burak, Nawfal W. Istfan, and Caroline M. Apovian
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Contents ix 29 Metabolic Effects of Progressive Weight Loss Faidon Magkos
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30 Older Drugs Used to Manage Obesity: Sympathomimetics and Orlistat Frank L. Greenway and George A. Bray
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31 Serotonergic Drugs for Treating Obesity Mireille J. Serlie
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32 Antidiabetic Drugs That Reduce Weight and Are Cardioprotective Carolina M. Perdomo, Javier Escalada, and Gema Frühbeck
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33 Approved Combination Agents: Phentermine/Topiramate W. Timothy Garvey
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34 Approved Combination Agents: Naltrexone-Bupropion Igho J. Onakpoya and Carl J. Heneghan
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35 Drugs That Affect Body Weight: The Glucagon-Like Peptide-1 Agonists Randa Ghazal Asswad and John P.H. Wilding
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36 Hydrogels in the Treatment of Obesity Frank L. Greenway
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37 Dual and Triple-Action Peptides Thinzar Min and Stephen C. Bain
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38 Antiobesity Medications on the Horizon Sarah R. Barenbaum and Louis J. Aronne
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39 Treatments for Rare Forms of Genetic Obesity Joan C. Han, Nandini Basuray, and Andrea M. Haqq
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40 Special Issues in Using Medications in Children and Adolescents Jaime M. Moore, Stephen R. Daniels, and Claudia K. Fox
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41 Dietary Supplements and Weight Management Carol J. Haggans, Rebecca B. Costello, Leila G. Saldanha, Abby G. Ershow, and William T. Cefalu
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Part 5 Surgical Interventions for Obesity
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42 Historical Overview of Metabolic and Bariatric Surgery Henry Buchwald
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43 Overview: Current Metabolic Operations and Long-Term Outcomes Robert C. Ross, Vance L. Albaugh, Ali Aminian, and Philip R. Schauer
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4 4 Effects of Metabolic Surgery on Type 2 Diabetes Pia Roser, Ghassan Chamseddine, and Francesco Rubino
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45 Cardiovascular Outcomes in Metabolic Surgery Wen Hui Tan, Tammy Kindel, Steven Nissen, and Philip R. Schauer
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46 Effect of Bariatric Surgery on Cancer Justin C. Brown, Andrea M. Stroud, Priya A. Rajdev, and Bruce M. Wolfe
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x Contents 47 Bariatric Surgery in Pediatric Patients Sarah Ogle and Thomas Inge
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48 Other Bariatric Procedures: Nerve Stimulation, Gastric Balloons, Intestinal Liners, and Others Cullen F. Roberts, Colston Edgerton, and Scott A. Shikora
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Index 511
Preface Welcome to the fifth edition of the Handbook of Obesity. The first edition was published in 1998 with subsequent editions in 2004, 2010, and 2014. The intervening years have seen enormous progress in our understanding of the etiology of obesity as well as innovative approaches to its prevention and treatment. The previous editions of the Handbook of Obesity were edited by George A. Bray and Claude Bouchard both of whom are subject to the laws of biology. For this reason, we invited four colleagues from the Pennington Biomedical Research Center to join us as Associate Editors in selecting and editing chapters for the two volumes that make up the 5th edition. We are thus pleased to publish this update of the Handbook of Obesity in the form of two coordinated and comprehensive volumes. Shortly after the first edition, translational research took hold, and it became evident that the “therapeutic” strategies for the treatment of obesity would need more space, and this was accomplished by splitting the 2nd edition into two volumes. Subsequently, the therapeutic volume was updated and published separately without the basic science volume. Between the publication of the last edition in 2014 and today, the growth of the science underlying the increase in the prevalence of obesity and the emphasis on translational research led to the need for a new edition of each volume with a high number of new authors and completely renewed content. During the 2 years that it took from inception to completion of this work, we have been confronted with the SARS-CoV-2 pandemic. Obesity is a risk factor for COVID-19. This pandemic even affected the Handbook of Obesity in other ways too. Several of the editors
have been infected along with many of the authors, and one author, Dr. David Haslam, even succumbed to COVID-19 before the publication was released by the publisher. In brief, Volume 1 covers the Epidemiology, Etiology, and Physiopathology of Obesity, and Volume 2 covers the Clinical Applications associated with the translation of basic science into treatment strategies for obesity. Mechanistic studies relevant to the regulation of energy balance have become increasingly powerful with the incorporation of genomic sequencing, multi-omics, computational biology, and bioinformatics. Many drugs that were available in 1998 are no longer available, and new and more potent ones have come on the market. With these two volumes, we believe that the reader has access to the latest research and clinical practice in the field. We are indebted to the authors for maintaining a tight writing schedule so that all chapters would appear in a reasonably short time after submission. We are also deeply indebted to Ms. Melanie Peterson for her tireless hard work as the Editorial Assistant for this publication. She has made extensive editorial suggestions and has facilitated the editing of chapters in a timely fashion. Without her diligent and continuing support this book might never have seen the light of day—thank you from the bottom of our hearts. We also thank the publisher, especially Ms. Shivangi Pramanik, Commissioning Editor at CRC Press of the Taylor & Francis Group, and her staff for helping us move this book from manuscript to the published Handbook of Obesity rapidly. Their timely help has allowed us to get the book assembled during the COVID-19 pandemic.
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About the Editors George A. Bray, MD, MACP, MACE is recognized for his research in obesity and is among the 1,000 most cited scientists. In 1989 he became the first Executive Director of the Pennington Biomedical Research Center of LSU in Baton Rouge, Louisiana, and is now a Boyd Professor Emeritus. He was a Principal Investigator for the Diabetes Prevention Program Study and the Look AHEAD study, two multicenter NIH-funded trials. He is a member of many professional societies, including the Obesity Society. In 1977 he co-founded the International Journal of Obesity. In 1982 he founded the North American Association for the Study of Obesity (now the Obesity Society), and in 1993 its journal Obesity, and he was a founding editor of Endocrine Practice in 1995. Dr. Bray has received the Goldberger Award from the American Medical Association, was elected to the Society of Scholars at Johns Hopkins University, and received the Osborne–Mendel Award from the American Society for Nutrition, the McCollum Award from the American Society of Clinical Nutrition, the Mead–Johnson Award, the Tops Award, Stunkard Award, the Presidential Medal from the Obesity Society and in 2019, the W.O. Atwater Award from the USDA and the American Society for Nutrition.
Claude Bouchard, PhD is Boyd Professor Emeritus at Pennington Biomedical Research Center. He served as the Executive Director of the Pennington Center for a decade and was the director of the Human Genomics Laboratory of the Center for 20 years. His research deals with the genetics of adaptation to exercise and nutritional challenges, as well as the genetics of obesity and its comorbidities. He is a Past President of The Obesity Society and of the International Society for the Study of Obesity. He has authored or coauthored more than 1,000 scientific papers and has written or edited 35 books. He has been a foreign member of the Royal Academy of Medicine of Belgium since 1996. He became an Officer of the Order of Leopold II of Belgium in 1994, a member of the Order of Canada in 2001, and a Chevalier in the Ordre National du Quebec in 2005. Dr. Bouchard has received seven Honoris Causa Doctorates. Early in his career, from 1965 to 1999, he was on the Kinesiology Faculty at Laval University, Quebec City, and he was made a Professor Emeritus, Faculty of Medicine, upon his retirement. He is a Fellow of the American Association for the Advancement of Science and six other scientific societies.
