Project Narrative Recent decades have witnessed a dramatic increase in obesity and metabolic disease (including metabolic syndrome, type 2 diabetes, atherosclerosis, cardiovascular disease). These health problems plague large sections of the population, and type 2 diabetes occurs at a higher rate in veterans than in the general United States population. A key feature of metabolic disease is the increase in plasma free fatty acids (FFA). This oversupply increases fatty acid deposition into peripheral tissues, including skeletal muscle. Normally, skeletal muscle serves a major function of plasma glucose uptake and utilization, and therefore, the health of this tissue plays a major role in diabetes. Moreover, in individuals who exhibit elevated plasma FFA, many muscle pathologies are observed, including fibrosis, wasting, inflammation, and myopathy. This proposal addresses the mechanism(s) by which FFA mediate these pathological processes in skeletal muscle. Specifically, we hypothesize that elevation of plasma FFA causes inappropriate synthesis of sphingolipids, key lipid mediators involved in numerous cell and organism processes. We propose to use cell culture and animal models to determine roles for specific sphingolipid signaling molecules in aberrant gene regulation and subsequent skeletal muscle pathology including inflammation and muscle wasting. This proposal directly addresses a primary health concern for veterans, namely, type 2 diabetes. In the general population, the incidence of diabetes is around 6%, (http://www.va.gov/pressrel/diabtsfs.htm). However, as found on the Department of Veterans Affairs Fact Sheet entitled "Advances in Diabetes Care", "Diabetes has particular importance for the Department of Veterans Affairs (VA) because the prevalence among VA patients -- one in six, or 16 percent -- is substantially higher than in the general population. . . VA is the largest integrated health care system to provide care to persons with diabetes." Therefore, there is little argument that diabetes and its sequelae represent a major concern for the VA. Furthermore, this disease is associated with aging, and as the average age of the population is increasing, DMII will become an even greater concern. Our proposal seeks to identify mechanisms of loss of skeletal muscle health in obesity, the metabolic syndrome, and diabetes. Completion of our specific aims will provide novel insights into the mechanisms by which these conditions decrease skeletal muscle health and function.