Project Summary The circadian clock is an auto-regulatory transcription feedback loop present in the brain and peripheral tissues that coordinates sleep/wake and physiology in anticipation of the rising of the sun each day. Epidemiologic, clinical and genetic studies have shown clock dysregulation contributes to both obesity and its metabolic co- morbidities. Recently, we have shown that abrogation of the core molecular clock component BMAL1 in hypothalamic hunger neurons leads to increased feeding at the wrong phase of the day/night cycle and causes impaired glucose tolerance, a hallmark of diabetes. AgRP neuron transcriptomics further identify circadian regulation of dopaminergic neurotransmitter synapse, indicating that clock disruption may lead to alterations in both the hedonic and homeostatic control of feeding. With a focus on understanding the mechanisms linking circadian systems to hedonic feeding, I have generated new data demonstrating that disruption of the molecular clock in dopaminergic neurons of the classical reward-promoting ventral tegmental area (VTA) results in hyperphagia of palatable high fat food and accelerates diet-induced obesity, hyperglycemia, impaired oxidative metabolism by respirometry, altered sleep patterns, and decreased daytime open field behavior. The scientific rationale underlying my present proposal is that the circadian clock modulates time-of-day dependent feeding and metabolic processes through the regulation of food-associated reward within midbrain dopaminergic neurons. This proposal seeks to contribute new insight into how neuronal clocks synchronize behavioral and transcriptional rhythms to impact physiology, findings which have broad implications for the treatment and prevention of sleep-loss related disorders of obesity, metabolic syndrome, and type 2 diabetes mellitus.