Strong evidence has implicated the molecular circadian clock as a key integrator of behavior and physiology, and both genetic and epigenetic perturbation of circadian systems has been associated with obesity and cardiovascular disease. Conversely, we have found that high-fat diet leads to disruption of circadian behavioral and molecular rhythms. Interestingly, we have also observed that animals provided high-fat diet only during the dark period gain less weight than those fed only during the light. Collectively, these observations underscore interconnections between overnutrition, circadian disruption, and cardiometabolic pathologies. Recently, we have made the discovery that Nampt, the rate-limiting enzyme in NAD+ biosynthesis, is a clock-controlled gene that produces 24 hr oscillations in levels of NAD+. NAD+ is also an essential cofactor in hepatic lipid and carbohydrate metabolism and may function as an oscillating nutrient sensor coupling circadian and metabolic pathways. Indeed, both Nampt and NAD+ levels are low in Clock19 and Bmal1-/- mice (and increased in Cry1-/-/Cry2-/-animals). In turn, alterations in Nampt/NAD+ modulate the nutrient-responsive deacetylase SIRT1, which we and others have found to inhibit transcription of the clock repressor Per2. Thus the overarching goal of this proposal is to test the hypothesis that high-fat diet, together with alterations in feeding time induced by high-fat intake, disrupts synchrony between cycles of energy storage and utilization in fat and liver and leads to alterations in the nutrient-responsive feedback loop comprised of CLOCK/BMAL1 and NAMPT/NAD+/SIRT1. Taken together, our recent combined findings on cardiometabolic, energy balance, and circadian clock networks have put us in position to test novel hypotheses regarding the mechanisms by which circadian coupled cellular processes regulate cardiometabolic function and energy balance.
The Specific Aims are as follows:
Specific Aim 1 : To test the hypothesis that high-fat diet disrupts circadian control of metabolic physiology due to (a) changes in feeding time and/or (b) due to changes in dietary nutrient composition.
Specific Aim 2 : To test the hypothesis that high-fat diet disrupts properties of the cell autonomous circadian oscillator either (a) due to changes in feeding time and/or (b) due to changes in nutrient composition of diet.
Specific Aim 3 : To test the hypothesis that high-fat diet disrupts the novel circadian-metabolic feedback loop involving NAD+ biogenesis and the NAD+-dependent deacetylase SIRT1.
/ Relevance Recent studies have provided compelling evidence for an interaction between the biological timing system and metabolism. The interrelationship between timing and body clocks originated with studies in experimental animals with mutations in the core endogenous clock gene network. Subsequently, we have found that high- fat Western Diet alone induces reciprocal disruption of circadian behavioral and metabolic rhythms, leading to alterations in the rest-activity, feeding, and glucoregulatory pathway. In addition, we have found that key circulating hormones important in cardiovascular health are controlled by the internal clock, and that a major effect of high-fat diet is to decouple the normal alignment between these internal physiological systems and the external light-dark, rest-activity cycle. These exciting and new observations have directed us in the present research proposal to systematically dissect the impact of high-fat diet on systems important in the homeostatic relationship between metabolism and the body clock. Ultimately, the results from our proposed research will improve knowledge on the mechanisms linking high-fat diet to cardiometabolic pathologies, and shed further light upon the role of internal timing systems in energy balance and metabolism.
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