Title Page -- Copyright Page -- Contents -- List of Contributors -- Preface -- Part I Fundamental Concepts -- Chapter 1 Cytosolic and Transcriptional Cycles Underlying Circadian Oscillations -- 1.1 Introduction -- 1.2 Assembling the transcriptional feedback loop -- 1.2.1 Discovering clock genes and their actions in lower species -- 1.2.2 Discovering clock genes and their actions in mammals -- 1.2.3 Imaging the transcriptional clock in real time: a multitude of cellular oscillators appears -- 1.2.4 Elaborating the core transcriptional clockwork -- 1.3 Keeping the transcriptional clockworks in tune -- 1.3.1 Entrainment of the SCN transcriptional clockwork -- 1.3.2 Entrainment of transcriptional clocks in peripheral tissues -- 1.3.3 Local tissue clocks direct local transcriptional and posttranscriptional programs -- 1.4 Building posttranslational mechanisms into the circadian pacemaker -- 1.4.1 Posttranslational control of the clock: localization and stability of clock proteins -- 1.4.2 Metabolic regulation of the transcriptional clockwork -- 1.4.3 Cause versus effect in circadian transcriptional regulation -- 1.5 Is the transcriptional clock paramount? -- 1.5.1 Cytosolic rhythms and the SCN pacemaker -- 1.5.2 Totally transcription-free pacemaking -- 1.5.3 A general model for mammalian cellular circadian timekeeping -- 1.6 Conclusion: cytoscillators, clocks and therapies -- Acknowledgements -- References -- Chapter 2 Molecular Determinants of Human Circadian Clocks -- 2.1 Molecular elements of human clocks: a brief review -- 2.2 Peripheral and central clocks -- 2.3 Signaling to peripheral circadian clocks -- 2.4 Human peripheral and central clocks -- 2.5 Human genetics -- 2.6 Technologies for measurement of human circadian clocks -- 2.7 Cellular methods -- 2.8 Omics-based methods to analyze human clocks -- 2.9 Summary and outlook -- References.

Chapter 3 The Suprachiasmatic Nucleus (SCN): Critical Points -- 3.1 SCN is site of master circadian pacemaker in mammals -- 3.2 SCN receives photic information through a specialized light detection pathway -- 3.3 SCN neurons are endogenous single cell oscillators that generate rhythms in neural activity -- 3.4 The SCN has circuit level organization that is just beginning to be unraveled -- 3.5 Coupling with the SCN circuit is mediated by a set of peptides with VIP on top of the hierarchy -- 3.6 SCN outputs -- 3.6.1 SCN neurons are directly neurosecretory cells -- 3.6.2 Body temperature rhythms as an output -- 3.6.3 SCN regulates the autonomic nervous system -- 3.6.4 Melatonin is a key hormone under circadian regulation -- 3.6.5 HPA axis is another important endocrine network regulated by the circadian system -- 3.6.6 The SCN regulates the arousal of the central nervous system -- 3.6.7 The SCN circuit controls the temporal patterning behaviors (activity, sleep, feeding) with widespread implications for our bodily function -- 3.7 SCN in aging and disease -- References -- Chapter 4 Sleep and Circadian Rhythms: Reciprocal Partners in the Regulation of Physiology and Behavior -- 4.1 Introduction -- 4.2 What is sleep -- 4.3 Circadian regulation of sleep -- 4.3.1 Behavioral studies: human sleep -- 4.3.2 Behavioral studies: rodent models -- 4.3.3 Neural mechanisms -- 4.3.4 Molecular mechanisms, local oscillators and local sleep -- 4.4 Reciprocity: sleep-wake feedback to the circadian clock -- 4.4.1 Feedback from waking states -- 4.4.2 Feedback from sleep states -- 4.5 Conclusions: Circadian clocks and sleep are intertwined processes -- References -- Chapter 5 Circadian Regulation of Arousal and its Role in Fatigue -- 5.1 Defining arousal -- 5.2 Brain structures important for arousal -- 5.3 Neurochemicals signaling the states of arousal.

5.4 Circadian regulation of the arousal system -- 5.5 Influence of input pathways on circadian regulation of arousal -- 5.6 Sustained states of fatigue: a disorder of the arousal network? -- 5.7 Conclusions -- References -- Part II Circadian Regulation of Major Physiological Systems -- Chapter 6 Physiology of the Adrenal and Liver Circadian Clocks -- 6.1 Introduction -- 6.2 Circadian control of adrenal function -- 6.2.1 Glucocorticoids (GCs) -- 6.2.2 Mineralocorticoids (MCs) -- 6.2.3 Catecholamines (CAs) -- 6.2.4 Adrenal clocks -- 6.2.5 Local control of MC rhythms -- 6.2.6 Local control of GC rhythms -- 6.3 Circadian control of liver function -- 6.3.1 Glucose metabolism -- 6.3.2 Lipid metabolism -- 6.3.3 Detoxification -- 6.3.4 Hepatocyte clocks -- 6.3.5 Local control of energy metabolism -- 6.3.6 Local control of biotransformation -- 6.4 Conclusion -- Acknowledgements -- References -- Chapter 7 Nutrition and Diet as Potent Regulators of the Liver Clock -- 7.1 Introduction -- 7.2 Food is a "zeitgeber": The FEO in the brain -- 7.2.1 Food entrainment and food anticipatory activity -- 7.2.2 Role of the SCN on the FEO -- 7.2.3 FEO formation and characteristics in the brain -- 7.3 The FEO in peripheral tissues -- 7.3.1 Discovery of the FEO in peripheral tissues -- 7.3.2 Effect of meal frequency and pattern on the FEO -- 7.3.3 Role of clock genes in FAA and FEO in the brain and FEO in peripheral tissues -- 7.4 What should we eat? What types of food can stimulate the peripheral clock? -- 7.4.1 Role of nutrients in the FEO -- 7.4.2 Foods beyond nutrients -- 7.4.3 Signal transduction in peripheral FEO -- 7.5 When should we eat? Application to human life science -- 7.6 Circadian rhythm and obesity and diabetes -- 7.6.1 Feeding frequency and patterns affect obesity and diabetes -- 7.6.2 Effect of rotation work and shift work on obesity, diabetes, and cancer.

