Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance

Soo Choi Cheol, Jonathan J. Fillmore, Jason K. Kim, Zhen Xiang Liu, Sheene Kim, Emily F. Collier, Ameya Kulkarni, Alberto Distefano, Yu Jin Hwang, Mario Kahn, Yan Chen, Chunli Yu, Irene K. Moore, Richard M. Reznick, Takamasa Higashimori, Gerald I. Shulman

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136 Scopus citations

Abstract

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and is strongly associated with obesity. Increased concentrations of intracellular fatty acid metabolites have been postulated to interfere with insulin signaling by activation of a serine kinase cascade involving PKCθ in skeletal muscle. Uncoupling protein 3 (UCP3) has been postulated to dissipate the mitochondrial proton gradient and cause metabolic inefficiency. We therefore hypothesized that overexpression of UCP3 in skeletal muscle might protect against fat-induced insulin resistance in muscle by conversion of intramyocellular fat into thermal energy. Wild-type mice fed a high-fat diet were markedly insulin resistant, a result of defects in insulin-stimulated glucose uptake in skeletal muscle and hepatic insulin resistance. Insulin resistance in these tissues was associated with reduced insulin-stimulated insulin receptor substrate 1- (IRS-1-) and IRS-2-associated PI3K activity in muscle and liver, respectively. In contrast, UCP3-overexpressing mice were completely protected against fat-induced defects in insulin signaling and action in these tissues. Furthermore, these changes were associated with a lower membrane-to-cytosolic ratio of diacylglycerol and reduced PKCθ activity in whole-body fat-matched UCP3 transgenic mice. These results suggest that increasing mitochondrial uncoupling in skeletal muscle may be an excellent therapeutic target for type 2 diabetes mellitus.

Original languageEnglish (US)
Pages (from-to)1995-2003
Number of pages9
JournalJournal of Clinical Investigation
Volume117
Issue number7
DOIs
StatePublished - Jul 2 2007

ASJC Scopus subject areas

  • Medicine(all)

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    Cheol, S. C., Fillmore, J. J., Kim, J. K., Liu, Z. X., Kim, S., Collier, E. F., Kulkarni, A., Distefano, A., Hwang, Y. J., Kahn, M., Chen, Y., Yu, C., Moore, I. K., Reznick, R. M., Higashimori, T., & Shulman, G. I. (2007). Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. Journal of Clinical Investigation, 117(7), 1995-2003. https://doi.org/10.1172/JCI13579