Obesity Before Birth (eBook)

Preface 6
Contents 8
Contributors 10
1 Obesity: Nature or Nurture 13
1.1 Introduction 13
1.2 Definitions 14
1.3 The Nurture Interpretation 14
1.3.1 Risk Factors for Obesity Ascribable to ''Nurture'' 15
1.3.2 Problems with the ''Nurture'' Interpretation 15
1.4 The Nature Interpretation 17
1.4.1 Risk Factors for Obesity Ascribable to ''Nature'' 18
1.4.2 Problems with the ''Nature'' Interpretation 19
1.5 Toward a More Biochemical Understanding of the Nature Versus Nurture Argument 19
1.6 Hyperinsulinemia and Leptin Resistance 19
1.6.1 Postnatal Hyperinsulinemia, Leptin Resistance, and Obesity 20
1.6.2 Two Clinical Paradigms Have Shown Improvement in Human Leptin Resistance 20
1.6.2.1 Forced Weight Loss 20
1.6.2.2 Insulin Suppression 21
1.6.3 Prenatal Hyperinsulinemia, Leptin Resistance, and Risk for Future Obesity 22
1.6.4 Studies of SGA and Future Obesity 22
1.6.5 Studies of LGA and Future Obesity 22
1.6.6 Studies of Prematurity and Future Obesity 23
1.6.7 Animal Models of Hypothalamic Maldevelopment: The Role of Neonatal Leptin 23
1.7 Stress, Glucocorticoids, and Visceral Adiposity 24
1.7.1 Postnatal Stress, Glucocorticoids, and Visceral Adiposity 25
1.7.2 Prenatal Stress, Glucocorticoid Exposure, and Risk for Future Visceral Adiposity 25
1.7.3 Prenatal Glucocorticoid Exposure in Animal Models 26
1.8 Conclusions 26
References 27
Part I Genetic Disorders Leading to Obesity 35
2 The Contribution of Heredity to Clinical Obesity 36
2.1 Introduction 36
2.2 Defining Heredity 36
2.3 Clinical Obesity 37
2.4 The Environment 37
2.5 The Obesogenic Environment and the Rise in Obesity 37
2.6 Why Arent We All Obese 38
2.7 Is Obesity Heritable 38
2.8 Twin Studies 38
2.8.1 Types of Twin Studies 40
2.8.1.1 The Classical Twin Study 40
2.8.1.2 The Extended Twin Study 40
2.8.1.3 The Co-twin Control Study 41
2.8.1.4 The Discordant MZ Twin Study 41
2.8.1.5 Twins Reared Apart 41
2.8.1.6 Twin Studies to Distinguish Between Genetic and Environmental Effects 42
2.8.2 Twin Studies and Obesity 42
2.9 Genetic Linkage Studies Using DZ Twins 42
2.10 Twin Studies of Obesity-Related Traits 43
2.10.1 BMI in Children 43
2.10.2 BMI in Adolescents 44
2.10.3 BMI in Adults 45
2.10.4 Other Anthropometric Measures 46
2.10.5 Body Composition 46
2.10.6 Eating Behavior 49
2.10.6.1 Restraint, Emotional Eating, and External Eating 49
2.10.6.2 Satiety and Food Responsiveness 50
2.10.6.3 Eating Rate and Eating Styles 50
2.10.7 Physical Activity 51
2.11 Adoption Studies 53
2.12 Family-Based Studies 54
2.13 CaseControl Studies and the Missing Heritability Problem 55
2.14 Heredity and Nongenetic Traits in Obesity 56
2.15 Conclusions 57
References 58
3 Monogenic Disorders Within the Energy Balance Pathway 64
3.1 Introduction 64
3.2 Gene Mutations That Affect the LeptinMelanocortin System 65
3.2.1 Melanocortin-4 Receptor (MC4R) 65
3.2.2 Leptin 68
3.2.3 Leptin Receptor (LepR) 68
3.2.4 Proopiomelanocortin (POMC) 69
3.2.5 Prohormone Convertase 1/3 (PC1/3) 70
3.3 Gene Mutations That Affect Neurodevelopment 71
3.3.1 SIM1 71
3.3.2 Brain-Derived Neurotrophic Factor (BDNF) 72
3.3.3 NTRK2 73
3.4 Treatment 73
3.5 Conclusions 75
References 76
4 Ciliary Syndromes and Obesity 81
4.1 Introduction 81
4.2 Ciliary Function, the Ciliopathies, and Clinical Phenotypes 82
4.3 An Overview of the Primary Vertebrate Cilium 83
4.4 Intraflagellar Transport (IFT) 84
4.5 A Role for Cilia in Developmental Signaling 85
