Hypothalamic Integration of Energy Metabolism (eBook)

Cover 1
List of contributors 6
Preface 10
Acknowledgments 12
Contents 14
Section I: Hypothalamic Integration of Energy Metabolism 18
Chapter 1. The human hypothalamus in metabolic and episodic disorders 20
The hypothalamus in disorders of eating and metabolism 20
Disorders accompanied by disturbances in eating and metabolism 28
Development of the fetal hypothalamus, birth and programing of metabolism 45
Summary and conclusions 52
Acknowledgment 53
Appendix: The Dutch Famine 1944–1945 53
References 54
Chapter 2. Synaptic plasticity mediating leptin’s effect on metabolism 64
Introduction 64
Leptin is a key metabolic signal associated with the rapid rewiring of hypothalamic pathways 65
Leptin-deficient ob/ob animals have altered synaptology and electrophysiological properties in the arcuate nucleus 67
Leptin induces rapid rewiring of arcuate nucleus-feeding circuits in ob/ob mice 68
What is the mechanism of action of leptin in triggering synaptic plasticity? 68
Are the synaptic organization and electrophysiological properties of the hypothalamic POMC neurons altered in mice with diet-induced obesity? 70
Acknowledgment 70
References 70
Chapter 3. The hypothalamus, hormones, and hunger: alterations in human obesity and illness 74
Obesity 74
Gut hormones and appetite 75
Gut hormones and downstream pathways 76
Prader–Willi syndrome 78
Hypothalamic neuropeptides and human illness 79
Functional neuroimaging of appetite 79
Functional neuroimaging in obesity 82
Functional neuroimaging in PWS 83
Functional neuroimaging in the future 85
Acknowledgments 86
References 86
Chapter 4. Glucocorticoids, chronic stress, and obesity 92
Glucocorticoids and function in the HPA axis 93
The central stress response network 98
The downside of the chronic stress response 108
References 108
Chapter 5. Design and synthesis of (ant)-agonists that alter appetite and adiposity 124
Melanocortin receptors 124
Selective melanocortin receptor agonists 125
In vivo efficacy of melanocortin receptor agonists 126
Investigation of the site of anorectic action of melanocortin receptor agonists 126
Development of NPY antagonists and their anorectic effects 128
Y1 antagonists 128
Y5 antagonists 130
Y5 binding and receptor occupancy 131
Melanocortin receptor agonists interact with NPY receptor responsive neurons 132
Summary and conclusions 132
Acknowledgments 133
References 133
Chapter 6. Monogenic human obesity syndromes 136
Introduction 136
Congenital leptin deficiency 136
Response to leptin therapy 137
Is there a heterozygous phenotype? 138
Leptin receptor deficiency 139
POMC 139
Prohormone convertase 1 deficiency 139
Human MC4R deficiency 139
Summary 140
References 140
Section II: Hypothalamic Integration of Blood-borne Signals 144
Chapter 7. The selfish brain: competition for energy resources 146
Introduction 147
Maintenance of glucose fluxes to the brain 147
The role of the hippocampus/amygdala system in energy homeostasis 149
The balance between food intake and glucose allocation 151
Obesity and diabetes mellitus type 2 as a brain disease? 152
Future treatment strategies for obesity and diabetes mellitus type 2 153
Conclusions 155
References 155
Chapter 8. Integration of metabolic stimuli in the hypothalamic arcuate nucleus 158
Electrophysiological properties of ARC neurons 160
Modulation of synaptic inputs by active conductances 162
KATP channels and central integration of humoral factors 164
Future perspectives 167
Abbreviations 167
Acknowledgments 168
References 168
Chapter 9. Adipokines that link obesity and diabetes to the hypothalamus 172
Adipose tissue 172
Leptin 174
Conclusion 185
Acknowledgment 185
References 185
Section III: Hypothalamic Control of Bone and Thyroid Metabolism 192
Chapter 10. The circadian modulation of leptin-controlled bone formation 194
Introduction 194
High bone mass in circadian gene-mutant mice 195
Bone has a peripheral clock 195
Increased osteoblast proliferation contributes to HBM in (Per1-/- Per2m/m) mice
The central control of bone formation 198
The peripheral clock is a target of sympathetic signaling in osteoblasts 200
Sympathetic signaling activates cell cycle clock via AP1 genes in osteoblasts 201
Leptin-dependent sympathetic signaling controls AP1 and clock genes in vivo 202
Discussion 203
Abbreviations 204
Acknowledgments 204
References 204