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Associate Editors Peter T. Katzmarzyk, PhD, FACSM, FTOS, FAHA is Professor and Associate Executive Director for Population and Public Health Sciences at the Pennington Biomedical Research Center where he holds the Marie Edana Corcoran Endowed Chair in Pediatric Obesity and Diabetes. Dr. Katzmarzyk is an internationally recognized leader in the field of physical activity and obesity, with a special emphasis on pediatrics and ethnic health disparities. He has over two decades of experience in conducting large clinical and population-based studies in children and adults. Dr. Katzmarzyk has a special interest in global health and has a record of building research capacity in physical activity and obesity research in developing countries. He has published his research in more than 625 scholarly journals and books and has delivered over 235 invited lectures in 16 countries. He is Associate Editor-in-Chief for Medicine and Science in Sports and Exercise, Associate Editor for the American Journal of Human Biology, and an editorial board member for Metabolic Syndrome and Related Disorders and Pediatric Exercise Science. Dr. Katzmarzyk served on the 2018 U.S. Physical Activity Guidelines Advisory Committee for the U.S. Department of Health and Human Services and the World Health Organization Guideline Development Group for the WHO 2020 Guidelines on Physical Activity and Sedentary Behaviour. John P. Kirwan, PhD is the Executive Director of the Pennington Biomedical Research Center and holds the George A. Bray, Jr. Endowed Super Chair in Nutrition. He also leads the Integrated Physiology and Molecular Metabolism Laboratory at Pennington Biomedical and is the Director/ Principal Investigator of the Louisiana Clinical and Translational Science Center.
His professional expertise includes over 30 years of research, teaching, and service in the obesity and diabetes fields. He received his clinical physiology training at Washington University School of Medicine in St. Louis, Missouri, his PhD in Human Bioenergetics at Ball State University, Muncie, Indiana, his MSc in Exercise Biochemistry from the University of Massachusetts, Amherst, Massachusetts, and his BA (Hons) from the University of Limerick, Republic of Ireland. Dr. Kirwan leads an internationally acclaimed biomedical research program focused on diabetes, obesity, nutrition, and exercise. To date, he has generated more than $60 million in research funding, most of which has come from NIH and the food, pharmaceutical, and medical device industries. He has published more than 275 scientific papers related to diabetes and metabolism in prestigious peer-reviewed journals, including the New England Journal of Medicine, JAMA, Diabetes and Diabetes Care. Leanne M. Redman, PhD is a Professor in the Division of Clinical Sciences and Associate Executive Director for Scientific Education at Pennington Biomedical Research Center in Baton Rouge, Louisiana. Her expertise is in human physiology as it relates to the quantification of energy balance, in both controlled and free-living conditions in humans. Her research is conducted with the goal to understand the mechanisms of body weight regulation to promote healthy aging across the lifespan, as well as to develop and test interventions for effective prevention and treatment of obesity and its comorbidities. Dr. Redman directs the Reproductive Endocrinology and Women’s Health Laboratory. The lab conducts extramurally funded studies in pregnant women (and their infants) and women with infertility with the goal to understand the impact of obesity and metabolic health on women and obesity risk in offspring. Dr. Redman is also involved in the scientific development, training, and mentoring of postdoctoral fellows and early career investigators. She has published more than 200 research articles, reviews, and book chapters around energy metabolism, insulin sensitivity, obesity, calorie restriction, exercise, and maternal/infant physiology.
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xvi Associate Editors Philip R. Schauer, MD is the United Companies Life Insurance Co./Mary Kay and Terrell Brown endowed Professor of Metabolic Surgery at Pennington Biomedical Research Center of Louisiana State University in Baton Rouge, Louisiana. He is also the Director of the MetamorTM Metabolic Institute at Pennington Biomedical. He is past president of the American Society for Metabolic & Bariatric Surgery. He is the former
Chair and founder of Obesity Week. Dr. Schauer’s clinical interests include obesity, diabetes, and metabolic surgery. He has performed more than 8,000 operations for severe obesity and diabetes and has trained more than 100 fellows in metabolic surgery. His research interests include the pathophysiology of obesity and type 2 diabetes, and outcomes of metabolic surgery. He has an H-index of 90 and has published more than 400 peer-reviewed articles in high-impact journals such as New England Journal of Medicine, Nature, JAMA, Lancet, Journal of the American College of Cardiology, Diabetes Care, Annals of Surgery, and others. He is the Principal Investigator of the STAMPEDE trial which showed that surgery can put type 2 diabetes into long-term remission.
Contributors Daniel G. Aaron Heyman Fellow at Harvard Law School Food and Drug Administration The Justice Initiative Cambridge, Massachusetts Vance L. Albaugh Metamor Institute Pennington Biomedical Research Center Baton Rouge, Louisiana Barbara Ameer Rutgers – Robert Wood Johnson Medical School New Brunswick, New Jersey Ali Aminian Cleveland Clinic Cleveland, Ohio Jaithri Ananthapavan Institute for Health Transformation Deakin Health Economics & Global Obesity Centre Deakin University Geelong, Australia Peter Andrews Natural History Museum London, United Kingdom Chika Vera Anekwe Massachusetts General Hospital Department of Medicine – Division of Endocrinology and Harvard Medical School Boston, Massachusetts Donato Angelino Faculty of Bioscience and Technology for Food, Agriculture and Environment University of Teramo Teramo, Italy Stephen D. Anton Department of Aging and Geriatric Research University of Florida Gainesville, Florida
Caroline M. Apovian Division of Endocrinology, Diabetes, and Hypertension Brigham & Women’s Hospital and Harvard Medical School Boston, Massachusetts Gabriela Argumedo National Institute of Public Health Center for Nutrition and Health Research Cuernavaca, Mexico Louis J. Aronne Comprehensive Weight Control Center Division of Endocrinology, Diabetes, & Metabolism New York, New York Elva Arredondo Department of Psychology College of Sciences San Diego State University San Diego, California Stephen C. Bain Department of Diabetes and Endocrinology, Singleton Hospital Swansea Bay University Health Board Swansea, United Kingdom Sarah R. Barenbaum Weill Cornell Medicine Comprehensive Weight Control Center Division of Endocrinology, Diabetes & Metabolism New York, New York Simon Barquera National Institute of Public Health Center for Nutrition and Health Research Cuernavaca, Mexico Nandini Basuray Department of Agricultural, Food, and Nutritional Science University of Alberta Edmonton, Canada Carolina Batis National Institute of Public Health Center for Nutrition and Health Research Cuernavaca, Mexico
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xviii Contributors Louise Baur Boden Initiative, Charles Perkins Centre University of Sydney and Specialty of Child and Adolescent Health Sydney Medical School University of Sydney Sydney, Australia and The Children’s Hospital at Westmead Westmead, Australia
André C. Carpentier Centre de recherche du Centre hospitalier universitaire de Sherbrooke Université de Sherbrooke Sherbrooke, Canada
Adam Biener Department of Economics Lafayette College Easton, Pennsylvania
William T. Cefalu National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland
George A. Bray Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana Justin C. Brown Pennington Biomedical Research Center Baton Rouge, Louisiana and LSU Health Sciences Center New Orleans School of Medicine and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center New Orleans, Louisiana Victoria Brown Institute for Health Transformation Deakin Health Economics & Global Obesity Centre Deakin University Geelong, Australia Stephanie T. Broyles Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana Henry Buchwald University of Minnesota Medical School Department of Surgery Minneapolis, Minnesota M. Furkan Burak Department of Molecular Metabolism Harvard T.H. Chan School of Public Health Boston, Massachusetts
