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

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.
Authors	Jason K Kim, Ruth E Gimeno, Takamasa Higashimori, Hyo-Jeong Kim, Hyejeong Choi, Sandhya Punreddy, Robin L Mozell, Guo Tan, Alain Stricker-Krongrad, David J Hirsch, Jonathan J Fillmore, Zhen-Xiang Liu, Jianying Dong, Gary Cline, Andreas Stahl, Harvey F Lodish, Gerald I Shulman
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 113 Issue 5 Pg. 756-63 (Mar 2004) ISSN: 0021-9738 [Print] United States
PMID	14991074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Adiponectin Blood Glucose Carrier Proteins Fatty Acid Transport Proteins Fatty Acids Insulin Intercellular Signaling Peptides and Proteins Membrane Transport Proteins Proteins Slc27a1 protein, mouse Slc27a4 protein, mouse Glucose
Topics	Adiponectin Adipose Tissue (metabolism) Animals Blood Glucose (metabolism) Carrier Proteins (metabolism, physiology) Diabetes Mellitus, Type 2 Fatty Acid Transport Proteins Fatty Acids (metabolism) Female Gene Deletion Gene Expression Regulation Glucose (metabolism) Insulin (metabolism) Insulin Resistance Intercellular Signaling Peptides and Proteins Male Membrane Transport Proteins Mice Mice, Knockout Models, Genetic Muscle, Skeletal (metabolism, pathology) Patch-Clamp Techniques Phenotype Proteins (metabolism) Signal Transduction

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