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

Project: Research project

Project Details

Description

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 ani
StatusFinished
Effective start/end date6/1/169/16/21

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK090625-09)

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