John Cawley Brooks School of Public Policy and Department of Economics Cornell University Ithaca, New York
Catherine M. Champagne Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana Ghassan Chamseddine Department of Metabolic and Bariatric Surgery Diabetes and Nutritional Sciences Division Kings College, London and Kings College Hospital London, United Kingdom Rebecca B. Costello Office of Dietary Supplements National Institutes of Health Bethesda, Maryland Noe C. Crespo College of Health and Human Sciences San Diego State University San Diego, California Stephen R. Daniels University of Colorado School of Medicine Children’s Hospital Colorado Aurora, Colorado Jean-Pierre Després VITAM – Centre de recherche en santé durable Université Laval Québec City, Canada William Dietz Milken Institute School of Public Health George Washington University Washington, DC
Contributors xix Monica Dinu Department of Experimental and Clinical Medicine University of Florence Florence, Italy Patricia Dionicio Department of Psychology San Diego State University San Diego, California Colston Edgerton Novant Health New Hanover Regional Medical Center Wilmington, North Carolina Abby G. Ershow Office of Dietary Supplements National Institutes of Health Bethesda, Maryland Javier Escalada Department of Endocrinology and Nutrition IdiSNA (Instituto de Investigación Sanitaria de Navarra) Pamplona, Spain and CIBEROBN (CIBER Fisiopatología de la Obesidad y Nutrición) Instituto de Salud Carlos III Madrid, Spain I. Sadaf Farooqi University of Cambridge Metabolic Research Laboratories Addenbrooke’s Hospital Cambridge, United Kingdom Claudia K. Fox Department of Pediatrics University of Minnesota Medical School Minneapolis, Minnesota Gema Frühbeck Department of Endocrinology and Nutrition IdiSNA (Instituto de Investigación Sanitaria de Navarra) Pamplona, Spain and CIBEROBN (CIBER Fisiopatología de la Obesidad y Nutrición) Instituto de Salud Carlos III Madrid, Spain Christine Gallagher Milken Institute School of Public Health George Washington University Washington, DC
W. Timothy Garvey Department of Nutrition Sciences and the UAB Diabetes Research Center University of Alabama at Birmingham Birmingham, Alabama Randa Ghazal Asswad Department of Diabetes and Endocrinology University of Liverpool Liverpool, United Kingdom Bethany Barone Gibbs Department of Epidemiology and Biostatistics West Virginia University Morgantown, West Virginia Frank L. Greenway Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana Nikko R. Gutierrez Salk Institute for Biological Studies Regulatory Biology Laboratory La Jolla, California Carol J. Haggans Office of Dietary Supplements National Institutes of Health Bethesda, Maryland Kevin D. Hall National Institute of Diabetes, Digestive, and Kidney Diseases Bethesda, Maryland Joan C. Han Department of Pediatrics Icahn School of Medicine at Mount Sinai New York, New York Andrea M. Haqq Department of Agricultural, Food, and Nutritional Science University of Alberta Edmonton, Canada Carl J. Heneghan Nuffield Department of Primary Care Health Sciences University of Oxford Oxford, United Kingdom
xx Contributors Christoph Höchsmann Pennington Biomedical Research Center Baton Rouge, Louisiana and Department of Sport and Health Sciences Technical University of Munich Munich, Germany Thomas Inge Lurie Children’s Hospital of Chicago Northwestern University School of Medicine Chicago, Illinois Nawfal W. Istfan Division of Endocrinology, Diabetes, and Hypertension Brigham & Women’s Hospital and Harvard Medical School Boston, Massachusetts John M. Jakicic Department of Internal Medicine University of Kansas Medical Center Kansas City, Kansas Veronica R. Johnson Northwestern Feinberg School of Medicine Chicago, Illinois Richard Johnson Division of Renal Diseases and Hypertension University of Colorado Anschutz Medical Campus Aurora, Colorado Peter T. Katzmarzyk Pennington Biomedical Research Center Baton Rouge, Louisiana Maura M. Kepper Prevention Research Center Washington University in St. Louis St. Louis, Missouri Tammy Kindel Department of Surgery Medical College of Wisconsin Milwaukee, Wisconsin Robert F. Kushner Departments of Medicine and Medical Education Northwestern University Feinberg School of Medicine Chicago, Illinois Mike Lean School of Medicine, Dentistry, and Nursing University of Glasgow Glasgow, Scotland
Tim Lobstein World Obesity Federation London, United Kingdom and Charles Perkins Centre University of Sydney Sydney, Australia and Centre for Health Economics & Policy Innovation Imperial College London, United Kingdom Faidon Magkos Department of Nutrition, Exercise, and Sports (NEXS) University of Copenhagen Copenhagen, Denmark Emily N. C. Manoogian Salk Institute for Biological Studies Regulatory Biology Laboratory La Jolla, California Corby K. Martin Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana Daniela Martini Department of Food, Environmental, and Nutritional Sciences (DeFENS) University of Milan Milan, Italy Chad Meyerhoefer Department of Economics Lehigh University Bethlehem, Pennsylvania Thinzar Min Department of Diabetes and Endocrinology, Neath Port Talbot Hospital Swansea Bay University Health Board Swansea, United Kingdom Marj Moodie Deakin Health Economics & Global Obesity Centre Deakin University Geelong, Australia Jaime M. Moore Department of Pediatrics University of Colorado School of Medicine Aurora, Colorado
Contributors xxi Ian J. Neeland University Hospitals Harrington Heart and Vascular Institute Case Western Reserve University Cleveland, Ohio Robert L. Newton, Jr. Population and Public Health Pennington Biomedical Research Center Baton Rouge, Louisiana Steven Nissen Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio Sarah Ogle Children’s Hospital Colorado University of Colorado Denver, Colorado Igho J. Onakpoya Department for Continuing Education University of Oxford Oxford, United Kingdom Stephen O’Rahilly University of Cambridge Metabolic Research Laboratories Institute of Metabolic Science Cambridge, United Kingdom Erika Padilla Division of Cardiovascular Medicine University of California San Diego La Jolla, California Carolina M. Perdomo Department of Endocrinology and Nutrition Clínica Universidad de Navarra Pamplona, Spain Michael G. Perri Department of Clinical and Health Psychology University of Florida Gainesville, Florida Suzanne Phelan Center for Health Research California Polytechnic State University San Luis Obispo, California Paul Poirier Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval Faculty Université Laval Québec City, Canada
Herman Pontzer Department of Evolutionary Anthropology & Duke Global Health Institute Duke University Durham, North Carolina Marisa Porrini Department of Food, Environmental, and Nutritional Sciences (DeFENS) University of Milan Milan, Italy Priya A. Rajdev Department of Surgery University of Arizona School of Medicine Phoenix, Arizona Juan Rivera-Dommarco National Institute of Public Health Center for Nutrition and Health Research Cuernavaca, Mexico Cullen F. Roberts Department of Surgery Brigham and Women’s Hospital Boston, Massachusetts Renee J. Rogers Professional Consultant Pittsburgh, Pennsylvania Barbara J. Rolls Department of Nutritional Sciences The Pennsylvania State University University Park, Pennsylvania Pia Roser Department of Endocrinology and Diabetes University Medical Center Hamburg-Eppendorf Hamburg, Germany Robert C. Ross Translational and Integrative Gastrointestinal and Endocrine Research Lab Pennington Biomedical Research Center Baton Rouge, Louisiana Francesco Rubino Department of Metabolic and Bariatric Surgery Kings College Hospital London, United Kingdom Donna H. Ryan Pennington Biomedical Research Center Baton Rouge, Louisiana
