Glucose and lipid homeostasis are normally maintained through a network of hormonal and nutrient signaling pathways that operate between insulin sensitive tissues. Indeed, disruptions in inter-tissue communication are often associated with type II diabetes, although initiating events that trigger this process have not been characterized. In recent studies, obesity was found to stimulate the phosphorylation and activation of the cAMP responsive factor CREB in adipose; mice deficient in adiposity CREB activity remained insulin sensitive in the context of dietary or genetic obesity. The current proposal addresses the importance of the CREB coactivator CRTC3 in mediating the metabolic effects of CREB in adipose. Three Aims are proposed; In Aim 1, the mechanism by which disruption of the CRTC3 gene confers insulin sensitivity and resistance to diet induced obesity will be characterized. Effects of nutritional and dietary status in triggering CRTC3-dependent changes in energy expenditure, food intake, and physical activity will be determined. And potential regulatory contributions from other CRTC family members will be explored. In Aim 2, the relative importance of CRTC3 in modulating energy expenditure through its effects on catecholamine signaling and adipogenesis will be evaluated. In Aim 3, the role of the nucleosome remodeling and deacetylase complex (NuRD) in silencing cAMP responsive genes through an association with CREB and CRTC3 will be characterized. These studies will provide insight into the importance of the CREB:CRTC3 pathway in triggering early changes in adipose that lead to the development of systemic insulin resistance in obesity. PUBLIC HEALTH RELEVANCE: Obesity is a major risk factor in the development of type II diabetes, a disease that affects more than 20 million individuals in the United States. The current application addresses how a fasting switch called CRTC3 promotes insulin resistance in the context of diet induced obesity. The studies will provide insight into molecular mechanisms by which increases in adiposity lead to systemic changes in insulin sensitivity.