PROJECT SUMMARY Exercise induces a wider-range of physiological responses, such as the changes in skeletal muscle, hepatic glucose metabolism and intermediary metabolism. These responses involve a coordinated multi-organ crosstalk between the brain, liver and skeletal muscle. A region in the brain knowns as the ventromedial hypothalamus (VMH) plays a critical role in the regulation of metabolism and the metabolic responses to exercise .The VMH is thought to act primarily through the sympathetic nervous system (SNS) and the release of catelcholamines, which then bind to adrenergic receptors in target tissues. We hypothesize that the VMH mediates some of the metabolic benefits of exercise via the β2AR isoform in skeletal muscle, and the α1bAR isoform in liver. The goal of this application is to investigate the contributions of these tissue-specific isoforms to the metabolic benefits of exercise using novel genetically engineered mice and novel metabolic flux analysis methods. We anticipate that the results from our investigation will provide novel insights into potential therapies to combat metabolic disease.