4.5.1 Cilia and Hedgehog Signaling 85
4.5.2 Cilia and Wnt Signaling 86
4.6 A Role for Primary Cilia in Appetite Control 87
4.6.1 Leptin Signaling in the Hypothalamus Regulates Body Weight 88
4.6.2 A Requirement for IFT in Leptin Signaling 88
4.6.3 BBS Proteins and the Control of Leptin Signaling 89
4.6.4 Other Roles for BBS Proteins in Neuronal Signaling and Obesity 91
4.7 Cilia and Adipogenesis 92
4.8 The Human Ciliopathies and Obesity 93
4.9 BardetBiedl Syndrome 93
4.10 Alstrm Syndrome 95
4.11 Concluding Remarks 96
References 96
5 Genome-Wide Association Studies and Human Population Obesity 104
5.1 Introduction 104
5.2 Genome-Wide Association (GWA) Studies 105
5.2.1 The International HapMap Project and High-Throughput Genotyping -- The Bedrocks of the Genome-Wide Association Approach 105
5.2.2 Two-Stage Design of GWA Studies 106
5.2.3 Imputation 107
5.2.4 Presentation of Genome-Wide Results 107
5.3 Three Waves of Discoveries 108
5.3.1 First Wave -- Discovery of FTO 108
5.3.2 Second Wave -- Discovery of MC4R 109
5.3.3 Third Wave -- Discovery of Nine New Loci 110
5.4 Impact and Predictive Value of the Established Obesity Loci 111
5.5 Follow-Up and Functional Characterization of the Established Loci 113
5.6 Clinical Applications 114
5.7 Approaches for Identifying More Loci for Obesity Through GWA Studies 115
5.7.1 Increased Sample Size 115
5.7.2 Studies in Populations of Different Ethnic Backgrounds 115
5.7.3 Genome-Wide Association Studies in Children and Adolescents 115
5.7.4 Studies on Other Obesity-Related Traits than BMI 116
5.7.5 Studies on the Risk of Obesity 116
5.7.6 Studies on Intermediary Traits of Obesity 116
5.7.7 Studies on Gene--Lifestyle Interaction 117
5.7.8 Replication of Variants with Less Stringent Significance Thresholds 117
5.7.9 Genome-Wide Association of Copy Number Variants (CNVs) 118
5.7.10 More Comprehensive Genotyping Chips 118
5.8 Conclusions 119
References 119
Part II Epigenetic Changes and the Development of Obesity 122
6 Known Clinical Epigenetic Disorders with an Obesity Phenotype: PraderWilli Syndrome and the GNAS Locus 123
6.1 Introduction 123
6.2 Genomic Imprinting 124
6.3 Genetic Subtypes and Clinical Differences in PWS 125
6.3.1 Genetics 125
6.3.2 Deletion Versus Maternal Disomy 15 127
6.3.3 Molecular Genetics and Deletion Types in PWS 128
6.3.4 Clinical Findings Associated with Type I Versus Type II Deletions 132
6.3.5 Expression of Four Genes Between BP1 and BP2 in PWS 134
6.4 PWS with Atypical 15q11q13 Deletions or Translocations and Causative Genes 135
6.5 Gene Expression in PWS 136
6.6 Clinical Stages and Natural History of PWS 137
6.7 Fatness Patterns and Body Composition Measures in PWS 140
6.8 Obesity and Nutritional Management in PWS 142
6.9 GNAS, a Complex and Imprinted Locus 144
6.10 Albright Hereditary Osteodystrophy (AHO), Pseudohypoparathyroidism (PHP), and Pseudopseudohypoparathyroidism (PPHP) 145
6.11 McCuneAlbright Syndrome 146
6.12 Applications to Other Areas of Health and Disease Related to Epigenetics and Obesity 148
References 149
7 Evidence for Epigenetic Changes as a Cause of Clinical Obesity 154
7.1 Introduction 154
7.2 Developmental Plasticity 155
7.3 Developmental Plasticity and Human Metabolic Disease 156
7.4 Experimental Models 158
7.5 Nutrition in Early Life and Gene Transcription 158
7.6 Epigenetic Mechanisms in Induced Risk of Obesity 162
