Ghrelin (eBook)

Cover 1
Contents 8
Former Editors 6
Contributors 14
Preface 18
Chapter 1: The Structure of Ghrelin 20
I. Introduction 21
II. Background 21
A. Experimental methods 21
B. Computational methods 23
III. Results of Structural Studies 24
A. Nuclear magnetic resonance 24
B. MD simulations 25
IV. Discussion 28
V. Conclusions 30
Acknowledgments 30
References 30
Chapter 2: Biochemistry of Ghrelin Precursor Peptides 32
I. Introduction 33
II. Ghrelin Gene Precursors 34
A. Organization of the ghrelin gene 34
B. Promoter activity 34
III. Posttranslational Products of Proghrelin 36
A. Ghrelin and desacyl ghrelin 36
B. C-ghrelin peptides 39
IV. Distribution of Proghrelin Peptides 41
V. Proghrelin Peptides in Lower Vertebrates 43
VI. Summary 44
References 44
Chapter 3: Structure of Mammalian and Nonmammalian Ghrelins 50
I. Introduction 51
II. Mammalian Ghrelin 52
A. Molecular forms of ghrelin in rat stomach 52
B. Multiple forms of ghrelin in human stomach 53
C. Molecular forms of ghrelin in several tissues 54
D. Other mammalian ghrelin 54
III. Nonmammalian Ghrelin 55
A. Bird ghrelin 55
B. Fish ghrelins 56
C. Frog ghrelin 58
D. Reptile ghrelin 59
IV. Ghrelin and Motilin Family 59
V. Activity Change by Fatty Acid Chain Length of Ghrelin 60
VI. Putative Ghrelin Acyl-Modifying Enzyme 60
VII. Conclusion 62
References 62
Chapter 4: The Growth Hormone Secretagogue Receptor 66
I. Introduction: A Case of Reverse Pharmacology 67
II. Genetics and Molecular Biology 68
A. The GHSR gene 68
B. Structure of GHSR1a 71
III. Regulation of Gene Expression 74
A. Promoter sequences 74
B. Hormonal regulation 75
C. Ligand-independent activity 76
IV. Signal Transduction 77
A. Pathways leading to GH secretion 77
B. Other signaling systems 80
V. GHSR1a: Tissue Distribution and Functions in Different Organ Systems 81
A. The hypothalamic-pituitary axis and energy balance 81
B. Energy balance 83
C. Immune system modulation and anti-inflammatory properties of ghrelin 86
D. Ghrelin, GHSR, and aging 90
E. Expression and effects in other tissues 93
VI. Other Ligands 93
A. Alternative forms of ghrelin 93
B. Adenosine 94
C. Cortistatin 96
VII. Evidence for Other Receptors 96
VIII. Future Directions 97
References 98
Chapter 5: Basic Aspects of Ghrelin Action 108
I. Introduction 109
II. Structure of GHSR1a: A G-Protein–Coupled Receptor 110
III. How to Define the Role of the System Ghrelin/GHSR1a? 115
IV. Are There Alternative Ligands for the GHSR1a? 116
V. Endocytosis of GHSR1a 117
VI. Homo- or Heteromeric Complexes for GHSR1a 118
VII. GHSR1a: G-Protein-Signaling Pathways 120
VIII. A Brief Commentary: ‘‘New’’ Receptors for Ghrelin and Desacyl Ghrelin 126
IX. Concluding Remarks 127
Acknowledgments 128
References 128
Chapter 6: Appetite and Metabolic Effects of Ghrelin and Cannabinoids: Involvement of AMP-Activated Protein Kinase 140
I. Introduction 141
II. Ghrelin 141
A. Function 141
B. Appetite effects 142
C. Metabolic effects 144
D. Effects on cardiovascular system 145
III. Cannabinoids 146
A. Function 146
B. Appetite effects 147
C. Metabolic effects 148
D. Effects on cardiovascular system 149
IV. Adenosine Monophosphate-Activated Protein Kinase 150
A. Structure 150
B. Role on appetite 152
C. Role on peripheral metabolism: Glucose and lipids 152
D. Role on cardiovascular function 153
V. The Effects of Ghrelin and Cannabinoids on AMPK 154
A. Human studies with rimonabant 156
References 157
Chapter 7: Ghrelin and Feedback Systems 168
I. Introduction 169
II. Regulation of Ghrelin Secretion 170
A. Starvation and feeding 170
B. Efferent vagus nerve 171
C. Body weight 171
D. Hormones and peptides 172
E. Brain neurotransmitters 176
F. Gastric bypass 177
III. Afferent Pathways of Ghrelin from the Stomach to the Hypothalamus 177
IV. Hyperphagia, Obesity, and Des-acyl Ghrelin 178
V. Hypothalamic Gene Expression and Plasma Des-acyl Ghrelin 180
VI. Conclusion 180
Acknowledgments 181
References 181
Chapter 8: Ghrelin Gene-Related Peptides Modulate Rat White Adiposity 190
