Neurobiology of obesity

Cover......Page 1
Half-title......Page 3
Title......Page 5
Copyright......Page 6
Contents......Page 7
Preface......Page 9
Contributors......Page 11
1 Introductory chapter......Page 15
1. Definition of obesity......Page 16
2. Complications of obesity......Page 19
3. Causes of obesity......Page 21
4. Treatments for obesity......Page 23
5. Conclusions......Page 26
References......Page 27
1. Introduction......Page 34
2.1 Leptin and leptin receptor deficiencies......Page 37
2.2 Proopiomelanocortin-derived peptides deficiency......Page 42
2.3 Proconvertase deficiency......Page 44
2.4 Other rare monogenetic forms......Page 45
3.1 Mutations in the melanocortin 4 receptor......Page 46
3.2 Other suspected genes......Page 49
4.2 Genomic regions......Page 50
4.3 Candidate genes......Page 51
4.4 Genes involved in the leptin/melanocortin axis......Page 52
4.5 Genes identified by positional cloning......Page 55
5. Lessons learned from genetic studies......Page 57
References......Page 58
2. Classical role of the hypothalamus in feeding regulation......Page 66
3. The hypothalamus mediates metabolic adaptations......Page 67
4. Overview of hypothalamic circuits controlling energy balance......Page 68
5. Peripheral nutrient-related signals and vagal inputs influence hypothalamic output......Page 71
6. Integration of peripheral signals by the arcuate nucleus......Page 73
7. Hypothalamic signal transduction......Page 74
8. Electrophysiological responses of hypothalamic neurons to energy fluxes......Page 78
9. Role for hypothalamic plasticity in energy balance?......Page 79
Neuropeptide Y......Page 80
Cocaine and amphetamine-regulated transcript......Page 81
Endocannabinoids......Page 82
Thyrotropin-releasing hormone......Page 83
10.3 Dorsomedial nucleus......Page 84
10.4 Lateral hypothalamic and perifornical areas......Page 85
11. Brainstem pathways......Page 86
13. Summary......Page 87
References......Page 88
1. Summary......Page 97
2. Introduction......Page 98
3. Is obesity a disease?......Page 99
4. Evidence in favor of tight regulation of energy balance......Page 100
5. Adiposity signals......Page 102
7. Current model of energy homeostasis......Page 103
8. Insulin as an adiposity signal: the catabolic nature of insulin action in the CNS......Page 107
9. Adiposity signal access to the CNS......Page 109
11. Insulin as an adiposity signal: other evidence......Page 110
13. Insulin and leptin signal transduction......Page 112
14. Cross-talk between leptin and insulin action in hypothalamus......Page 113
15. Important unanswered questions: relative role of JAK-STAT vs. PI3K signaling......Page 115
16. Differential coupling in anabolic (NPY) vs. catabolic (POMC) neurons......Page 116
17. Termination of adiposity signaling......Page 117
18. Insulin and leptin as adiposity signals, energy homeostasis and obesity......Page 118
19. What is the difference between ‘‘experimental obesity’’ and common human obesity or rodent diet-induced obesity?......Page 119
21. Concordance of diabetes and obesity: a common mechanism for the development of adiposity signal resistance?......Page 120
22. Dietary induction of adiposity signal resistance and propensity to weight gain......Page 122
23. Macronutrient composition and weight loss......Page 124
24. ‘‘Reward’’ and potentiation of obesity; role of insulin and leptin......Page 126
References......Page 128
1. Introduction......Page 141
Receptors......Page 143
The receptor substrates......Page 145
Inositol lipid signaling......Page 146
The p42/p44 MAPK cascade......Page 148
SH2-B......Page 150
Suppressor of cytokine signaling (SOCS)-3......Page 151
The mTOR pathway......Page 152
AMP kinase......Page 153
PDE3B......Page 154
Other signaling molecules......Page 155
SHP2......Page 156
PTEN......Page 157
SHIP2......Page 158
3.1 Interplay between insulin and leptin signaling......Page 159
3.2 Novel therapeutic strategies for the treatment of obesity and T2DM......Page 160
Conclusions......Page 161
References......Page 162
1. Introduction......Page 178
1.1 Survival, the \"thrifty phenotype\" and obesity......Page 179
1.3 Metabolic sensing neurons and the regulation of energy homeostasis......Page 180
2. Animal models of diet-induced obesity......Page 181
2.1 Diet-induced obesity in rodents......Page 182
2.2 Factors predisposing to DIO:why some individuals become obese......Page 185
3. Diet-induced obesity in non-rodent species......Page 191
3.1 Dogs......Page 192
3.2 Baboons......Page 193
3.3 Rhesus macaques......Page 195
4. Summary and conclusions......Page 196
References......Page 197
1. Introduction......Page 210
2.1 POMC and AGRP neurons......Page 211
2.2 Melanocortin receptors......Page 213
3. Comparative vertebrate physiology of the melanocortin system......Page 215
4. Rodent genetic models of altered melanocortin function......Page 216
5.1 Regulation of appetite and food intake......Page 222
5.2 Dissection of the component processes underlying melanocortin effects on intake......Page 224
5.3 Regulation of the autonomic nervous system......Page 225
Control of brown adipose tissue and thermogenesis......Page 226
Control of white adipose tissue metabolism......Page 227
6. Electrophysiologic actions of melanocortins......Page 228
7. Peripheral actions of melanocortins relevant for energy balance......Page 229
8. Pharmacotherapy......Page 231
References......Page 235
1. Discovery and characterization of the endogenous opioids and their receptors......Page 246
2. Opioids and feeding behaviour: early studies......Page 247
3. Opioids and reward-related feeding......Page 249
4. Effects of opioids on macronutrient intake......Page 251
5.1 Receptor subtype agonists and ventricular studies......Page 252
5.2 Site-specific effects of opioid agonists upon feeding......Page 254
5.3 Site-specific effects of opioid antagonists upon feeding......Page 255
6.1 Ingestive behaviors affect opioid peptide and receptor genes......Page 256
6.2 Knockout and antisense approaches alter opioid-mediated ingestion......Page 257
7. Opioid-feeding interactions with dopamine and neuropeptides......Page 260
References......Page 261
1. Introduction......Page 280
2. Ghrelin: the endogenous GHS......Page 281
2.1 Ghrelin and food intake......Page 282
2.2 Ghrelin receptorsrole in energy balance......Page 285
2.3 Ghrelin and the hypothalamic regulation of energy balance......Page 286
The brainstem and food intake......Page 288
Ghrelin and circadian rhythmicity......Page 289
2.6 Clinical implications......Page 290
References......Page 291
1. Background......Page 299
2. Molecular mechanisms of apoptosis......Page 301
3. Adipocyte apoptosis......Page 302
4.2 Melanocortins......Page 303
4.3 Cocaine and amphetamine-regulated transcript (CART)......Page 304
4.4 Ciliary neurotrophic factor......Page 306
5. Role of CNS in bone marrow adipose apoptosis......Page 307
References......Page 309
11 Potential therapies to limit obesity......Page 316
1.1 Drugs acting on satiety......Page 318
1.2 Drugs acting on appetite through unknown mechanisms......Page 321
2. Drugs acting peripherally......Page 322
2.2 Peripheral satiety signaling hormones......Page 323
2.3 Drugs which stimulate energy expenditure......Page 326
3. Summary......Page 327
References......Page 328
Index......Page 334