7.6.1 Epigenetic Mechanisms and Gene Regulation 162
7.6.2 Evidence for the Involvement of Altered Epigenetic Regulation in Human Cardiometabolic Disease 163
7.6.3 Epigenetic Regulation in Animal Models 164
7.6.4 Mechanisms for Induced Changes in the Epigenome 165
7.6.5 Prevention and Reversal of an Altered Epigenotype and Phenotype 166
7.7 Conclusions 168
References 168
8 Epigenetic Changes Associated with Intrauterine Growth Retardation and Adipogenesis 174
8.1 Introduction 174
8.2 Chromatin Structure, DNA Methylation, and Gene Expression 175
8.2.1 Histone Modifications 175
8.2.2 DNA Methylation 175
8.2.3 Noncoding RNAs 176
8.3 Epigenetic Regulation of Gene Expression in Intrauterine Growth Retardation 176
8.3.1 Chromatin Remodeling in the ß-Cell of IUGR Rats 177
8.3.2 Chromatin Remodeling in the Muscle of IUGR Rats 178
8.4 Epigenetics of the Adipocyte 180
8.5 Stages of the Developing Adipocyte: Determination and Differentiation 182
8.6 Experimental Systems for Studying Adipogenesis 182
8.7 Adipogenesis 184
8.7.1 CAAT/Enhancer-Binding Proteins (C/EBPs) 184
8.7.2 PPAR-y -- A Master Regulator of Adipogenesis 185
8.8 Epigenetic Regulation of Adipogenesis 185
8.8.1 Epigenetic Regulation of Preadipocyte Determination 185
8.8.2 Chromatin Remodeling and C/EBP Transcription Factors 188
8.8.3 Epigenetic Regulation of PPAR: The Role of Histone Acetylation 189
8.8.4 Histone Methylation in Adipogenesis 190
8.8.5 DNA Methylation and Gene Expression 191
8.9 Conclusions 191
References 192
Part III Developmental Programming and the Development of Obesity 197
9 Exposure to Diabetes In Utero, Offspring Growth, and Risk for Obesity 198
9.1 Introduction 198
9.2 Maternal Hyperglycemia and Fetal Growth 200
9.3 Early Life Growth Patterns and Risk for Obesity in Offspring of Diabetic Mothers 200
9.4 Abnormal Glucose Tolerance and T2DM in Offspring of Diabetic Mothers 202
9.5 The Role of Fetal Hyperinsulinemia 203
9.6 Less Conclusive Findings 203
9.7 An Independent Effect of Intrauterine Exposure: Beyond Genetics and Postnatal Environment 204
9.8 The Long-Term Consequences Are Independent of Maternal Diabetes Type 205
9.9 Public Health Consequences 205
9.10 Prevention and Risk Reduction Strategies 206
References 206
10 Maternal Weight Gain During Pregnancy and Obesity in the Offspring 210
10.1 Introduction 210
10.2 The Physiology of Weight Gain During Pregnancy Among Obese and Non-obese Women 210
10.3 The Institute of Medicine (IOM) Weight Gain Guidelines 212
10.4 Epidemiology and Trends of Pregnancy Weight Gain 212
10.5 Association Between Gestational Weight Gain (GWG) and Childhood Obesity 213
10.6 Optimal Weight Gain for Obese Women an Ongoing Controversy 215
10.7 Interventions to Prevent Excessive Pregnancy Weight Gain 216
10.8 Special Diets for Obese Women During Pregnancy 217
References 218
11 Intrauterine Growth Restriction, Small for Gestational Age, and Experimental Obesity 220
11.1 Introduction 220
11.2 Programming of Obesity 221
11.3 Effects of the In Utero Environment on Fetal Development 222
11.4 Animal Models 223
11.5 Animal Species 224
11.6 Programming Mechanisms and Results: Appetite and Adipogenesis 225
11.7 Appetite Physiology 226
11.8 Development of Appetite and Satiety Mechanisms 227
11.8.1 Role of Leptin 227
11.8.1.1 Animal Leptin Physiology 227
11.8.1.2 Human Leptin Physiology 229
11.8.1.3 Research on Neural Stem Cell Cultures (NSC) 229
11.8.2 Role of Adipose Tissue 229