xxii Contributors Leila G. Saldanha Office of Dietary Supplements National Institutes of Health Bethesda, Maryland Philip R. Schauer Metamor Institute Pennington Biomedical Research Center Baton Rouge, Louisiana Mauro Serafini Faculty of Bioscience and Technology for Food, Agriculture, and Environment University of Teramo Teramo, Italy Mireille J. Serlie Department of Endocrinology and Metabolism University of Amsterdam Amsterdam, the Netherlands Scott A. Shikora Professor of Surgery Harvard Medical School and Center for Metabolic and Bariatric Surgery Brigham and Women’s Hospital Boston, Massachusetts Francesco Sofi Department of Experimental and Clinical Medicine University of Florence Florence, Italy Fatima Cody Stanford Department of Pediatrics – Division of Endocrinology Harvard Medical School Boston, Massachusetts Andrea M. Stroud Department of Surgery Oregon Health & Science University Portland, Oregon Wen Hui Tan Department of Surgery Medical College of Wisconsin Milwaukee, Wisconsin George Thom School of Medicine Dentistry and Nursing University of Glasgow Glasgow, Scotland Matthew J. Townsend Duke University Medical Center Durham, North Carolina
Jena S. Tronieri Department of Psychiatry Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Amanda Velazquez Departments of Medicine and Surgery Director of Obesity Medicine Cedars-Sinai Los Angeles, California Thomas A. Wadden Department of Psychiatry Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Michael A. Weintraub New York Presbyterian Hospital Weill Cornell Medical Center New York, New York Sean Wharton The Wharton Medical Clinic Toronto, Canada Mariel White National Institute of Public Health Center for Nutrition and Health Research Cuernavaca, Mexico John P. H. Wilding Department of Diabetes and Endocrinology Liverpool University Hospitals NHS Foundation Trust and Department of Metabolic and Cardiovascular Medicine University of Liverpool Liverpool, United Kingdom Michael J. Wilkinson Division of Cardiovascular Medicine University of California San Diego La Jolla, California Bruce M. Wolfe Department of Surgery Oregon Health & Science University Portland, Oregon Faris M. Zuraikat Department of Medicine Columbia University Irving Medical Center New York, New York
Introduction to Volume 2 We are happy to introduce the 5th Edition of the Handbook of Obesity. Volume 2 focuses on clinical applications for evaluation, diagnosis, prevention and treatment of obesity. Since the last edition of this volume on Clinical Applications, there have been several major developments. First, the SARS-CoV-2 pandemic has shown that people with obesity are at greater risk for serious outcomes from infection with this virus, emphasizing the need to offer effective treatment to as many people as possible. Second, two major American clinical trials, the Diabetes Prevention Program and the Action for Health in Diabetes (Look AHEAD) study, which were highlighted in the last edition have been extended to focus on the concept of “Precision Medicine” with the possibility that treatments can be further individualized. Third, several medications that were available when this volume on Clinical Applications was last published in 2014 have been withdrawn due to potential cardiovascular risks. The good news is that newer agents have received approval from the US Food and Drug Administration and can now offer patients with obesity weight loss of 15 to 20% or more which approaches that compare with the weight loss commonly achieved by bariatric/metabolic surgery. The expansion of this area of research has led to splitting an earlier section into 2 parts, one dealing with lifestyle including diet, behavioral change strategies and exercise, and the other dealing with the expanding pharmaceutical options available for management of obesity. Finally, the clear-cut health benefits of significant weight loss on mortality, myocardial infarction, diabetes mellitus, stroke and cancer have been revealed by the careful analysis of patients treated surgically for their obesity. We are thus at the dawn of a new era in the understanding of the clinical effects of weight loss on health and human well-being.
PART 1: PREVENTION AND ECONOMIC OUTCOMES OF OBESITY The high prevalence of obesity that was documented in Volume 1 of the Handbook poses a major threat to the health care systems of many countries. Thus, there is a real need to develop effective preventive strategies. This section opens with two chapters that explore insights from evolution on changes in diet and physical activity, and the implications for the prevention of obesity. The results of efforts to prevent obesity in adults and children are also reviewed in two separate chapters in Part 1. To date, there are promising results, but there is clearly a need for more research. One such strategy discussed in the chapter
is re-engineering the environment to make it easier to obtain the physical activity level needed to help keep body weight down and improve health. The health care costs associated with obesity and the cost-effectiveness of obesity prevention and treatment are the subjects of the final two chapters in this Part of Volume 2.
PART 2: EVALUATION OF THE PATIENTS WITH OVERWEIGHT OR OBESITY Evaluation of patients who are overweight or obese is the first requirement in developing a plan of therapy. Approaches to classifying obesity and how to use this information to evaluate patients with obesity are developed in the first chapter. The importance of central adiposity, including waist circumference or girth, one of the commonly used measurements in assessing the overweight individual, is examined in the next chapter. This is followed by a cogent discussion of the genetic and metabolic syndromes that have obesity as a major component. The argument is put forth that weight loss is valuable because it will prolong life and its quality. The final chapter in this section is new and addresses ethnic and racial considerations in evaluating patients with obesity.
PART 3: LIFESTYLE IN THE MANAGEMENT OF OBESITY: BEHAVIORAL MODIFICATION, DIET, AND EXERCISE Behavioral management of obesity has been a cornerstone of clinical treatment for over 40 years. The current state of practice with behavioral therapy is reviewed in the first chapter and is followed by newer approaches through e-health, with considerations for personalizing treatment for different ethnicities and individual characteristics or phenotypes. Just as important as weight loss is maintaining the weight loss once it has been achieved. The area of “weight maintenance” has drawn a great deal of attention in recent years, and a chapter is devoted to this important topic. Diet, dietary composition, and meal timing are major elements in treatment strategies. Low calorie diets and other dietary approaches, along with strategies to xxiii
xxiv Introduction to Volume 2 reduce sedentary time and increase physical activity are other key components of weight loss and weight loss maintenance strategies and are discussed in three separate chapters.
PART 4: MEDICATIONS IN THE MANAGEMENT OF OBESITY Medications can cause weight gain as well as weight loss. From the point of view of clinical applications of basic science, selecting drugs for overweight patients that cause weight loss or that are weight neutral is a primary responsibility for the primary care physician. To this end, one chapter discusses the drugs which produce weight gain and provides a glimpse into alternatives that are often available. This is followed by a series of chapters discussing various classes of drugs, including the sympathomimetics, the drugs that alter fat absorption, a new drug that acts on serotonin receptors in the brain, and the glucagon-like peptide-1 agonists. In addition, there are two chapters focusing on combinations of two drugs that produce weight loss. Herbal agents that have been claimed by some to have effects in lowering body weight and the studies supporting the various herbal products are reviewed, giving this chapter importance to the practicing physician. Children often present unique therapeutic challenges, and there is an entire chapter devoted to treatment of obesity in pediatric populations. Genetic diseases that cause obesity often manifest in childhood and make genetic targets attractive as ways to treatment of their obesity. The final chapter looks at the role of drugs in treating the dyslipidemias that occur with excess body weight.