Chapter 11. Hypothalamic thyroid hormone feedback in health and disease 206
Introduction 207
Thyroid hormone feedback in the human hypothalamus 207
Major depression and glucocorticoid treatment 214
Hyperthyroidism 217
Nonthyroidal illness 220
Conclusion 221
Acknowlegdments 221
References 221
Chapter 12. The TRH neuron: a hypothalamic integrator of energy metabolism 226
Role of hypophysiotropic TRH neurons in energy homeostasis 227
Role of nonhypophysiotropic TRH neurons in energy homeostasis 240
Conclusions 244
References 244
Section IV: Rhythms, Sleep and Energy Metabolism 254
Chapter 13. The seventeenth C.U. Ariëns Kappers Lecture: an introduction 256
References 258
Chapter 14. Staying awake for dinner: hypothalamic integration of sleep, feeding, and circadian rhythms 260
Regulation of sleep and wakefulness: the flip–flop switch model 260
Role of the orexin neurons in behavioral state regulation 264
The hypothalamic integrator for circadian rhythms 265
References 267
Chapter 15. Circadian timing in health and disease 270
The suprachiasmatic nuclei as central pacemaker 270
Circadian clock genes 271
Entrainment of the SCN clock 274
Real-time imaging of molecular time-keeping in the SCN 275
Local circadian time-keeping in peripheral tissues underpins metabolic rhythms 277
Circadian timing in disease 279
Circadian timing and neurodegenerative disease 281
Acknowledgements 283
References 283
Chapter 16. Circadian time keeping: the daily ups and downs of genes, cells, and organisms 288
History of circadian rhythms: from hobby gardening to feedback loops in gene expression 288
A circadian clock in the test tube: protein kinases and phosphatases 290
Zeitgeber time, circadian time, and jet lag 291
The mammalian circadian timing system: a clock in every cell? 292
Human behaviour: larks and owls 294
Perspectives 297
Acknowledgments 297
References 297
Chapter 17. The hypothalamic clock and its control of glucose homeostasis 300
Introduction 300
A daily rhythm in plasma glucose concentrations 301
Circadian control of the autonomic nervous system 313
Clinical implications 315
Abbreviations 317
Acknowledgments 318
References 318
Chapter 18. Mechanisms and functions of coupling between sleep and temperature rhythms 326
Introduction 326
Description of the coupling between sleep and temperature rhythms 327
Possible sites of interaction in the circadian regulation of sleep and body temperature 330
A modulatory role of body temperature on sleep-regulating systems 331
The functional direction of coupling between sleep and increased skin temperature revisited 333
An alternative function for the increase in skin blood flow 335
Sleep deprivation 336
Acknowledgments 338
References 338
Chapter 19. What can we learn from seasonal animals about the regulation of energy balance? 342
Introduction 342
Seasonal strategies 343
A re-resetting of body weight set point 344
Body weight change by altered food intake or energy expenditure? 344
The role of compensatory energy balance systems 345
The leptin paradox 346
In search of novel systems of control 347
Gene expression changes are linked to photoperiod not secondary events 348
Temporal changes in gene expression 349
A hypothetical model of interaction between H3R and VGF 350
Perspective 351
Acknowledgment 352
References 352
Section V: Hypothalamic Integration of ‘‘Sensory’’ Information 356
Chapter 20. Organization of circadian functions: interaction with the body 358
Introduction 359
Circadian rhythm of SCN neurons and their anatomical organization 359
Hypothalamic projections of the SCN 361
SCN prepares the body for changes in activity 364
Autonomic control of our organs 366
An unbalanced autonomic output leading to disease?
Input to the biological clock 370
Transmission of metabolic information to the SCN 372
Conclusions 373
References 373
Chapter 21. Hypoglycemia in diabetes: pathophysiological mechanisms and diurnal variation 378
Introduction 379
Hypoglycemia-associated autonomic failure 379
Mechanisms of HAAF 379
Diverse causes of HAAF 381
Acknowledgments 381
References 381
Chapter 22. Hypothalamic integration of immune function and metabolism 384
Introduction 385
Summary of afferent signals 396
Arcuate nucleus 398
Paraventricular nucleus 400
Ventromedial hypothalamus 403
Lateral hypothalamic area 404
Supraoptic nucleus 405
Abbreviations 414
Acknowledgment 414
References 414
Subject Index 424