I. Introduction 191
II. Effects of Ghrelin on Rat Retroperitoneal Adipocyte Endocrine Functions 195
A. Animals 195
B. RP adipocyte isolation 195
C. Set up of the adipocyte culture system for evaluation of the leptin-releasing activity of ghrelin-related substances 196
D. Adipocyte RNA isolation and analyses 196
E. Leptin measurement 197
F. RP adipocyte endocrine function 198
III. Desacyl Ghrelin as a Potential Physiological Modulator of Adiposity 202
A. Isolation and differentiation of RP preadipocytes 203
B. Determination of glucose concentration in culture medium 204
C. RT-PCR analysis 205
IV. Discussion and Remarks 212
Acknowledgments 218
References 218
Chapter 9: Cardiac, Skeletal, and Smooth Muscle Regulation by Ghrelin 226
I. Introduction 227
II. Structure and Distribution of Ghrelin 229
A. Structure 229
B. Distribution 229
C. Receptors 233
III. Contractile Effects of Ghrelin 236
A. Myocardium 236
B. Smooth muscle 242
C. Skeletal muscle 246
Acknowledgments 249
References 249
Chapter 10: Ghrelin and Bone 258
I. Bone Balance: Resorption and Formation 258
II. Interplay Between the Gastrointestinal System and Bone: The Effect of Gastrectomy/Fundectomy on Bone 259
III. Effects of GH and GHS on Bone Metabolism 261
IV. Correlation Between Ghrelin and Bone Parameters in Clinical Studies 263
V. Effects of Ghrelin on Osteoblastic Cells In Vitro 264
VI. Conclusions 268
References 268
Chapter 11: Ghrelin in Pregnancy and Lactation 278
I. Introduction 279
II. GHSRs in Pregnancy 279
III. Ghrelin in the Fallopian Tubes, Uterus, and Placenta 281
IV. Ghrelin Secretion in Pregnancy 281
A. Diurnal profile: Effect of meals, sleep, and tobacco 283
B. Ghrelin secretion at delivery 283
V. Placenta as a Source of Ghrelin? 284
VI. Physiological Actions of Ghrelin in Pregnancy 285
A. Appetite and adipose tissue metabolism 285
B. Hyperinsulinemia and insulin resistance 287
C. Ghrelin and the GH axis 287
D. Hypertensive disorders: Preeclampsia 290
E. Direct effects of maternal ghrelin levels on the fetus 291
F. Birth 291
G. Other effects 291
VII. Lactation 292
VIII. Fetal Ghrelin 293
A. Fetal ghrelin and fetal and neonatal growth 294
IX. Future Directions for Research 295
X. Summary 295
Acknowledgments 296
References 296
Chapter 12: Ghrelin and Reproduction: Ghrelin as Novel Regulator of the Gonadotropic Axis 304
I. Introduction: Ghrelin Is a Multifunctional Regulator with Key Roles in Energy Balance 305
II. Neuroendocrine Control of Reproduction: The Gonadotropic Axis 306
III. Reproduction and the Energy Status Are Functionally Linked 307
IV. Ghrelin as Putative Regulator of the Gonadotropic Axis 308
V. Role of Ghrelin in the Control of Gonadotropin Secretion 308
VI. Putative Roles of Ghrelin in Puberty Onset 310
VII. Molecular Diversity of Ghrelin: Reproductive Effects of UAG and Obestatin 311
VIII. Expression and Direct Actions of Ghrelin in the Gonads 312
IX. Futures Perspectives and Conclusions 314
Acknowledgments 316
References 317
Chapter 13: Ghrelin and Prostate Cancer 320
I. Prostate Cancer 321
II. Influences of Hormones on Prostate Cancer Progression 322
III. The Peptide Hormone Ghrelin and Prostate Cancer 326
A. The many faces of the ghrelin biology 326
B. Effects on cell growth 330
C. Ghrelin and its receptors in human prostate tumors and related cell lines 331
D. Functional role of ghrelin in prostate cancer 333
IV. Conclusions 334
Acknowledgments 335
References 335
Chapter 14: Novel Connections Between the Neuroendocrine and Immune Systems: The Ghrelin Immunoregulatory Network 344
I. Neuroendocrine–Immune Interactions 345
II. The Growth Hormone Secretagogue Receptor 346
A. Growth hormone secretagogues 346
B. GHSR properties 347
C. GHSR expression on immune cells 347
III. Ghrelin: Hormone or Cytokine? 348
A. Properties of ghrelin 348
B. Sources of ghrelin production 349
C. Biological and functional activities of ghrelin 351
IV. Conclusions 360
Acknowledgments 361
References 361
Index 366