Obesity has become a worldwide epidemic that stems from multifaceted causes that includes genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. The health-related impact of obesity is associated with diabetes mellitus, coronary heart disease, non-alcoholic fatty liver disease (NAFLD) and some forms of cancer. The mitogen-activated protein kinases (MAPKs) are key regulators of metabolism. Therefore, elucidating how the MAPKs are regulated will be essential to our understanding of the mechanisms that control metabolism. The MAPKs are dephosphorylated, and hence inactivated, by the MAPK phosphatases (MKPs). Despite the established role for MKPs in MAPK inactivation very little is known about their physiological or pathophysiological impact on metabolic control. MKP-1 is the archetypal MKP which localizes to the nucleus. The central tenant of this proposal is that MKP-1 functions as a "critical node" in the nucleus to control the flow of MAPK-dependent signaling in the maintenance of metabolic homeostasis. We have found that MKP-1 inactivates the nuclear pool of MAPKs to attenuate gene expression events that promote energy expenditure and hepatic fatty acid oxidation. Hence, MKP-1-deficient mice are resistant to diet-induced obesity and are protected from the development of hepatic steatosis. The broad goals of this proposal are to determine how mechanistically, and where physiologically, MKP-1 negatively regulates body mass and to identify the pathways that MKP-1 interferes with in the pathogenesis of NAFLD. We will accomplish these goals by executing the following specific aims: In aim 1, we will determine the mechanism of how MKP-1 regulates cytokine-induced MAPK-dependent signaling events that control mitochondrial respiration in skeletal muscle. In aim 2, a genetic approach using tissue-specific ablation of MKP-1 in skeletal muscle and brain will be performed to determine the contribution of MKP-1 at these sites to regulate body mass. Aim 3 will determine whether obesity-induced overexpression of MKP-1 in the liver promotes the development of hepatic steatosis. Intercrosses between MKP-1-deficient mice with mouse models of obesity and MKP-1 anti-sense approaches will be generated to test this. Finally, mechanisms linking MKP-1 overexpression in the liver during obesity to the dysregulation of hepatic lipid homeostasis will be delineated. [unreadable] [unreadable] [unreadable]