Marc Gilbert is Professor of Physiology, Metabolism and Cell Biology at Pierre and Marie Curie University, France. His research interests include diabetes and obesity.Sergej Pirkmajer is Associate Professor of Pathophysiology and Research Group Leader at the Faculty of Medicine, University of Ljubljana, Slovenia. His research interests include the regulation of energy metabolism and ion transport.

• Preface ixChapter 1 Historical Overview of Endocrinology, Neurology and Immunology 11.1 The history of endocrinology 11.2 The history of neurology 41.3 The history of immunology 7Chapter 2 Regulatory Systems Integrating External and Internal Changes 112.1 Regulatory systems: endocrine, nervous and immune 112.1.1 Endocrine system 142.1.2 Nervous system 182.1.3 Immune system 192.2 Origin and diversity of signals and communication modes 202.2.1 Origin 202.2.2 Diversity 272.2.3 Communication modes 272.3 Integration of extracellular signals: plasma membrane receptors 362.3.1 Chemical signals and mechanisms of action: receptor types and signaling modulation 362.3.2 Integration of multiple signal inputs: ratio of stimulatory vs inhibitory signals 582.3.3 Physical signals 682.4 Nuclear receptors 692.4.1 Chemical nature of signals and functional characteristics of nuclear receptors 692.4.2 Molecular mechanisms underlying regulation of gene transcription 72Chapter 3 Intracellular Events in Response to Signals 753.1 Signaling pathways 753.1.1 General overview 753.1.2 Signal termination 763.1.3 Control of protein activities: allostery, covalent modifications and proteolytic cleavage 883.1.4 Impaired cellular responses to extracellular signals 933.1.5 Subcellular localization and sequestration 1003.1.6 Crosstalk 1083.2 Sensing of extracellular and intracellular cues 1143.2.1 Sensing of extracellular cues 1143.2.2 Sensing of intracellular cues 1213.3 Functional diversity of proteins 1303.3.1 Multifaceted "master regulators" 1303.3.2 Molecular motor proteins 1383.3.3 Interactional domains 1393.3.4 Carrier proteins 1423.3.5 Decoy molecules 1433.3.6 Heat shock proteins as molecular chaperones 1453.3.7 Hormone-like peptides: molecular mimicry 1463.3.8 Telomerase and integrity of linear chromosomes 146Chapter 4 Integrative Aspects: From Cellular to Whole-Body Level 1494.1 Homeostasis equilibrium: dynamic steady state 1494.1.1 Regulation of systemic glucose homeostasis 1504.1.2 Tissue homeostasis 1524.1.3 Muscle and bone mass homeostasis 1574.1.4 Whole-body energy homeostasis 1584.1.5 Metabolism and cellular energy homeostasis 1604.1.6 The gut microbiome and glucose homeostasis 1604.1.7 Synaptic homeostasis 1614.1.8 Open issues: membrane lipid homeostasis and acid–base homeostasis 1624.2 Homeostasis disruption 1624.2.1 Endocrine disorders: excess or impaired hormone secretion 1634.2.2 Muscle energy wasting 1654.2.3 Energy 1654.2.4 Cell number and activity 1654.3 Crosstalk between organs, tissues and regulatory systems 1684.3.1 Axis concept 1694.3.2 Crosstalk between neuroendocrine axes 1774.3.3 Crosstalks between organs and brain 1794.3.4 Crosstalk between immune, endocrine and nervous systems 1934.3.5 Immune system and cancer cell interactions 1994.3.6 Adjustments of intermediary metabolism: brain, skeletal muscle, cancer cells 202Chapter 5 Epigenetics and Circadian Rhythms: Role of Environmental Factors 2135.1 Epigenetics: general overview 2135.1.1 Epigenetic modifications of DNA and regulation of biological processes 2165.1.2 Genomic imprinting 2205.1.3 Setting and maintenance of DNA methylation 2225.1.4 Evidence for non-genomic inheritance: epigenetic mechanisms 2245.1.5 Nutritional influences on developmental epigenetics 2265.1.6 Gut microbiome and epigenetic changes 2315.1.7 Metabolites and epigenetic changes 2315.1.8 Social environment and endocrine disruptor: epigenetic changes 2325.1.9 Importance of epigenetics in the etiology of cancer 2345.1.10 In vitro reprogramming systems 2405.2 Circadian rhythms 2415.2.1 Circadian rhythms and the concept of a circadian clock 2425.2.2 Overview of the mammalian clock 2435.2.3 Mechanisms by which circadian clocks govern biological processes 2455.2.4 How is the SCN clock connected to tissue and cellular functions? 2465.2.5 Avian circadian clock 2545.3 Conclusion 255Concluding Remarks 257References 261Index 319

Marc Gilbert is Professor of Physiology, Metabolism and Cell Biology at Pierre and Marie Curie University, France. His research interests include diabetes and obesity.Sergej Pirkmajer is Associate Professor of Pathophysiology and Research Group Leader at the Faculty of Medicine, University of Ljubljana, Slovenia. His research interests include the regulation of energy metabolism and ion transport.

