New Transcription Factors and Their Role in Diabetes and Therapy (eBook)

Cover 1
Contents 6
Preface 8
List of contributors 10
Chapter 1. Transcription factor genes in type 2 diabetes 14
1. Introduction 14
2. The PPARG gene 15
3. Maturity onset diabetes of the young (MODY) 15
4. Transcription factor MODY genes 18
5. Conclusion 23
Acknowledgements 23
References 23
Chapter 2. PPAR., a key therapeutic target in the metabolic syndrome – unique insights derived from the study of human genetic variants 28
1. Introduction 29
2. PPAR. – a ‘metabolic’ nuclear receptor 31
3. PPAR. – human genetic variants 32
4. PPAR. – a rational therapeutic target in the human metabolic syndrome 35
5. Conclusions and future directions 48
References 49
Chapter 3. PPARd: Emerging therapeutic potential of novel agonists in lipid and glucose homeostasis 56
1. Introduction 56
2. PPARd: the rise of an abandoned orphan 59
3. PPARd in lipid and carbohydrate metabolism: a potential phoenix from the ashes 61
Acknowledgements 70
References 70
Chapter 4. Liver X receptors as potential drug targets for diabetes and its disorders 76
1. Introduction to LXR 76
2. LXR signaling in carbohydrate metabolism 83
3. LXR signaling in lipid and cholesterol metabolism 85
4. The LXRs control energy homeostasis 89
5. The LXRs are anti-atherosclerotic and anti-inflammatory factors 90
6. Cross-talk between the LXRs and other NRs regulates overall body homeostasis 93
7. Perspectives 95
References 96
Chapter 5. SREBP-1c regulation of nutrient homeostasis and lipid accumulation 104
1. Introduction 104
2. Structure, genes and tissue distribution of SREBP isoforms 105
3. Regulation of SREBP-1c transcriptional activity 106
4. SREBP target genes 110
5. Mechanisms involved in glucose action: involvement of the ‘‘Carbohydrate Response Element Binding Protein’’ transcription factor 114
6. SREBPs and physiopathology 115
7. Conclusion 117
Acknowledgments 118
References 118
Chapter 6. The adipocyte and adipose tissue as endocrine organs: Impact on the insulin resistance phenotype 128
1. Embryonic development of adipose tissue and the role of angiogenesis 128
2. Expansion of adiose tissue mass: hypertrophy versus hyperplasia and impact on adipocyte function 129
3. Adipose tissue distribution and its relation to metabolism-depot specificity 131
4. Impact of PPAR agonists on adipokines in disease states 140
References 145
Chapter 7. FOXC2 in the adipocyte 156
1. Introduction 156
2. The gene and its expression profile 157
3. Function in metabolism 157
4. Regulation of FOXC2 159
5. WAT versus BAT 159
6. Protection against diet-induced insulin resistance 160
7. Human data 161
8. The autonomic nervous system 162
9. Future 163
Acknowledgment 163
References 163
Chapter 8. Regulation of adipocyte differentiation and metabolism by Wnt signaling and C/EBP transcription factors 166
1. Introduction 166
2. Roles for Wnt signaling in adipogenesis and glucose homeostasis 168
3. Role of C/EBPS in hepatocyte differentiation and liver metabolism 172
4. Roles for C/EBPs in adipocyte differentiation and metabolism 173
Acknowledgments 178
References 178
Chapter 9. GATA proteins as molecular gatekeepers of adipogenesis 186
1. Transcriptional activators of adipogenesis 187
2. Negative regulators of adipogenesis 187
3. Gata transcription factors 189
4. A role for GATA co-factors in adipogenesis? 193
5. Future directions 194
References 194
Chapter 10. Forkhead proteins and the regulation of hepatic gene expression 200
1. Hepatic fuel metabolism 200
2. Foxo proteins: molecular targets of hormonal regulation 205
3. Physiological function of FoxO-proteins in hepatic metabolism and insulin action 212
4. Conclusions 215
References 215
Chapter 11. Disruption of CREB regulated of gene expression in diabetes 224
1. Introduction 225
2. CREB and C/EBP involvement in cellular differentiation 226
3. CREB and C/EBP proteins in the vasculature 228
4. CREB regulation of smooth muscle cell phenotype 230
5. Impact of C/EBP isoforms on SMC activation 235
6. CREB-C/EBP responses in SMC life and death decisions
7. CREB function beyond the cardiovascular system 238
8. Summary 238
Acknowledgments 239
Reference 239
Chapter 12. Regulation of PGC-1 in humans with insulin resistance and type 2 diabetes: Functional implications 246
1. Introduction 246
2. PGC-1 family members and their interactions with other molecules 247
3. Regulation of PGC-1a and ß 248
4. Role of PGC-1a and ß in normal physiology 249
5. Role of PGC-1a and ß in pathophysiology of type 2 diabetes 252
6. Role of genes in the regulation of PGC-1a and ß in humans 255
7. Implications for human disease and treatment of T2DM, obesity and insulin resistance 257
Acknowledgments 258
References 258
Chapter 13. Hepatic CCAAT/enhancer binding protein ß (C/EBPß): engineer of diabetes, obesity, and inflammatory disease processes 268
1. Introduction 268
2. Transcriptional control of gluconeogenesis: PEPCK as a model target 269
3. Insulin, glucose, adiponectin, and resistin and PEPCK gene transcription 278
4. Role of C/EBPs in inflammation and ER stress response 280
5. Summary and future perspective 283
References 284
Chapter 14. Insulin resistance, inflammation, and the IKK/I.B/NF-.B pathway 292
1. The obesity/T2DM epidemic 293
2. Insulin resistance in obesity 293
3. The IKK/I.B/NF-.B pathway 294
4. Making the connection: The IKK/I.B/NF-.B pathway and insulin resistance 295
5. Tissue specificity: Insights from targeted manipulations of the IKK/I.B/NF-.B pathway in vivo 296
6. Of mice and men: Relevance of rodent studies to human obesity/T2DM 299
7. Putative mechanisms of insulin resistance arising from activation of the IKK/I.B/NF-.B pathway 300
8. Potential mechanisms of activation of the IKK/I.B/NF-.B pathway in obesity 304
9. Therapeutics 306
10. Conclusions 308
Acknowledgments 308
References 309
Subject Index 316
Colour plate section 324