11.9 Programming of Adiposity 230
11.9.1 Enhanced Adipogenesis and Lipogenesis 230
11.9.1.1 Research in Primary Adipocyte Cultures 232
11.10 Programmed Obesity: Putative Causative Mechanisms 233
11.11 Therapies and Applications 233
11.12 Conclusions 234
References 235
12 Experimental Models of Maternal Obesity andINTtie High-Fat Diet During Pregnancy and Programmed ObesityINTnl
12.1 Introduction 245
12.2 Animal Models to Study the Role of Maternal Diet in Pregnancy on Offspring Health and Disease 246
12.3 Animal Models of Maternal Obesity, Hypercaloric Diet, and High-Fat Feeding 247
12.4 What Is the Stimulus to Developmental Programming Following Maternal Obesity, Hypercaloric Diet, or High-Fat Feeding 248
12.4.1 Elucidating the Programming Effects of Maternal Obesity and Fat Feeding 249
12.4.2 Programming Effects of Maternal Diets Differing in Types of Fatty Acids 250
12.4.3 The Relative Importance of Maternal Obesity vs. Maternal Fat Intake in Pregnancy 251
12.4.4 The Effect of Maternal Hypercholesterolemia in Developmental Programming 252
12.5 The Postnatal Period Is Important and Implicates a Role for Altered Appetite Circuitry in the Development of Programmed Obesity 253
12.6 Development of the Appetite Regulatory System 254
12.7 Programming of SNS Activity, Obesity, and Hypertension 256
12.8 Perspectives 258
References 258
13 High-Carbohydrate Intake Only During the Suckling Period Results in Adult-Onset Obesity in Mother as well as Offspring 264
13.1 Introduction 264
13.2 Metabolic Programming of the Fetus for Adult-Onset Disease 265
13.3 Altered Dietary Experience in the Immediate Postnatal Period (Suckling Period) 266
13.4 The High-Carbohydrate (HC) Rat Model 266
13.5 Effects of the HC Milk Formula Observed in Rat Pups (F0) During the Period of the Dietary Modification 268
13.6 Long-Term Effects of the HC Dietary Modification Observed in Adulthood 268
13.7 The Transgenerational Effect of HC Dietary Modification 269
13.8 The HC Female Rat (F0) in the Prepregnancy Period 269
13.9 The HC Pregnant Rat (F0 Generation) 269
13.10 The HC Fetus (F1 Generation) 271
13.11 The HC Offspring (F1) in the Postnatal Period 272
13.12 Reversal of the Transgenerational Effect 273
13.13 Maternal Obesity due to High-Fat Diet Consumption and Programming Effects on the Offspring 274
13.14 Mechanisms Supporting the Phenomenon of Metabolic Programming 275
13.15 Conclusions 275
References 277
14 Prenatal Stress, Glucocorticoids, and the Metabolic Syndrome 281
14.1 Early Life Programming 281
14.2 The Role of Glucocorticoids 282
14.3 Glucocorticoids and Fetal Development 282
14.4 11ß-Hydroxysteroid Dehydrogenase Type 2 and the Feto-placental Glucocorticoid Barrier 283
14.5 Glucocorticoid Programming 285
14.6 Programming of Cardiovascular and Metabolic Systems 286
14.6.1 Programming of Blood Pressure and Vascular Function 286
14.6.2 Programming of Glucose and Insulin Homeostasis 287
14.6.3 Programming of the Pancreas 289
14.6.4 Fatty Liver 289
14.6.5 Programming of Muscle and Fat 290
14.7 Evidence for Glucocorticoid Programming in Humans 290
14.8 Mechanisms of Early Life Programming 292
14.9 Conclusions and Implications for Human Health 292
References 293
15 Hypothalamic Fetal Programming of Energy Homeostasis 303
15.1 Introduction 303
15.2 Prenatal Programming and Obesity 304
15.2.1 Epidemiological Studies 304
15.2.1.1 Human Maternal Undernutrition 304
