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, several environmental factors associated with industrialization are now believed to be linked to the development of obesity and metabolic dysfunction, including an increase in night-time shiftwork, jetlag, sleep restriction, and late-night eating, all of which can be traced to the spred of electric light. More recently, the overuse of illuminated screens that emit blue light in eReaders are also believed to induce a persistent jetlag state. While epidemiologic studies have provided mounting evidence for circadian disruption as a risk factor for metabolic disease, this work is limited as it is primarily correlative and the mechanistic basis linking circadian disorder to metabolic pathophysiology are not well established. Transformative discoveries have been that the core clock transcription factors CLOCK/BMAL1 are present not only in master pacemaker neurons of the hypothalamus, but also with within peripheral metabolic tissues, and that mutation of the mammalian Clock gene leads to obesity and metabolic syndrome, characterized by alterations in feeding time and intake, sleep, and energy expenditure. Further, during our previous grant cycle, we established that CLOCK/BMAL1 dysfunction specifically in pancreas leads to hypoinsulinemic diabetes mellitus independently of effects of the mutation on early growth and development. With analysis of the interplay between the ?-cell and brain clock as the centerpiece of our grant, we have now developed inducible genetic and genomic approaches to define the molecular regulatory mechanisms through which (i) the ?-cell clock controls rhythms of endogenous glucose-stimulated insulin secretion, nutrient signaling, and triggering of vesicle release through pathways involving protein kinase C and phosphoinositide, and (ii) the brain clock coordinates feeding time with activity of hypothalamic neurons regulating energy homeostasis. Our long-term objective is to test the hypothesis that circadian disruption, and the corresponding misalignment of rhythmic genomic cycles in peripheral ?-cells and liver with those of brain, contributes to metabolic disorders by impairing glucose- responsive insulin secretion and desynchronizing hepatic gluconeogenesis with the sleep/wake-fasting/feeding cycle. An innovation of our work is the integration of 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 uncover new insight into how the central and peripheral clocks synchronize behavioral and transcriptional rhythms to impact physiology, findings which have broad implications for the treatment and prevention of obesity, metabolic syndrome, and type 2 diabetes mellitus.
The rising incidence of obesity and type 2 diabetes over the past quarter century poses an unprecedented public health challenge in the US and throughout the globe. The major thrust of our research plan is based upon our discovery of a physiologic role for the circadian gene program in both brain and ? -cells in the coordination of feeding time and rhythms of glucose metabolism across the daily sleep-wake cycle. Our work in both genetic mouse models and in human islets seeks to understand how 'time-of-day' impacts the ability to metabolize glucose, and ultimately, these studies will define new avenues for the evaluation, treatment, and prevention of obesity and diabetes.
|Hong, Hee-Kyung; Maury, Eleonore; Ramsey, Kathryn Moynihan et al. (2018) Requirement for NF-?B in maintenance of molecular and behavioral circadian rhythms in mice. Genes Dev 32:1367-1379|
|Peek, Clara Bien; Levine, Daniel C; Cedernaes, Jonathan et al. (2017) Circadian Clock Interaction with HIF1? Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle. Cell Metab 25:86-92|
|Bass, Joseph T (2017) The circadian clock system's influence in health and disease. Genome Med 9:94|
|Spaeth, Jason M; Gupte, Manisha; Perelis, Mark et al. (2017) Defining a Novel Role for the Pdx1 Transcription Factor in Islet ?-Cell Maturation and Proliferation During Weaning. Diabetes 66:2830-2839|
|Perelis, Mark; Ramsey, Kathryn Moynihan; Marcheva, Biliana et al. (2016) Circadian Transcription from Beta Cell Function to Diabetes Pathophysiology. J Biol Rhythms 31:323-36|
|Bass, Joseph; Lazar, Mitchell A (2016) Circadian time signatures of fitness and disease. Science 354:994-999|
|Perelis, Mark; Marcheva, Biliana; Ramsey, Kathryn Moynihan et al. (2015) Pancreatic ? cell enhancers regulate rhythmic transcription of genes controlling insulin secretion. Science 350:aac4250|
|Peek, C B; Ramsey, K M; Levine, D C et al. (2015) Circadian regulation of cellular physiology. Methods Enzymol 552:165-84|
|Perelis, M; Ramsey, K M; Bass, J (2015) The molecular clock as a metabolic rheostat. Diabetes Obes Metab 17 Suppl 1:99-105|
|Peek, Clara Bien; Affinati, Alison H; Ramsey, Kathryn Moynihan et al. (2013) Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 342:1243417|
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