• Preface ixChapter 1 Historical Overview of Endocrinology, Neurology and Immunology 11.1 The history of endocrinology 11.2 The history of neurology 41.3 The history of immunology 7Chapter 2 Regulatory Systems Integrating External and Internal Changes 112.1 Regulatory systems: endocrine, nervous and immune 112.1.1 Endocrine system 142.1.2 Nervous system 182.1.3 Immune system 192.2 Origin and diversity of signals and communication modes 202.2.1 Origin 202.2.2 Diversity 272.2.3 Communication modes 272.3 Integration of extracellular signals: plasma membrane receptors 362.3.1 Chemical signals and mechanisms of action: receptor types and signaling modulation 362.3.2 Integration of multiple signal inputs: ratio of stimulatory vs inhibitory signals 582.3.3 Physical signals 682.4 Nuclear receptors 692.4.1 Chemical nature of signals and functional characteristics of nuclear receptors 692.4.2 Molecular mechanisms underlying regulation of gene transcription 72Chapter 3 Intracellular Events in Response to Signals 753.1 Signaling pathways 753.1.1 General overview 753.1.2 Signal termination 763.1.3 Control of protein activities: allostery, covalent modifications and proteolytic cleavage 883.1.4 Impaired cellular responses to extracellular signals 933.1.5 Subcellular localization and sequestration 1003.1.6 Crosstalk 1083.2 Sensing of extracellular and intracellular cues 1143.2.1 Sensing of extracellular cues 1143.2.2 Sensing of intracellular cues 1213.3 Functional diversity of proteins 1303.3.1 Multifaceted "master regulators" 1303.3.2 Molecular motor proteins 1383.3.3 Interactional domains 1393.3.4 Carrier proteins 1423.3.5 Decoy molecules 1433.3.6 Heat shock proteins as molecular chaperones 1453.3.7 Hormone-like peptides: molecular mimicry 1463.3.8 Telomerase and integrity of linear chromosomes 146Chapter 4 Integrative Aspects: From Cellular to Whole-Body Level 1494.1 Homeostasis equilibrium: dynamic steady state 1494.1.1 Regulation of systemic glucose homeostasis 1504.1.2 Tissue homeostasis 1524.1.3 Muscle and bone mass homeostasis 1574.1.4 Whole-body energy homeostasis 1584.1.5 Metabolism and cellular energy homeostasis 1604.1.6 The gut microbiome and glucose homeostasis 1604.1.7 Synaptic homeostasis 1614.1.8 Open issues: membrane lipid homeostasis and acid–base homeostasis 1624.2 Homeostasis disruption 1624.2.1 Endocrine disorders: excess or impaired hormone secretion 1634.2.2 Muscle energy wasting 1654.2.3 Energy 1654.2.4 Cell number and activity 1654.3 Crosstalk between organs, tissues and regulatory systems 1684.3.1 Axis concept 1694.3.2 Crosstalk between neuroendocrine axes 1774.3.3 Crosstalks between organs and brain 1794.3.4 Crosstalk between immune, endocrine and nervous systems 1934.3.5 Immune system and cancer cell interactions 1994.3.6 Adjustments of intermediary metabolism: brain, skeletal muscle, cancer cells 202Chapter 5 Epigenetics and Circadian Rhythms: Role of Environmental Factors 2135.1 Epigenetics: general overview 2135.1.1 Epigenetic modifications of DNA and regulation of biological processes 2165.1.2 Genomic imprinting 2205.1.3 Setting and maintenance of DNA methylation 2225.1.4 Evidence for non-genomic inheritance: epigenetic mechanisms 2245.1.5 Nutritional influences on developmental epigenetics 2265.1.6 Gut microbiome and epigenetic changes 2315.1.7 Metabolites and epigenetic changes 2315.1.8 Social environment and endocrine disruptor: epigenetic changes 2325.1.9 Importance of epigenetics in the etiology of cancer 2345.1.10 In vitro reprogramming systems 2405.2 Circadian rhythms 2415.2.1 Circadian rhythms and the concept of a circadian clock 2425.2.2 Overview of the mammalian clock 2435.2.3 Mechanisms by which circadian clocks govern biological processes 2455.2.4 How is the SCN clock connected to tissue and cellular functions? 2465.2.5 Avian circadian clock 2545.3 Conclusion 255Concluding Remarks 257References 261Index 319

Marc Gilbert is Professor of Physiology, Metabolism and Cell Biology at Pierre and Marie Curie University, France. His research interests include diabetes and obesity.Sergej Pirkmajer is Associate Professor of Pathophysiology and Research Group Leader at the Faculty of Medicine, University of Ljubljana, Slovenia. His research interests include the regulation of energy metabolism and ion transport.