PART 5: SURGICAL INTERVENTIONS FOR OBESITY Improvements in bariatric surgery and longer-term followup of surgical patients have revolutionized the field of bariatric/metabolic surgery. The historical background for the development of bariatric and metabolic surgery starts off this section. This is followed by a review of surgical procedures that are available. Bariatric surgical treatment reduces mortality, risk of myocardial infarction, stroke, cancer, the incidence of new cases of diabetes and in many cases will reverse existing diabetes and these are discussed in 2 chapters. Bariatric/metabolic surgery is being done ever more often in adolescents and this subject is covered in one chapter. Finally, this section ends with a description of other surgical techniques including electric stimulation of the vagus nerve, gastric balloons, intestinal liners, and liposuction, a plastic surgical technique used for remodeling the subcutaneous fat. We, the editors, hope that you will find the information about the management of obesity that you want in this volume of the Handbook of Obesity. George A. Bray, MD Claude Bouchard, PhD Editors Peter T. Katzmarzyk, PhD John P. Kirwan, PhD Leanne M. Redman, PhD Philip R. Schauer, MD Associate Editors September 12, 2022
PART 1
Prevention and Economic Outcomes of Obesity
Dietary Changes in Human Evolution Implications for the Prevention of Obesity
1
Peter Andrews and Richard Johnson
1.1 EVOLUTION, OBESITY, AND SURVIVAL Since the initiation of the Phanerozoic Eon, there has been a wide evolutionary diversification of species, with the greatest taxonomic diversity in the multi-canopied forests at the equator where the greatest resources provide the highest nutritional energy in the world (sometimes referred to as the gross primary productivity or GPP). While the presence of nutritional energy has a critical role in evolution, other factors such as climate change and habitat heterogeneity can also have major effects on evolutionary rate and change, and can be associated with classic ecogeographic rules [1]. In general, animal size and biovolume have increased by more than two orders of magnitude over time, where it correlates more with improved oxygen delivery than food availability [2]. Other factors are also important in driving evolution and species diversity, including solar radiation, the percentage of greenhouse gasses, and even subtle changes in climate that can affect food availability, especially in seasonal ecosystems [3–5]. An example of an evolutionary response to environmental pressures relates to the change in dentition of herbivorous mammals during a period of global cooling that occurred during the Miocene. During this period the replacement of the Miocene forests by savannas (in Africa) and steppe environments (in Asia) resulted in changes in availability of edible plants. Large herbivores have crenulated tooth crowns for breaking down tough plant material, and the tougher the food the more quickly their teeth wear down. In response to changing habitats, larger teeth were selected during the evolutionary past of such species, and in particular tooth heights increased. DOI: 10.1201/9781003432807-2
This is known as hypsodonty, and the higher the crown (more hypsodont) the longer the life of the tooth [6]. Over the past 10–15 million years, hypsodonty in the teeth of many large herbivores has increased in response to increasingly tough food items, which are thought to reflect climatic-linked changes in the environment [7]. The ability to store fat also has a critical role in the evolution and survival of species. For animals in the wild, fat is often desired, as it can provide both a source of energy and metabolic water when food and water are unavailable [8]. While most animals in nature tightly regulate their weight to maintain a percentage of body fat that can provide some protection in the event of unexpected food or water shortage, other animals will purposely develop transient obesity, often with features of metabolic syndrome, as a mechanism to aid survival during limited periods of food shortage. Animals hibernating during severe winters, or those that estivate during the dry season, need fat stores to survive; similarly, bird species that undergo long-distance migration, or nesting birds, also require fat reserves to cover these periods of activity [9]. Other animals carry high percentages of body fat most of the time. Desert rodents often store large amounts of fat in their tails, while camels have humps of fat that provide metabolic water [8]. Likewise, marine mammals also carry large amounts of fat to provide metabolic water in addition to insulation from the cold ocean waters [10]. Today obesity is widespread in many human populations, and it is also observed in domesticated animals and animals kept in zoos. Often obesity is attributed to overeating coupled with sedentary behavior; however, obesity has much more complex origins, and our contention is that much more can be gleaned from studies of nature and human evolution and their interactions with environmental change and changes in 3
4 Handbook of Obesity nutrition. Recognizing that in nature the presence of obesity may represent a survival response can provide key insights into the pathogenesis of obesity today [11].
1.2.1 Fossil Apes and Human Ancestors
left in Europe and few in Asia. Other species also suffered, and it is estimated that nearly 30% of all species became extinct during the “mid-Miocene disruption” (Figure 1.2). Nevertheless, there is evidence that not all of the fossil apes in Eurasia became extinct. Indeed, fossil apes from Turkey and Pakistan during this period (16–10 Ma) shared characteristics with the orangutan, suggesting they may have migrated to Asia to evolve into the modern orangutan [14, 15]. While fossil evidence is more limited, there is also some evidence that European fossil apes made the return journey to Africa, becoming the ancestors of the living African ape [16, 17]. One candidate is Kenyapithecus, for the earliest fossil evidence is from Paşalar, Turkey, which predates the presence of Kenyapithecus in Africa by two million years [18, 19]. Since the orangutan and the African apes share a common ancestor [20], it is possible that the common ancestor of the great ape and human clade may have originated in Eurasia. The global cooling in the mid-Miocene was associated with the transition of our ancestors from frugivorous primates living in trees to apes that spent much time on the ground and had to diversify their diet (Figure 1.2). It is perhaps not surprising that this period correlates with a time of rapid evolutionary change in the hominin genome [21]. Among the various genetic changes was a mutation in a gene called uricase, a liver enzyme that degrades uric acid. Studies show that uricase activity decreased stepwise in the great ape and human clade due to a series of mutations that involved the promoter region, only to end in the gene being
The earliest fossil apes lived in the tropical forest canopy and subsisted primarily on fruit (Figure 1.1). These early ape species were extremely successful and within a few million years had diversified to numerous species, genera, and families. Beginning around 18 to 17 Ma, the climate became cooler, linked with an increase in ice in the Antarctic, and with falling sea levels, the island continent of Africa, which had been separate from Eurasia since the break-up of Gondwana, became connected by land bridges to Europe and Asia. Numerous species, including fossil apes, spread into Eurasia across the land bridge. While initially there were relatively minimal changes in habitat in Africa, the progressive cooling led to contraction of the tropical rainforests, replaced by seasonal deciduous woodlands. In Eurasia, subtropical and temperate regions had highly seasonal climates, with colder temperatures in Europe during the winter season and prolonged dry periods in tropical Africa [3]. The change in climate reduced fruit availability, and several groups of fossil apes acquired adaptations for life on the ground. Survival, especially in Eurasia, was challenging, and many apes showed evidence of starvation (such as the presence of dental linear enamel hypoplasia). During this period there were many adaptations to facilitate survival, including changes in the axial skeleton associated with knuckle walking and adaptations in dentition for eating harder foods, such as tubers and roots, to replace the dwindling fruit supplies [6]. Despite these adaptations, the progressive cooling led to progressive extinctions in Europe, and by 8 Ma there were no apes
FIGURE 1.1 Proconsul skeleton showing its quadrupedal form. Early Miocene apes looked nothing like the apes of today, but had long, curved backs and a narrow thorax. In these respects, apes like Proconsul shared major skeletal adaptations with arboreal monkeys and their behaviour and way of life would have been entirely monkey-like. Monkeys today and in the past are an evolutionarily successful group occupying mainly tropical forests and woodlands, and their success in part is due to the evolution of adaptations of their digestive systems that allowed them primary access to the fruits that they and early apes depended on [20]. Apes were to a certain extent marginalized in their shared habitats as a result, and they could not maintain their monkey-like life in trees, becoming more terrestrial and thus able to emigrate out of Africa [17]. They adapted in the process the more upright, broad thorax morphologies ancestral to the living great apes.
