Energy Metabolism and Obesity (eBook)

Preface 6
Contents 7
Contributors 9
Molecular Physiology of Monogenic and Syndromic Obesities in Humans 12
Wendy K. Chung and Rudolph L. Leibel 12
Introduction 12
Molecular Elements in the Control of Body Weight 13
Nonsyndromic Monogenic Obesity 15
Leptin Deficiency 15
Leptin Receptor Deficiency 17
Pro-opiomelanocortin Deficiency 18
Mahogany and Mahoganoid 19
Prohormone Convertase 1 Deficiency 20
Melanocortin 4 Receptor Deficiency 20
TUB 21
Lessons to Be Learned from Nonsyndromic Obesity 21
Syndromic Obesity 22
Prader-Willi Syndrome 22
SIM1 24
Bardet-Biedl Syndrome 25
Alstrom Syndrome 26
Cohen Syndrome 27
Borjeson-Forssman-Lehmann Syndrome 27
Lessons to Be Learned from Syndromic Obesity 28
Conclusion 28
Acknowledgments 28
References 29
Leptin Signaling In the Brain 34
Ofer Reizes, Stephen C. Benoit, and Deborah J. Clegg 34
Introduction 35
The Dual-Centers Hypothesis 35
Challenges to the Hypothesis 35
Beyond the Hypothesis 36
CNS Control of Food Intake 37
The Termination of Meals: Satiety 38
Leptin: Molecular Signaling Pathways 39
Leptin Receptor Neurophysiology 41
Integration of Adiposity Signals 42
Central Signals Related to Energy Homeostasis 43
Catabolic Systems 44
Ciliary Neurotrophic Factor and Axokine 44
Melanocortins 45
Plasticity in the System 46
Conclusion 47
References 47
Inactivating Melanocortin 4 Receptor Mutations and Human Obesity 55
Ya-Xiong Tao 55
Introduction 55
MC4R and Rodent Energy Homeostasis 56
Naturally Occurring Mutations in the MC4R Gene and Human Obesity 57
Functional Characterizations of the MC4R Mutations Identified from Obese Patients 58
Molecular Classification of Inactivating MC4R Mutations 59
Therapeutic Implications 62
Conclusion 64
References 64
The Role of Central Melanocortins in Cachexia 69
Daniel L. Marks 69
Introduction 70
Cytokine Action in the Central Nervous System 71
The Arcuate Nucleus 71
The Role of the Central Melanocortin Systemin the Regulation of Feeding and Metabolic Rate 71
Agouti-Related Peptide 72
The Role of the Central Melanocortin System in Cachexia 73
Small-Molecule Synthetic Melanocortin Antagonists 73
Conclusion 74
References 75
The Efferent Arm of the Energy Balance Regulatory Pathway: Neuroendocrinology and Pathology 83
Robert H. Lustig 83
Introduction 84
The Afferent Arm of the Energy Balance Pathway 84
Neuroendocrinology 84
Pathology 85
The Efferent Arm of the Energy Balance Pathway 86
Neuroendocrinology 86
The SNS 86
The Vagus 88
Measurement of Autonomic Function in Humans 90
Pathology 91
Conclusion 94
Acknowledgments 95
References 95
Adiponectin: A Multifunctional Adipokine 100
Kristen Clarke and Robert L. Judd 100
Introduction 100
Discovery of Adiponectin 101
Adiponectin Protein Structure 102
Adiponectin Gene Expression 104
Adiponectin Receptors 105
Physiologic Functions of Adiponectin 106
Regulation of Adiponectin Gene Expression and Secretion 110
Role of Adiponectin in Human Disease 112
Conclusion 113
References 113
The Role of the Gastrointestinal Hormones Ghrelin, Peptide YY, and Glucagon-like Peptide-1 in the Regulation of Energy Balance 119
Ruben Nogueiras, Hilary Wilson, Diego Perez-Tilve, and Matthias H. Tschöp 119
Introduction 119
Ghrelin 119
Ghrelin and Energy Balance 120
Ghrelin and Glucose Homeostasis 121
Ghrelin and Ghrelin Receptor Knockout Mice 122
Obestatin 123
Peptide YY 124
Central Effects Versus Peripheral Effects 125
Mechanism of Action 126
Glucagon-like Peptides 127
Biological Effects on Food Intake and Mechanisms of Action 127
Oxyntomodulin 128
Conclusion 129
References 129
The Role of Growth Hormone Secretagogues and Ghrelin in Feeding and Body Composition 136
Cyril Y. Bowers, Blandine Laferrère, David L. Hurley, and Johannes D. Veldhuis 136
Introduction 137
Chemistry and Function 139
Receptor 142
GHRP-2 Clinical Studies 145
Children 147
Nitrogen Retention 148
Food Intake 152
GHRP-2 Long-term Continuous Delivery Approach 154
Additional Actions of GHRP-2 Continuous Delivery 155
Twenty-four Hour Ghrelin Continuous Delivery 156
Future Outlook 159
Conclusion 161
Acknowledgments 162
Addendum 162
References 162
