Project Summary Overnutrition and physical inactivity promote the accumulation of sphingolipids such as ceramides which block insulin signaling and anabolic metabolism. Implementation of pharmacological or genetic interventions to block ceramide synthesis in rodents prevents or reverses an impressive array of metabolic pathologies (e.g. insulin resistance, diabetes, steatohepatitis, hypertension, cardiomyopathy, and atherosclerosis). Herein we aim to evaluate the therapeutic potential of inhibiting dihydroceramide desaturase-1 (DES1), our preferred target in the ceramide synthesis pathway, in the treatment of insulin resistance and non-alcoholic fatty liver disease. Aims will involve the following: 1. Evaluating the consequences of inhibiting DES1 on metabolic disorders in mice 2. Determining the mechanism by which the subtle molecular changes to ceramides caused by DES1 inhibition alter cellular function Findings obtained from these studies could lead to new pharmacological approaches for treating diabetes and other cardiometabolic diseases.