Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. Journal   The Journal of clinical investigation. Citation   J Clin Invest. 113(5):756-63 Publication date   2004 Mar Authors   Kim JK Gimeno RE Higashimori T Kim HJ Choi H Punreddy S Mozell RL Tan G Stricker-Krongrad A Hirsch DJ Fillmore JJ Liu ZX Dong J Cline G Stahl A Lodish HF Shulman GI Investigators   Jason K. Kim Grant agencies   National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Grants   NHLBI P01 HL66105-01 NIDDK P30 DK-45735 NIDDK R01 DK-40936 NIDDK R37 DK47618-13 NIDDK U24 DK-59635 MeSH headings   Adipose Tissue Carrier Proteins Intercellular Signaling Peptides and Proteins Membrane Transport Proteins Muscle, Skeletal MeSH qualifiers   metabolism physiology pathology Abstract   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.