15.2.1.2 Human Maternal Overnutrition 304
15.2.2 Animal Studies 305
15.3 Models to Induce Prenatal Maternal Undernutrition 305
15.3.1 Caloric Restriction 305
15.3.2 Protein Restriction 306
15.4 Models to Induce Prenatal Maternal Overnutrition 306
15.4.1 High-Fat Diet 306
15.4.2 Gestational Diabetes Mellitus (GDM) 308
15.5 Central Mechanisms for Fetal Programming 308
15.5.1 Perinatal Hypothalamic Controls of Energy Homeostasis 308
15.5.2 Perinatal Leptin 310
15.6 Abnormal Hypothalamic Regulation of Fetal Programming 312
15.6.1 Fetal Hypothalamic Alterations in Maternal Overnutrition 312
15.6.2 Fetal Hypothalamic Alterations in Maternal Undernutrition 314
15.7 Conclusions 316
References 317
16 Adipocyte Development and Experimental Obesity 322
16.1 Introduction 322
16.2 Mechanisms of Adipose Tissue Growth and Function 323
16.2.1 Hyperplasia Versus Hypertrophy 323
16.2.2 Adipocyte Hypertrophy and Lipogenesis 327
16.2.3 Adipocyte Lipolysis 328
16.3 Endocrinology of Adipose Tissue 328
16.4 Prenatal Development of Adipose Tissue Depots 329
16.4.1 White Adipose Tissue 329
16.4.2 Brown Adipose Tissue 330
16.4.3 Developmental Origins of WAT Versus BAT 331
16.4.4 Body Fat Distribution 331
16.5 The Prenatal Nutritional Environment, Body Composition, and Obesity Risk 332
16.5.1 Prenatal Undernutrition, Low Birth Weight, and Adiposity 332
16.5.2 Role of Accelerated Postnatal Growth (''Catch-Up Growth'') 333
16.6 Prenatal Undernutrition, LBW, and Adipocyte Biology 335
16.6.1 Adipogenesis, Lipogenesis, and Lipolysis in SGA Humans 335
16.6.2 Adipogenesis, Lipolysis, and Lipogenesis in Experimental Models 336
16.7 Hormone Signaling in SGA-Associated Obesity and Experimental Models 337
16.8 Adipokines in SGA-Associated Obesity and Experimental Models 339
16.9 Future Directions: Potential Role of Epigenetic and Developmental Mechanisms in Prenatal Undernutrition-Associated Obesity 340
16.10 Conclusions 341
References 342
Part IV Environmental Obesogens 354
17 The Obesogen Hypothesis of Obesity: Overview andINTtie Human Evidence
17.1 Introduction 355
17.2 Developmental Origins of Health and Disease Paradigm 356
17.3 Environmental Toxicants 357
17.4 The Obesogen Hypothesis of Obesity 358
17.5 Human Data Supporting the Obesogen Hypothesis of Obesity 360
17.5.1 Smoking 360
17.5.2 Persistent Organic Pollutants 361
17.6 Adult Exposures to Environmental Agents and Obesity 362
17.6.1 Fructose 362
17.6.2 Monosodium Glutamate (MSG) 362
17.6.3 Phthalates 363
17.7 Recommendations 363
References 364
18 Perinatal Exposure to Endocrine Disrupting Chemicals with Estrogenic Activity and the Development of Obesity 366
18.1 Introduction 366
18.2 The Developmental Origins of Adult Disease 367
18.3 Experimental Evidence for Involvement of Environmental Estrogens in Obesity 369
18.4 Diethylstilbestrol (DES) 369
18.5 Bisphenol A 374
18.6 Phytoestrogens 376
18.7 Other EDCs 376
18.8 Proposed Modes of Action 377
18.9 Conclusions 377
References 378
19 The Role of Environmental Obesogens in the Obesity Epidemic 382
19.1 Introduction 382
19.2 An Archetype for Prenatal Chemical Exposure Leading to Obesity (Obesogens): Tributyltin 383
19.3 Obesogens Acting on Estrogen/Androgen Metabolism 384
19.4 Obesogens Acting on Glucocorticoid Metabolism 386
19.5 Obesogens Acting on Peroxisome Proliferator-Activated Receptors 388
19.6 Epigenetics: The GeneEnvironment Connection 389
19.7 Conclusion 391
References 392
Index 399