Interaction Between Physical Activity and Genetic Factors in Complex Metabolic Disease 166
Paul W. Franks and Stephen M. Roth 166
Introduction 167
Pre-Existing Evidence for Gene 1X Physical Activity Interactions in Type 2 Diabetes 169
Functional Evidence for Interaction BetweenGenetic Factors and Physical Activity in MetabolicDysregulation 171
Methodological Issues in the Study of GEI in Human Populations 174
Preserving Statistical Power in Studies of Interaction 174
Characterizing the Architecture of ``Interaction'' Genes 175
Functional Studies 177
Conclusion 178
Acknowledgments 178
References 179
11-Hydroxysteroid Dehydrogenase Type 1 and Obesity 185
Roland H. Stimson and Brian R. Walker 185
Introduction 186
Primary Glucocorticoid Excess 186
Glucocorticoids in Obesity and the Metabolic Syndrome 187
The 11-Hydroxysteroid Dehydrogenases 188
Transgenic Manipulation of 11-HSD1 in Mice 189
11-HSD1 in Human Idiopathic Obesity 189
11-HSD1 in Liver 190
11-HSD1 in Subcutaneous Adipose Tissue 191
11-HSD1 in Visceral Adipose Tissue 192
11-HSD1 in Skeletal Muscle 192
11-HSD1 in Other Forms of Obesity 193
Polycystic Ovarian Syndrome 193
HIV Treatment--Associated Lipodystrophy 193
Growth Hormone Deficiency and Hypothalamic Obesity 193
Plasticity of 11-HSD1 194
Effects of Diet and Weight Loss 194
Hormonal Regulation 195
11-HSD1 Polymorphisms and Obesity 195
Cortisone Reductase Deficiency 196
Inhibition of 11-HSD1 196
Conclusion 199
Acknowledgments 199
References 199
Prader-Willi Syndrome: A Model of Disordered Energy Homeostasis 207
Andrea Haqq 207
Introduction 207
Etiology: Genetics of Prader-Willi Syndrome 208
Clinical Management 210
Diagnosis 210
Medical 213
Long-term Prognosis 222
Future Studies and Therapies 222
Conclusion 223
Acknowledgments 223
References 223
Antipsychotic Medication--Induced Weight Gain and Risk for Diabetes and Cardiovascular Disease 233
John W. Newcomer 233
Introduction 234
Metabolic Contributions to Medical Risk 234
Metabolic Risk in a Major Mental Disorder 236
Antipsychotic Medication Overview 237
Evidence of Antipsychotic Effects on Metabolic Risk 238
Evidence of Antipsychotic Effects on Weight and Adiposity 238
Evidence of Antipsychotic Effects on Metabolic Risk 241
Clinical Significance of Medication-Related Metabolic Effects 246
Pathophysiology 247
Prevention and Management of Antipsychotic-Induced CVD Risk 248
Conclusion 249
Acknowledgments 249
References 249
Treatment of Insulin Resistance in Youth: The Role of Metformin 256
Molly Emott and Michael Freemark 256
Introduction 257
Insulin Resistance and Metabolic Complications 257
Risk Factors for Insulin Resistance 259
Diagnosing Insulin Resistance 260
Pathogenesis of Insulin Resistance in Obesity 261
Insulin Resistance and PCOS 262
Pharmacologic Approaches to the Treatment of Insulin Resistance and Prevention of Type 2 Diabetes 263
Metformin: Mechanisms of Action 264
Metformin Use in Obesity-Related Insulin Resistance 266
Metformin Use in PCOS 268
Metformin and Antipsychotic Therapy 268
Adverse Effects of Metformin 269
Other Medications That May Prove Useful in Children with Insulin Resistance (Reviewed in Refs. 3, 21, and 66) 269
Balancing Pharmacotherapy and Lifestyle Interventions (Figs. 13.5, 13.6, and 13.7) 270
References 272
The Surgical Approach to Morbid Obesity 277
Edward E. Mason, Mohammad K. Jamal, and Thomas M. O'Dorisio 277
Introduction 278
Mechanisms of Weight Reduction 280
Digestive Tract Hormones Contribute to Weight Control 281
Operation-Related Risks 283
Thirty-Day Complications and Operative Mortality 284
Lifelong Mortality 284
Lifelong Complications Related to Operation 285
Type 2 Diabetes Mellitus and High Insulin Levels 287
Surgical Treatment Through Endogenous GLP-1 288
Ileal Transposition 289
An Endocrinologist's Approach to Nesidioblastosis 290
Incretin-Mimetics and Restriction Operations 291
Restriction Operations 291
Vertical Banded Gastroplasty 292
Michael Long Gastroplasty 292
Gastric Banding 292
Need for Lifelong Follow-up 295
Weight Loss and Diabetes Control 296
Biliopancreatic Diversion 297
Recommendations 299
References 301
Index 305