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

J Clin Invest. 2007 Jul;117(7):1995-2003. doi: 10.1172/JCI13579.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases
  • Aging / physiology
  • Animals
  • Enzyme Activation
  • Gene Expression Regulation*
  • Hormones / blood
  • Humans
  • Insulin / blood
  • Insulin Resistance*
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Isoenzymes / metabolism
  • Lipid Metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Multienzyme Complexes / metabolism
  • Muscle, Skeletal / metabolism*
  • Protein Kinase C / metabolism
  • Protein Kinase C-theta
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Uncoupling Protein 3
  • Weight Gain

Substances

  • Hormones
  • Insulin
  • Ion Channels
  • Isoenzymes
  • Mitochondrial Proteins
  • Multienzyme Complexes
  • UCP3 protein, human
  • Ucp3 protein, mouse
  • Uncoupling Protein 3
  • Akt2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Prkcq protein, mouse
  • Protein Kinase C
  • Protein Kinase C-theta
  • AMP-Activated Protein Kinases