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

• Published in: The Journal of clinical investigation Vol. 117; no. 7; pp. 1995 - 2003
• Main Authors: Choi, Cheol Soo, Fillmore, Jonathan J, Kim, Jason K, Liu, Zhen-Xiang, Kim, Sheene, Collier, Emily F, Kulkarni, Ameya, Distefano, Alberto, Hwang, Yu-Jin, Kahn, Mario, Chen, Yan, Yu, Chunli, Moore, Irene K, Reznick, Richard M, Higashimori, Takamasa, Shulman, Gerald I
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2007
• Subjects: Aging - physiology; AMP-Activated Protein Kinases; Animals; Biomedical research; Body fat; Complications and side effects; Enzyme Activation; Fatty acids; Gene Expression Regulation; Health aspects; Hormones - blood; Humans; Insulin - blood; Insulin Resistance; Ion Channels - genetics; Ion Channels - metabolism; Isoenzymes - metabolism; Lipid Metabolism; Male; Metabolites; Mice; Mice, Transgenic; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Multienzyme Complexes - metabolism; Muscle proteins; Muscle, Skeletal - metabolism; Muscles; Obesity; Prevention; Protein Kinase C - metabolism; Protein Kinase C-theta; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Protons; Uncoupling Protein 3; Weight Gain; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci13579

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 PKCtheta 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 PKCtheta 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.