The expansion across industrialized nations of both visceral obesity and metabolic syndrome has caused an escalation of co-morbidities including cardiovascular disease, stroke, blindness, renal failure and thrombosis. The clear rise in these disorders tracks with high-saturated fat diet and overnutrition, suggesting that macronutrient and lipid specifically play a major role in the onset and progression of disease. A surprising observation has been that both shiftwork and night-eating are associated with increased risk of metabolic syndrome. Exciting studies completed subsequent to our previous submission of this proposal now establish that the molecular clock, a conserved internal system that evolved to synchronize physiology in anticipation of the rotation of the Earth, regulates mitochondrial oxidative capacity and that circadian disruption phenocopies the metabolic myopathy syndrome in humans that is characterized by liver lipid accumulation, mitochondrial dysfunction, and fasting-induced seizures. Remarkably, we have also established that we can reverse the mitochondrial defects in circadian disruption using the prodrug NMN, which boosts intracellular NAD+ levels and enhances the activity of NAD+-dependent deacetylases critical in metabolic adaptation. Indeed, it is now apparent that clocks exist throughout all tissues of the body and that the normal phase alignment of the brain clock with peripheral tissue clocks undergoes misalignment with shiftwork, night-eating, and even with high-fat diet. Thus a long-term objective of our proposal is to test the hypothesis that circadian disruption contributes to metabolic disorders by altering mitochondrial oxidative capacity across the sleep/wake-fasting/feeding cycle. An innovation of our work is to integrate studies of clock and mitochondrial biology and to dissect the impact of clock time on macronutrient metabolism. Ultimately, we are now poised to create deeper insight into the contribution of timing to mitochondrial function that will be applicable to obesity, metabolic syndrome, and type 2 diabetes therapeutics.
The rising incidence of both obesity and type 2 diabetes in the recent decades poses a serious public health concern in both the US and the developing world. The emphasis of our research plan is based on our recent and exciting discovery that disruption of the circadian clock leads to obesity and metabolic syndrome, as is often the case for shift or night workers, who routinely disrupt their daily cycles of sleep/wake-fasting/feeding. To better understand the interplay between the timing of food intake and its effect on metabolism, we propose a series of experimental studies using state-of-the-art technologies in order to understand how dietary fat and circadian time interact to regulate energy efficiency, potentially uncovering novel therapeutic interventions for diabetes, obesity, and other metabolic disorders arising from circadian disruption.
|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|
|Rai, Rahul; Ghosh, Asish K; Eren, Mesut et al. (2017) Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan. Cell Rep 21:1471-1480|
|Bass, Joseph T (2017) The circadian clock system's influence in health and disease. Genome Med 9:94|
|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|
|Perelis, M; Ramsey, K M; Bass, J (2015) The molecular clock as a metabolic rheostat. Diabetes Obes Metab 17 Suppl 1:99-105|