Metabolic homeostasis is essential for balancing dietary needs with the availability of stored energy. Disruption of this balance has many deleterious effects, most notably obesity and type 2 diabetes in humans. Recent evidence has revealed that the circadian clock profoundly influences metabolic homeostasis and, conversely, that metabolism can feed back to control circadian cycles. The primary goal of this proposed research is to investigate the molecular mechanisms that underlie this coordination. The fruit fly, Drosophila melanogaster, is a model organism that is uniquely amenable to achieving this goal, given its ease of genetic manipulation and its biological and physiological similarity to humans. The degree of coordination between behavioral and physiological systems will first be determined by analyzing changes in stored (triacylglycerol and glycogen) and circulating (trehalose) forms of energy during the day-night cycle. Single animals will be analyzed to assess correlations between metabolites as well as metabolite concentration variability within a population of wild-type animals. Characterized circadian mutants will be tested to determine the role of the circadian clock in these responses. Isogenic lines will be generated and used to determine the contribution of genetic diversity on the dynamics and variability of metabolite levels. Finally, preliminary data has revealed a robust, circadian oscillation in glycogen concentration. An unbiased and open-ended genetic screen will be performed to identify regulators of this response. The Specific Aims of this proposal are: 1) To determine which forms of energy are regulated by the circadian clock in Drosophila. 2) To determine if genetic diversity can account for the large variability in metabolite concentrations seen within a population. 3) To use genetics to characterize the circadian oscillation in glycogen concentration. PUBLIC HEALTH RELEVANCE: Metabolic processes and the circadian cycle are closely intertwined. Humans who chronically misalign feeding and sleeping with their natural, internal clock are more susceptible to cancer, heart disease and diabetes than people with normal sleeping and eating patterns. Characterizing the genetic factors that coordinate the clock and metabolism will provide new insights into the basis of these human disorders.