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- Title
Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance.
- Authors
Cheol Soo Choi; Fillmore, Jonathan J.; Kim, Jason K.; Zhen-Xiang Liu; Sheene Kim; Collier, Emily F.; Kulkarni, Ameya; Distefano, Alberto; Yu-Jin Hwang; Kahn, Mario; Yan Chen; Chunli Yu; Moore, Irene K.; Reznick, Richard M.; Higashimori, Takamasa; Shulman, Gerald I.
- 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.
- Subjects
TYPE 2 diabetes; INSULIN resistance; DIABETES complications; DRUG resistance; OBESITY; FATTY acid-binding proteins
- Publication
Journal of Clinical Investigation, 2007, Vol 117, Issue 7, p1995
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI13579