• Preface ixChapter 1 Historical Overview of Endocrinology, Neurology and Immunology 11.1 The history of endocrinology 11.2 The history of neurology 41.3 The history of immunology 7Chapter 2 Regulatory Systems Integrating External and Internal Changes 112.1 Regulatory systems: endocrine, nervous and immune 112.1.1 Endocrine system 142.1.2 Nervous system 182.1.3 Immune system 192.2 Origin and diversity of signals and communication modes 202.2.1 Origin 202.2.2 Diversity 272.2.3 Communication modes 272.3 Integration of extracellular signals: plasma membrane receptors 362.3.1 Chemical signals and mechanisms of action: receptor types and signaling modulation 362.3.2 Integration of multiple signal inputs: ratio of stimulatory vs inhibitory signals 582.3.3 Physical signals 682.4 Nuclear receptors 692.4.1 Chemical nature of signals and functional characteristics of nuclear receptors 692.4.2 Molecular mechanisms underlying regulation of gene transcription 72Chapter 3 Intracellular Events in Response to Signals 753.1 Signaling pathways 753.1.1 General overview 753.1.2 Signal termination 763.1.3 Control of protein activities: allostery, covalent modifications and proteolytic cleavage 883.1.4 Impaired cellular responses to extracellular signals 933.1.5 Subcellular localization and sequestration 1003.1.6 Crosstalk 1083.2 Sensing of extracellular and intracellular cues 1143.2.1 Sensing of extracellular cues 1143.2.2 Sensing of intracellular cues 1213.3 Functional diversity of proteins 1303.3.1 Multifaceted "master regulators" 1303.3.2 Molecular motor proteins 1383.3.3 Interactional domains 1393.3.4 Carrier proteins 1423.3.5 Decoy molecules 1433.3.6 Heat shock proteins as molecular chaperones 1453.3.7 Hormone-like peptides: molecular mimicry 1463.3.8 Telomerase and integrity of linear chromosomes 146Chapter 4 Integrative Aspects: From Cellular to Whole-Body Level 1494.1 Homeostasis equilibrium: dynamic steady state 1494.1.1 Regulation of systemic glucose homeostasis 1504.1.2 Tissue homeostasis 1524.1.3 Muscle and bone mass homeostasis 1574.1.4 Whole-body energy homeostasis 1584.1.5 Metabolism and cellular energy homeostasis 1604.1.6 The gut microbiome and glucose homeostasis 1604.1.7 Synaptic homeostasis 1614.1.8 Open issues: membrane lipid homeostasis and acid–base homeostasis 1624.2 Homeostasis disruption 1624.2.1 Endocrine disorders: excess or impaired hormone secretion 1634.2.2 Muscle energy wasting 1654.2.3 Energy 1654.2.4 Cell number and activity 1654.3 Crosstalk between organs, tissues and regulatory systems 1684.3.1 Axis concept 1694.3.2 Crosstalk between neuroendocrine axes 1774.3.3 Crosstalks between organs and brain 1794.3.4 Crosstalk between immune, endocrine and nervous systems 1934.3.5 Immune system and cancer cell interactions 1994.3.6 Adjustments of intermediary metabolism: brain, skeletal muscle, cancer cells 202Chapter 5 Epigenetics and Circadian Rhythms: Role of Environmental Factors 2135.1 Epigenetics: general overview 2135.1.1 Epigenetic modifications of DNA and regulation of biological processes 2165.1.2 Genomic imprinting 2205.1.3 Setting and maintenance of DNA methylation 2225.1.4 Evidence for non-genomic inheritance: epigenetic mechanisms 2245.1.5 Nutritional influences on developmental epigenetics 2265.1.6 Gut microbiome and epigenetic changes 2315.1.7 Metabolites and epigenetic changes 2315.1.8 Social environment and endocrine disruptor: epigenetic changes 2325.1.9 Importance of epigenetics in the etiology of cancer 2345.1.10 In vitro reprogramming systems 2405.2 Circadian rhythms 2415.2.1 Circadian rhythms and the concept of a circadian clock 2425.2.2 Overview of the mammalian clock 2435.2.3 Mechanisms by which circadian clocks govern biological processes 2455.2.4 How is the SCN clock connected to tissue and cellular functions? 2465.2.5 Avian circadian clock 2545.3 Conclusion 255Concluding Remarks 257References 261Index 319