1.2 HUMAN EVOLUTION AND ITS RELATIONSHIP WITH NUTRITION The earliest fossil evidence for primates has been dated to about 55 million years ago (Ma), but genetic evidence suggests that primates first evolved during the Cretaceous Period 80 to 70 Ma [12]. A major advancement was the divergence of apes from monkeys that occurred at least 25 Ma in the African tropical rain forest. It has been known since the times of Linnaeus, Darwin, and Huxley that among these apes was a common ancestor for not only humans but also the living great apes (including chimpanzees, gorillas, and orangutans), and today, this has been recognized at the genetic level [13]. They provide means of comparisons both of living apes with humans and fossil apes with both [14].
1 • Dietary Changes in Human Evolution 5
Key periods in human evolution 200-450kyr
Periods of dietary and/or climate change
1Ma700kyr 1.8Ma 2.5-3Ma 6Ma 12-15Ma
~30Ma
Homo sapiens, Neanderthals, Denisovans, African populations
Homo erectus, enter savanna, fire, exit Africa, brain size increase, meat-eating Homo habilis, stone tool technology, more meat
Chimpanzee-human divergence
16Ma 25Ma
Anatomically modern Homo sapiens, art, writing
Great ape and human divergence, uricase mutation Emigration of apes out of Africa, woodland, semi-terrestrial, frugivorous Early Miocene apes, Africa only, forest-living, arboreal, frugivorous
Monkey-ape divergence
FIGURE 1.2 Ape and human clades. From bottom left: divergence of monkeys and apes; early Miocene apes were living in African forests, and were arboreal and frugivorous; at or before 16 Ma, a land bridge formed connecting Africa to the Middle East, and at the same time apes moved from tropical evergreen forest habitats to seasonal woodland, becoming partly terrestrial but still eating fruit; this was the mid-Miocene environmental crisis; the common ancestor of great apes and humans, 15–12 Ma, is identified by the earliest fossils with the first species to branch off, fossil apes with apparent orangutan characters; all great apes and humans shared the mutation of the uricase gene, so the mutation must have preceded the branching of the orangutan; the human-chimpanzee common ancestor lived about 6 Ma, identified by DNA divergence data, and both ancestral apes and early hominins were still mainly arboreal and eating fruit, as in the earlier apes; Homo habilis at 3 to 2 Ma, had started eating meat, used stone tool technology, and had become mainly bipedal; Homo erectus was the first hominin to leave the woodlands for open savanna, at or soon after 2 Ma; it had complex societies, was fully bipedal and lived on the ground and probably had acquired the use of fire. Genetic evidence for the split of Homo sapiens from other hominins is dated to 600,000 years ago and did not move to Europe until much later.
completely silenced around 15 Ma, shortly before the separation of the orangutan from the African ape and human clade [22]. Evidence that this mutation may have provided a selective advantage is suggested by the finding that a parallel mutation in uricase occurred in the Lesser Ape lineage a few million years later [23]. A natural question is what was the benefit of the uricase mutation. The primary effect would have been to raise uric acid levels, and studies in existent great apes as well as individuals on a hunter-gatherer diet suggest that the uricase mutation probably doubled levels of serum uric acid, from a level of approximately 1–2 mg/dl to approximately 3–4 mg/dl [24]. We have suggested that the main evolutionary advantage of the higher level of serum uric acid from this mutation was that the increase aided animals to gain fat and develop insulin resistance [25]. There is also some evidence that the mutation could have provided survival benefit by reducing oxidative stress, as uric acid can function as an antioxidant [26]. The basis of the argument relates to a recently discovered role for uric acid in how ingestion of fructose causes metabolic syndrome. Specifically, fructose has been shown to be a nutrient that uniquely activates a survival pathway that stimulates foraging, hunger, fat storage, elevations in blood pressure, and insulin resistance. The mechanism relates to the ability of fructose to lower energy (adenosine triphosphate or ATP) levels in the liver followed by the degradation of adenine nucleotides to uric acid [27]. The uric acid plays a role in this biologic response by paradoxically causing oxidative stress to the mitochondria while at the same time inhibiting AMP-activated
protein kinase [28, 29]. In this scenario, inhibiting uricase leads to a greater uric acid response to fructose than observed in normal rats, and this results in more fat accumulation and worse features of metabolic syndrome [30]. Similarly, we can demonstrate a greater production of fat in human liver cells in which the ancestral uricase is silenced compared to when it is present [22]. Given these observations, we have suggested that the uricase mutation most likely occurred in Europe or Turkey since it occurred before the split of the ancestors of the orangutan, humans, and African apes [25]. By amplifying the effects of fructose to stimulate the storage of fat, the mutation would have provided a survival advantage for the apes that were starving from a loss of fruit availability. The spread of the mutation would have been enhanced by the small and geographically isolated ape populations in Europe, which as the climate deteriorated, placed increased stress on the surviving populations as they retreated more and more into refuge areas [31]. Uric acid is also generated from eating umami-based foods where it may also drive fat storage and features of the metabolic syndrome [32]. This might facilitate omnivorous intake, such as scavenging meat or bone marrow from animal kills. At this stage of hominid evolution, millions of years before the first hominins are known, we do not believe that the significance of uricase mutation was that it resulted in obesity, but rather it helped defend against starvation by maximizing the effects of fructose and umami-based foods to generate fat. Many animals that survive hostile climates do so by putting on weight during times of plenty to see them through times of scarcity.
6 Handbook of Obesity Following the split of the orangutan and the African apes/ human ancestors around 15 to 12 Ma, it is thought that some of the apes returned to Africa. However, on their return they would have found a much dryer environment than when they left, in which obtaining sufficient food would have continued to be difficult. While it is likely that the uricase mutation provided continued benefit during this time, there is also evidence for another mutation that may have also provided additional survival advantage. Specifically, ripe fruit that had fallen on the ground and had started to ferment was not edible as the alcohol could not be digested easily. However, a mutation occurred in alcohol dehydrogenase-4 that resulted in a 40-fold improved ability to digest alcohol, and this allowed ingestion of ripe fruit where the remaining fructose could be used [33, 34]. In addition, the alcohol also stimulates additional fructose production in the liver by activating the enzyme aldose reductase [35]. Thus, both mutations in alcohol dehydrogense-4 and uricase likely had survival effects and allowed the early apes to maximize what fruits were available to enhance their fat stores (Figure 1.3) [33]. Towards the end of the Miocene, the apes and humans finally diverged at about 6 Ma. The last common ancestor (LCA) of humans and chimpanzees took place within the deciduous woodland / part-arboreal, part-terrestrial / frugivorous guild [20]. Deciduous woodlands in Africa, like those of temperate regions, are strongly seasonal with annual periods of food scarcity, being cold in temperate climates, dry in the tropics. The lack of precipitation or low temperatures slow down or even stop GPP, making food hard to find, and this would apply particularly to seasonal food items like fruit. However, the earliest members of the human lineage at 6 Ma were still mainly
frugivorous, partly living and finding food in trees; they were also partly terrestrial, coming down to the ground to some extent like their ape ancestors (Figure 1.2). For at least the following three million years (6–3 Ma), fruit-eating remained the staple diet in human ancestors, as in chimpanzees today [36], and the major change in human evolution during this period was that hominins (Hominini, or human ancestors) developed bipedal walking on the ground. Importantly, during this time, no significant increase in brain size occurred and there was no change in diet [37].
