Chronic increases in circulating free fatty acids (FA) and dysfunctional FA metabolism contribute to obesity-associated insulin resistance and cardiovascular disease. The work proposed in this application is based on recent findings showing that exogenous FA modulate the physical protein-protein interactions involved in AMP kinase (AMPK) activation (Samovski et al, Diabetes 2015) and in insulin receptor (IR) signaling (preliminary data). This molecular regulation couples exogenous FA availability to FA processing, optimizing FA utilization. Persistently high exogenous FA would disrupt this regulation resulting in dysfunctional FA metabolism and the accumulation of deleterious metabolites that impair insulin signaling. In this proposaI I will examine the signal transduction basis for FA-regulation of FA and glucose metabolism and of FA-induced insulin resistance.