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Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle
Jason K. Kim, … , Harvey F. Lodish, Gerald I. Shulman
Jason K. Kim, … , Harvey F. Lodish, Gerald I. Shulman
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):756-763. https://doi.org/10.1172/JCI18917.
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Article Metabolism

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

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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

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Figure 1

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Generation of FATP1 KO mice. (A) Map of the FATP1 genomic locus and the ...
Generation of FATP1 KO mice. (A) Map of the FATP1 genomic locus and the targeting constructs. The 5′ and 3′ probes that were used to verify the homologous recombination event are indicated. (B) Southern blot using genomic DNA from the tail of F2 animals digested with EcoRI and SacI and hybridized with the 5′ and 3′ probes, respectively. The size of KO and WT alleles is indicated. (C) DNA products obtained by PCR amplification using the genotyping primers described in Methods and genomic DNA from the tail of F2 animals as a template. nt, nucleotide. (D and E) FATP1 mRNA levels in white adipose tissue (WAT) and skeletal muscle of KO and WT animals.
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