7.6.3 Effect of calorie restriction on circadian rhythm and life span -- 7.6.4 Role of circadian rhythm in pharmacological and nutritional actions -- References -- Chapter 8 The Cardiovascular Clock -- 8.1 Introduction -- 8.2 The vascular clock -- 8.3 Circadian clock regulation of the endothelial cell layer of blood vessels -- 8.4 The circadian clock in vascular disease -- 8.5 The circadian clock and vascular cell signaling -- 8.6 The circadian rhythm in blood pressure, nighttime hypertension, and cardiovascular disease in humans -- 8.7 Diabetes, obesity, and blood pressure -- 8.8 AT influences the circadian rhythm in experimental hypertension -- 8.9 The circadian clock and fluid balance -- 8.10 The circadian clock and peripheral vascular resistance -- 8.11 Conclusion -- References -- Chapter 9 Hypertension Caused by Disruption of the Circadian System: Blood Pressure Regulation at Multiple Levels -- 9.1 Introduction -- 9.2 Effects of deleting Cry genes -- 9.3 Reduced α-adrenoceptor responsiveness in peripheral vessels and primary aldosteronism of Cry-null mice -- 9.4 Rapid blood pressure control system: enhanced baroreflex in Cry-null mice -- 9.5 Conclusion -- Acknowledgments -- References -- Chapter 10 Chronobiology of Micturition -- 10.1 Introduction -- 10.2 Human studies -- 10.2.1 Children and nocturnal enuresis -- 10.2.2 Aging and nocturia -- 10.2.3 Nocturnal polyuria -- 10.2.4 Daily change in bladder capacity -- 10.2.5 Central control of the kidneys and the bladder -- 10.3 Animal models -- 10.3.1 Rats -- 10.3.2 Mice -- 10.4 The circadian clock and micturition -- 10.5 The clock in the bladder -- 10.5.1 The bladder has rhythm: demonstration of the circadian clock in the bladder -- 10.5.2 Connexin43 (Cx43) is a clock-controlled gene in the bladder -- 10.6 Future directions -- 10.6.1 Basic research -- 10.6.2 Clinical research -- References.

Chapter 11 Disruption of Circadian Rhythms and Development of Type 2 Diabetes Mellitus: Contributions to Insulin Resistance and Beta-cell Failure -- 11.1 Introduction -- 11.2 Mechanisms underlying pathophysiology of Type 2 diabetes mellitus: interaction between insulin resistance and beta-cell failure -- 11.2.1 Circadian disruption and predisposition to Type 2 diabetes mellitus: accumulating evidence from epidemiological, clinical and animal studies -- 11.3 Mechanisms underlying the association between circadian disruption and T2DM -- potential role of obesity and insulin resistance -- 11.4 Mechanisms underlying the association between circadian disruption and T2DM -- potential role of impaired beta-cell secretory function and mass -- 11.5 Conclusion -- References -- Chapter 12 Circadian Clock Control of the Cell Cycle and Links to Cancer -- 12.1 Introduction -- 12.2 Epidemiology -- 12.3 Does circadian clock disruption have any relevance in a clinical setting? -- 12.4 Circadian clock control of the cell cycle in healthy tissues -- 12.5 How might the cellular circadian clock regulate cell cycle timing? -- 12.6 Clock disruption and cancer -- 12.7 Does alteration in clock gene expression in human tumors correlate with the survival of patients? -- 12.8 Circadian-based chemotherapy (Chronotherapy): timing cancer treatment to improve survival -- 12.9 Conclusion -- References -- Chapter 13 How Shift Work and a Destabilized Circadian System may Increase Risk for Development of Cancer and Type 2 Diabetes -- 13.1 Introduction -- 13.2 Shift work and cancer -- 13.2.1 Epidemiologic studies of shift work and breast cancer risk -- 13.2.2 Epidemiologic studies of shift work and prostate cancer -- 13.2.3 Epidemiologic studies of shift work and risk of other cancers -- 13.2.4 Summary of evidence for an association between shift work and cancer.

13.2.5 Consideration of obesity in epidemiologic studies of night shift work and cancer risk.