OBESITY BEFORE BIRTH

ENDOCRINE UPDATES Shlomo Melmed, M.D., Series Editor For further volumes: http://www.springer.com/series/5917

OBESITY BEFORE BIRTH

Maternal and Prenatal Inuences on the Offspring
Edited by Robert H. Lustig Professor of Pediatrics University of California San Francisco, CA, USA

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Editor Robert H. Lustig, MD Professor of Pediatrics Division of Endocrinology Director, Weight Assessment for Teen and Child Health Program University of California San Francisco, CA 94143, USA

ISSN 1566-0729 ISBN 978-1-4419-7033-6 e-ISBN 978-1-4419-7034-3 DOI 10.1007/978-1-4419-7034-3 Springer New York Dordrecht Heidelberg London
Library of Congress Control Number: 2010935733 Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identied as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

The editor would like to dedicate this volume to his family: his wife Julie and his two daughters, Miriam and Meredith. No academician could ask for more understanding, encouragement, sacrice, and support through service call, out-patient clinic, grant writing, mentoring others, and a busy lecture schedule. I am blessed beyond measure.

Preface

In my beginning is my end. T. S. Eliot, #2 of Four Quartets

Eliot had no idea that his observations on the life cycle would start even before birth. And indeed, ones earliest beginning predicts both the timing and means to that end. The concept that obesity was inherent, and not just the sum result of the behaviors of gluttony and sloth was surmised early in the twentieth century, but began in earnest with the postulation of a thrifty genotype by James Neel in 1962. However, the eld lay dormant for another 30 years, awaiting biological and genetic conrmation. To compound the biological directive, the notion that prenatal biological inuences could impact postnatal outcomes for obesity dates to 1989, when David Barker, an epidemiologist from Southampton, UK, rst made the observation that now bears his name, the Barker hypothesis. He noted that maternal nutrition impacted on the fetus, such that small for gestational age infants were predicted to be at increased risk for obesity and metabolic syndrome in the future. Thus, the precept of developmental programming to amend ones genetic predisposition was advanced. In the interval 21 years since Barkers discovery, numerous observations have slowly amended these two complementary hypotheses. Leptin, the rst gene that of the energy balance pathway, was discovered in 1994. While already deemed essential for adult body weight regulation, Richard Simerly, then at Oregon Regional Primate Center, showed in animal models in 2004 that leptin likely was molding our hypothalami even before we took a swig of baby formula. Leptin opened up our understanding of the energy balance pathway, including genes such as MC4R, and their role in the genetics of obesity. Recent genome-wide association scans suggest that genetic linkages to obesity are primarily in the CNS. We learned in the late 1990s that large for gestational age and premature infants also became obese; and in the early 2000s that maternal obesity and weight gain during pregnancy are also risk factors. Furthermore epigenetics, which led credence to the ability of experiential phenomena in the mother to affect genetic expression in the newborn, was already a hot discipline when Randy Jirtles group at Duke discovered in 2003 that they could alter offspring weight and color coat in genetically determined Agouti mice through
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altered maternal nutrition. This line of investigation has expanded exponentially ever since. The phenomenon of epigenetics has tied in very nicely with the above observations, explaining how vertical transmission of obesity can occur exclusive of DNA base changes. Lastly, data accrued by Retha Newbold at NIEHS and Bruce Blumberg at UC Irvine in 2005 found that environmental toxins not only contribute to obesity in adult animals but also program the liver and adipocyte during gestation. Moreover, each of these phenomena has been noted in human models. Lastly, we now recognize that developmental programming of obesity can be promulgated by actions in numerous target organs in the energy balance pathway. Actions on the hypothalamus can result in an altered energy setpoint; actions on the liver can result in an altered metabolic prole; and actions on the adipocyte can result in an altered storage capacity. These actions are not mutually exclusive, giving rise to phenotypes of hyperphagia (or not), insulin resistance (or not), and subcutaneous vs. visceral fat. Understanding these tissue-specic effects on these gestational perturbations will likely allow for understanding of the different obesity syndromes and their downstream co-morbidities. Taken as a whole, these various phenomena clearly demonstrate that disruption of the normal energy balance paradigm during gestation has profound consequences for the offspring. These observations have led to a new branch of science and medicine: the Developmental Origins of Health and Disease (DOHaD). Given that (1) the obesity epidemic has gone global; (2) attempts at diet and exercise have failed to control the global obesity epidemic; and (3) we now have an epidemic of obese 6-month-olds, it is time to think out of the box. Is there an exposure that is causing this? Are pregnant women doing something to make their children fat? Are we promoting obesity before birth? The purpose of this unique volume is to elucidate, in both animal and human models, the state-of-the-art evidence for each of these phenomena. The evidence, and indeed, our author roster, comes from around the world. Each of the sections of this volume (genetics, epigenetics, developmental programming, environmental obesogens) will start out with the role of pathogenetic mechanism in question in human obesity and will then follow up with the evidence in animal models. In this way, the strength and relevance of each of these pathogenetic mechanisms and their effects can be assessed. It is hoped that by assembling each of these concepts in one volume, we will build a framework that will (1) inform physician and patient education into the causes of the obesity epidemic; (2) provide a nidus for further investigative efforts into the developmental nature of obesity and chronic disease; (3) provide a starting point for changes in policies to improve maternalchild health; and (4) provide data to assist public health ofcials to monitor and control environmental exposures, whether they be nutritional or toxicological. San Francisco, CA March 25, 2010 Robert H. Lustig

