Molecular Basis of Circadian Desynchrony in Cardiometabolic Disease

Northwestern University At Chicago, Evanston IL

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Abstract

DESCRIPTION (provided by applicant): 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. (End of Abstract)