Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle

Insulin resistance in skeletal muscle plays a major role in the development of type 2 diabetes and may be causally associated with increases in intramuscular fatty acid metabolites. Fatty acid transport protein 1 (FATP1) is an acyl-CoA synthetase highly expressed in skeletal muscle and modulates fatty acid uptake and metabolism by converting fatty acids into fatty acyl-CoA. To investigate the role of FATP1 in glucose homeostasis and in the pathogenesis of Insulin resistance, we examined the effect of acute lipid infusion or chronic high-fat feeding on Insulin action in FATP1 KO mice. Whole-body adiposity, adipose tissue expression of Adiponectin, intramuscular fatty acid metabolites, and Insulin sensitivity were not altered in FATP1 KO mice fed a regular chow diet. In contrast, FATP1 deletion protected the KO mice from fat-induced Insulin resistance and intramuscular accumulation of fatty acyl-CoA without alteration in whole-body adiposity. These findings demonstrate an important role of intramuscular fatty acid metabolites in causing Insulin resistance and suggest that FATP1 may be a novel therapeutic target for the treatment of Insulin resistance and type 2 diabetes.