Contents

1 Obesity: Nature or Nurture? . . . . . . . . . . . . . . . . . . . . . Robert H. Lustig Part I Genetic Disorders Leading to Obesity

2 The Contribution of Heredity to Clinical Obesity . . . . . . . . . Johanna C. Andersson and Andrew J. Walley 3 Monogenic Disorders Within the Energy Balance Pathway . . . . Ivy R. Aslan, Sayali A. Ranadive, and Christian Vaisse 4 Ciliary Syndromes and Obesity . . . . . . . . . . . . . . . . . . . David S. Parker and Nicholas Katsanis 5 Genome-Wide Association Studies and Human Population Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . Ruth J.F. Loos and Tuomas O. Kilpelinen Part II Epigenetic Changes and the Development of Obesity

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6 Known Clinical Epigenetic Disorders with an Obesity Phenotype: PraderWilli Syndrome and the GNAS Locus . . . . . Merlin G. Butler 7 Evidence for Epigenetic Changes as a Cause of Clinical Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . Graham C. Burdge and Karen A. Lillycrop 8 Epigenetic Changes Associated with Intrauterine Growth Retardation and Adipogenesis . . . . . . . . . . . . . . . . . . . . Sara E. Pinney and Rebecca A. Simmons Part III Developmental Programming and the Development of Obesity

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9 Exposure to Diabetes In Utero, Offspring Growth, and Risk for Obesity . . . . . . . . . . . . . . . . . . . . . . . . . Tessa Crume and Dana Dabelea

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10 Maternal Weight Gain During Pregnancy and Obesity in the Offspring . . . . . . . . . . . . . . . . . . . . . Naomi E. Stotland and Janet C. King 11 Intrauterine Growth Restriction, Small for Gestational Age, and Experimental Obesity . . . . . . . . . . . . . . . . . . . Michael G. Ross, Ivan Huber, and Mina Desai 12 Experimental Models of Maternal Obesity and High-Fat Diet During Pregnancy and Programmed Obesity in the Offspring . . . . . . . . . . . . . . . . . . . . . . . . . . . . Larissa Jane Prior, Geoffrey Albert Head, and James Andrew Armitage 13 High-Carbohydrate Intake Only During the Suckling Period Results in Adult-Onset Obesity in Mother as well as Offspring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mulchand S. Patel and Malathi Srinivasan 14 Prenatal Stress, Glucocorticoids, and the Metabolic Syndrome . . Amanda J. Drake and Jonathan R. Seckl 15 Hypothalamic Fetal Programming of Energy Homeostasis . . . . Clement C. Cheung and Holly A. Ingraham 16 Adipocyte Development and Experimental Obesity . . . . . . . . Elvira Isganaitis and Mary-Elizabeth Patti Part IV Environmental Obesogens

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17 The Obesogen Hypothesis of Obesity: Overview and Human Evidence . . . . . . . . . . . . . . . . . . . . . . . . . Jerrold J. Heindel 18 Perinatal Exposure to Endocrine Disrupting Chemicals with Estrogenic Activity and the Development of Obesity . . . . . Retha R. Newbold 19 The Role of Environmental Obesogens in the Obesity Epidemic . Amanda Janesick and Bruce Blumberg Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Contributors