1.2.2 Protein Intake, the Introduction of Fire, and an Increase in Brain Size Between 3 and 2 Ma, a major shift in hominin diet occurred coinciding with the development of stone tool technology [38]. Hominins (such as Homo habilis) had begun eating increasing amounts of animal products, probably beginning with scavenging predator kills [39]. The eating of large mammals is indicated by cut marks on animal bones made by the stone tools [40], and this was associated with a modest increase in brain size (Figure 1.4) [41, 42]. It is likely that early hominins (6–3 Ma) were carnivorous at least to the extent of chimpanzees today [43, 44], but the carnivory of hominins differs in that they utilized animals larger than themselves, and they had the use of stone tools. The evidence for predation (which “run down” their prey) suggest that the biomass of prey had increased to support them
Uricase mutation in common ancestor of great apes and humans, 16 Ma Orangutan ancestor migrates to Asia, has uricase mutation, 10 Ma
Global cooling, fossil apes retreat to refugia, 12 to 8 Ma
Some ape species migrate to Europe, 16 Ma
Fossil apes present only in Africa, 25 to 17 Ma
Return to Africa, 10 to 8 Ma, ADH4 mutation in ancestor of African apes and humans, has uricase mutation
Middle Miocene Disruption (15–12 MYA) East Africa Tums to Savannas (15–6 MYA)
FIGURE 1.3 Timing of mutations and movements of apes out of Africa and back. Clockwise from bottom left, forest-living apes in Africa before 16 Ma, emigration of apes out of Africa and into Europe, global cooling after the mid-Miocene crisis led first to restriction of apes in refuge area in Europe, the final shut-down of the uricase gene, return to Africa of some groups of ape and movement of orangutan ancestors east into Asia at about 12 Ma, both with the uricase mutation, and finally the occurrence of the ADH4 mutation in African ancestors of the great ape and humans. (Used with permission from [33])
1 • Dietary Changes in Human Evolution 7 1800 1600
Homo sapiens, Neanderthals, and Homo heidelbergensis
Cranial capacity (cc)
1400 1200
Homo erectus
1000 800
Homo habilis 600 400
Great apes
Australopithecus
200 0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Age in millions of years FIGURE 1.4 Fossil evidence for major increase in brain size (estimated from cranial capacity) in early human ancestors occurred after 3–2 Ma, at the time of the origin of Homo species. Earlier fossil ancestors had brain sizes no larger than those of living great apes, and small brains were retained for the first three million years of human evolution in the species of Ardipithecus, Australopithecus, and Paranthropus [37]. The early species of Homo, Homo habilis, had brains larger than great ape brains [41, 42], and increases were continued with Homo erectus after 2 Ma and Homo sapiens, originating in Africa 600,000 years ago [48, 49].
[45], and this higher biomass and more energetic modes of life required more food and energy than did earlier faunas. This suggests that GPP also increased to support the expansion and escalation of life activities seen in living ecosystems. Around 2 Ma Homo erectus appears in Africa, with evidence for radiation to Europe and Asia shortly after 2 Ma [41]. With near-human bipedal adaptations, Homo erectus was probably almost entirely terrestrial, and with well-developed skills as a hunter and opportunist, and the capacity to adapt to the wide range of environments, it was able to adapt to a variety of environments while crossing the Asian continent. Beginning after 2 Ma, the climate cooled further leading to increasing seasonality that was associated with improved stone tool technologies. The finding of large mammals at fossil localities indicates that Homo erectus had become carnivorous, but it is still not certain whether the fossil hominins were hunting animals or scavenging the remains of carnivore kills [39, 40]. At or soon after 2 to 1.8 Ma, the first evidence for use of fire comes from Wonderwerk Cave in South Africa [46] and Geshir Benot Ya’akov [47]. This was associated with the first evidence of cooking of foods, although at both sites the presence of hominins is indicated only by the tools they left behind, and no actual hominin fossils have been found. One of the most remarkable aspects of Homo erectus (and to a lesser extent, Homo habilis) in the fossil record is that of remarkable increase in brain size (Figure 1.4) [37, 41, 42, 48,
49]. The human brain utilizes as much as a sixth of the daily energy expended and prefers glucose as its fuel. The greatest relative energy needs are in childhood, where the brain uses glucose at a rate equivalent to 66% of the body’s resting metabolism and 43% of the body’s daily energy requirement, and glucose demand for the brain is related inversely to body growth from infancy to puberty [50]. These energy demands remain high for many years due to the protracted growth of the brain that occurs with childhood [50]. Given the large requirements that the brain has for energy, there must have been strong evolutionary advantages for the increase in brain size at this time. It is easy to look back in time when we see the benefits of large brains and high intelligence to our technological societies, but 2 Ma with only gradual increase in brain size (it doubled in size in less than one million years) and only the beginnings of stone tool technology associated with hominins like Homo habilis and Homo erectus, some other factor(s) must have been involved. This has led to several hypotheses to account for this evolutionary change. The “expensive tissue hypothesis” proposes that the increasing size of the brain must be countered by decreasing metabolic costs of some other bodily function, which in this case is the gut [51]. This hypothesis is based on the observation that the two greatest users of energy are the gut and the brain; less digestible foods such as plant products require a longer gut, and it links the great expansion of the human brain, which
8 Handbook of Obesity comes at a great metabolic cost, with decrease in gut size. This could explain the increased brain size in apes as initially their diet was fruit, which is more easily digestible than leaves and grass [52, 53], and again with fossil hominins changing their diet to include more animal products (Figure 1.5). Herbivores consuming diets of lower digestibility have longer guts than animals eating diets that are more easily digestible such as fruits, seeds, and animals. Animal eaters with even shorter guts may have larger brains than herbivores and frugivores for the same reason [51]. According to the hypothesis, the high food value of meat both produces more energy per unit weight and at the same time enables the reduction in gut size, so that energy could be diverted to growing a larger brain [51]. Reinforcing the increase in brain size through a meat-rich diet, the acquisition and control of fire made both meats and plants more easily digestible and almost certainly also had a major role in brain growth [54]. Of note, habitat aridity also has a positive relationship with large intestine length, complicating the simple diet/gut relationship [52]. An alternative hypothesis is that as Homo erectus moved out into the savanna, social bonding would have become
Expensive tissue hypothesis (Aiello and Wheeler 1995) Cut mark 1 cm
More complex feeding strategy
Higher quality diet Higher quality food reduces bulk and promotes faster digestion
Complex diet requires better memory, use of fire for cooking
Larger brain
Reduced size of gut
Smaller guts freeup energy for increase in brain size: diet changes from fruit to meat
FIGURE 1.5 Meat eating and brain size. Higher quality diets are usually widely dispersed in the environment and require stronger brain power to locate; mammals with a diet of fruit have larger brains than those that eat herbage. When any form of animal is the intended food, this effect is increased, for animals can run away and are therefore harder to catch [45]. Evidence of meat eating is based on the presence of cut marks on large animal bone (inset). However, early in human evolution (6–3 Ma) it cannot be certain whether fossil hominins were hunting animals or scavenging the remains of carnivore kills [39, 40]. Increase in brain size in Homo habilis coincided both with the first evidence of meat-eating and with the first appearance of the stone tools that left cut marks on animal bones. For Homo erectus, the evidence is stronger that it actively hunted large mammals and that its diet consisted of a large proportion of meat [56, 69]. Since meat has more calories, weight for weight, than vegetable foods, the expensive tissue hypothesis predicts that hominins after 2 Ma were able to reduce gut size and divert the energy released into increasing brain size. Hominin use of fire also appears in the fossil record at the same time as Homo erectus [46], and it is likely that animal remains from scavenged carcasses [39] were made both more palatable and digestible by cooking [54].
