Integration of Feeding Time and Glucose Metabolism by the Circadian Gene Network

The escalation in the linked epidemics of obesity and diabetes mellitus has led to intensive investigation into environmental and genetic factors that contribute to the spread of these diseases. In addition to sedentary lifestyle and overnutrition, one environmental factor associated with industrialized that has been tied to obesity and metabolic dysfunction is the increase in night-time shiftwork, jetlag, sleep restriction, and late-night eating, all of which can be traced to the spread of electric light and more recently, to overuse of illuminated screens that emit blue light in eReaders that induce a persistent jetlag state. Epidemiologic studies have provided mounting evidence for circadian disruption however this work is limited as it is primarily correlative and the mechanistic basis linking circadian disorders to metabolic pathophysiology have been less well established. The present grant proposal originates with exciting studies exploiting genetic models of circadian gene disruption that originally showed that mutation of the mammalian clock (in ClockΔ19 mice) leads to obesity and metabolic syndrome characterized by alterations in feeding time and intake, sleep, energy expenditure, and peripheral molecular clock function. A transformative discovery was that CLOCK/BMAL1, the core transcription factors in master pacemaker neurons of the hypothalamus, are also expressed within peripheral metabolic tissues, and during our previous grant cycle we have established that CLOCK/BMAL1 dysfunction leads to hypoinsulinemic diabetes mellitus independently of effects of the mutation on early growth and development. With analysis of the interplay between the β-cell clock and brain as the centerpiece of our grant, we have now developed both genetic and genomic approaches to define the molecular regulatory mechanisms through which the β-cell clock controls rhythms of endogenous glucose-stimulated insulin secretion in wild-type animals, and, through comparison with animals harboring tamoxifen-inducible adult-life clock disruption, we have uncoverd direct functions of the clock in β -cell nutrient signaling, insulin trafficking, and triggering of vesicle release through pathways involving protein kinase C and phosphoinositide. We have also probed the role of clock transcription cycles in the coordination of feeding time with activity of hypothalamic neurons regulating energy homeostasis. The long-term objective of our proposal is to test the hypothesis that circadian disruption and misalignment of rhythmic genomic cycles in peripheral b-cells and liver, with those originating from brain, contributes to metabolic disorders by impairing glucose responsive insulin secretion and desynchronizing hepatic gluconeogenesis with the slee/wake-fasting/feeding cycle. An innovation of our work is to integrate studies of cellular and brain clock with genomic analyses to dissect the impact of clock time on glucose metabolism. Ultimately we are now poised to create deeper insight into the role of timing in both insulin responsiveness and signal response to nutrient in b-cell, and the coordination of these processes with feeding and brain control of hepatic glucose metabolism that will have implications for the treatment and prevention of obesity, metabolic syndrome, and type 2 diabetes mellitus.