Johanna C. Andersson Department of Genomics of Common Disease, Faculty of Medicine, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK, j.andersson@imperial.ac.uk James Andrew Armitage Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia, james.armitage@med.monash.edu.au Ivy R. Aslan Department of Endocrinology, Childrens Hospital and Research Center, Oakland, 747 52nd Street, Oakland, CA 93609, USA, iaslan@mail.cho.org Bruce Blumberg Department of Developmental and Cell Biology and Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697-2300, USA, blumberg@uci.edu Graham C. Burdge Institute of Human Nutrition, University of Southampton School of Medicine, Southampton SO16 6YD, UK, g.c.burdge@southampton.ac.uk Merlin G. Butler Departments of Psychiatry and Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, KS, USA, mbutler4@kumc.edu Clement C. Cheung Departments of Pediatrics and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA, clement.cheung@ucsf.edu Tessa Crume Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, CO, USA, tessa.crume@ucdenver.edu Dana Dabelea Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, CO, USA, dana.dabelea@ucdenver.edu Mina Desai Department of Obstetrics and Gynecology, David Geffen School of Medicine at Harbor-UCLA Medical School, Torrance, CA, USA, mdesai@obgyn.humc.edu

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Amanda J. Drake Centre for Cardiovascular Science, The Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK, mandy.drake@ed.ac.uk Geoffrey Albert Head Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia, geoff.head@bakeridi.edu.au Jerrold J. Heindel Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Durham, NC, USA, heindelj@niehs.nih.gov Ivan Huber Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA, USA, ivan@randomtech.com Holly A. Ingraham Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA, holly.ingraham@ucsf.edu Elvira Isganaitis Division of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA, elvira.isganaitis@joslin.harvard.edu Amanda Janesick Department of Developmental and Cell Biology, University of California, Irvine, CA 92697-2300, USA, ajanesic@uci.edu Nicholas Katsanis Department of Cell Biology, Center for Human Disease Modeling, Durham, NC 27710, USA, katsanis@cellbio.duke.edu Tuomas O. Kilpelinen MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, UK, tuomas.kilpelainen@mrc-epid.cam.ac.uk Janet C. King Childrens Hospital Oakland Research Institute, Oakland, CA, USA, jking@chori.org Karen A. Lillycrop School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK, k.a.lillycrop@soton.ac.uk Ruth J.F. Loos MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, UK, ruth.loos@mrc-epid.cam.ac.uk Robert H. Lustig Division of Pediatric Endocrinology, Department of Pediatrics, University of California, San Francisco, CA 94143-0434, USA, rlustig@peds.ucsf.edu Retha R. Newbold National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC 27709, USA, newbold1@niehs.nih.gov; newboldretha@hotmail.com David S. Parker Department of Cell Biology, Center for Human Disease Modeling, Durham, NC 27710, USA, dave.parker@duke.edu

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Mulchand S. Patel Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA, mspatel@buffalo.edu Mary-Elizabeth Patti Division of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA, maryelizabeth.patti@joslin.harvard.edu Sara E. Pinney Division of Endocrinology and Diabetes, Department of Pediatrics, The Childrens Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, pinneys@email.chop.edu Larissa Jane Prior Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia, larissa.prior@bakeridi.edu.au Sayali A. Ranadive Department of Endocrinology, Childrens Hospital and Research Center Oakland, 747 52nd Street, Oakland, CA 93609, USA, sranadive@mail.cho.org Michael G. Ross Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA, USA, mikeross@ucla.edu Jonathan R. Seckl Centre for Cardiovascular Science, The Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK, j.seckl@ed.ac.uk Rebecca A. Simmons Division of Neonatology, Department of Pediatrics, The Childrens Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, rsimmons@mail.med.upenn.edu Malathi Srinivasan Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA, malathi@acsu.buffalo.edu Naomi E. Stotland Department of Obstetrics and Gynecology, University of California, San Francisco, CA, USA, stotlandn@obgyn.ucsf.edu Christian Vaisse Department of Medicine, Diabetes Center, University of California, San Francisco, CA, USA, vaisse@diabetes.ucsf.edu Andrew J. Walley Department of Genomics of Common Disease, Faculty of Medicine, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK, a.walley@imperial.ac.uk