critical; for the first time, hominins had moved away from the trees that had provided them with food and safety for the first four million years of their existence. Leaving the trees for savanna habitats made them vulnerable to large predators, and the “social hypothesis” proposes that, in essence, larger brains were necessary to cope with the increasing complexity of human societies for bonding, for locating and securing food, and for defense [55].
1.2.3 Hunter-Gatherers and the Introduction of Modern Humans Around 600,000 years ago, genetic evidence shows that Homo sapiens had diverged from other fossil hominins (13), and between 120,000 and 70,000 years ago it made one or more migrations out of Africa. The introduction of fire and the greater reliance on meat led to a diet probably little different from that of modern hunter-gatherer diets [56]. While half or more of their calories may have come from animal products, hunting does not provide a dependable source of food, for animals are hard to catch, and much of the diet of hunter-gatherers in recent times is in fact based on plant products [56]. Obesity seems to be rare in hunter-gatherers, as are other diseases of civilization, regardless of the proportion of macronutrients consumed. Most wild foods lack high amounts of energy and this feature, in combination with the slow transit of food particles through the human digestive tract, would have served as a natural check to obesity and certain other diseases of civilization. Nevertheless, there is some evidence that obesity was occasionally observed and may even have been a sign of high status. For example, the appearance of carved figurines of obese women (sometimes referred to as “Venus Figurines”) in Upper Paleolithic Europe during the last glacial advance provides sufficient realism to assure that it had been observed. Interestingly, this occurred during a time of worsening temperatures and a contraction of the local populations [57] and may have represented symbols of survival and motherhood [58].
1.2.4 Introduction of Agriculture and Pastoralism Around 11,000 to 10,000 years ago we observe the first evidence for agricultural communities. For the first time in human evolution there was a dependable source of food that so far exceeded what could be obtained by hunting or gathered from wild plants that it could be stored against times of shortage. Not only that, but agriculture marked a return to diets that are carbohydrate-based similar in some respects to the ancestral diets of apes and early humans [43]. The introduction of agricultural and pastoral communities was associated with several genetic changes. Starchcontaining foods are not normally sweet to most animals, but a mutation in amylase that occurred in primates before the split
1 • Dietary Changes in Human Evolution 9 of the Old World monkeys from the apes (likely 30–25 Ma) resulted in it being produced not only in the pancreas but also in the saliva [59]. This allowed the breakdown of some starch in the mouth to glucose, that could stimulate intake as it would activate the sweet taste buds and lead to a dopamine response in the brain. With the advent of agriculture, there was a progressive increase in salivary amylase activity due to mutations that led to multiple copies of the salivary amylase. While these duplications are not observed in all humans, they are significantly higher in agricultural communities compared to huntergatherer societies [60]. Likewise, lactase is an important enzyme that can break down the lactose in breast milk, but expression normally disappears as adults. However, mutations occurred in the lactase gene in pastoral communities in Europe, and separately in Africa, that allowed the persistence of lactase into adulthood [61]. The introduction of agricultural communities was associated with some obesity and diabetes, but overall it remained rare up to and including mediaeval human populations in England, in which timing of food consumption was earlier in the day, leaving time for daily activities to work off calories rather than storing them [62]. However, with the introduction and increase in ingestion of sugar, the rise in obesity and diabetes has been remarkable [63]. A number of studies suggest that this is because of the unique abilities of fructose to induce metabolic syndrome. Interestingly, other foods that include high glycemic carbohydrates, salty foods, and umami foods can also engage this same metabolic pathway that leads to the storage of fat and development of insulin resistance [32, 64, 65]. Today, all non-Western populations appear to develop diseases of civilization if they consume Western foods and have sedentary lifestyles [56].
1.3 THRIFTY GENES AND THEIR CONTRIBUTION TO THE OBESITY EPIDEMIC In the early 1960s the geneticist James Neel suggested that gene(s) acquired in our past during times of food shortage and starvation might be responsible for increasing our risk for obesity and diabetes when food is more available [66]. By augmenting storage of fat during times of plenty, survival becomes possible in times of famine, and any genetic change that favors fat storage would also allow survival in those environments where seasonal change produces regular famine. This “thrifty gene” hypothesis is especially relevant to the uricase mutation, as it appears to have helped protect against starvation by amplifying the effects of fructose in fruit to increase fat stores, but in today’s society, where fructose intake has increased markedly from the intake of added sugars, it may contribute to the increase of obesity [67]. Not all experts have accepted the thrifty gene hypothesis, and some have suggested that any genes that increase
body fat probably did not provide survival advantage because famines are unlikely to select for these genes, especially in the post-agricultural era since the time period of selection is short, and that most mutations in the genes that predispose us to obesity are neutral and have been drifting over evolutionary time—so-called drifty genes [68]. According to this reasoning, the presence of genes that favor obesity likely resulted from some other aspect of the gene that carries other benefits, such as stimulating increased intake of proteins (the protein leverage hypothesis). However, here we suggest that the mutations in uricase occurred long before the hominin lineage diverged from the great apes, during periods of starvation that were not limited to a few seasons but built up over millions of years. They did not occur recently but about 15 Ma. We also suggest that the uricase mutation did not in itself cause obesity, but it acted more as a means for preventing starvation, and it required an interaction with umami and fructose-containing foods that further raise uric acid to increase the risk for obesity in the population. In addition, there is no doubt that many other genetic and environmental factors are also involved in the pathways that lead to obesity.
1.4 CONCLUSIONS In conclusion, it is apparent that much can be learned from understanding the evolution of humans and their diet as it relates to environmental change. There remains a complex interplay between diet, habitat heterogeneity, and climate change that has played a role in the evolution of humans. Importantly, evolutionary changes in our past may be important in predicting the risk for obesity and diabetes today. Disclosures: RJJ has equity with XORTX Therapeutics and Colorado Research Partners LlC, and has received honoraria from Danone and Horizon Pharma. PA has no disclosures. Running Title: Nutrition in Evolution
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