Role of Muscle c-Jun NH₂-Terminal Kinase 1 in Obesity-Induced Insulin Resistance

Abstract

Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH₂-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1^−/− mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (M^KO) mice exhibit improved insulin sensitivity compared with control wild-type (M^WT) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed M^WT mice but is suppressed only in the liver and adipose tissue of M^KO mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.

We thank D. Lee and P. Tso for the analysis of blood lipoproteins (Mouse Metabolic Phenotyping Center, University of Cincinnati); M. Das for providing the floxed Jnk1 mice; V. Benoit, J. Reilly, and J.-H. Liu for expert technical assistance; and K. Gemme for administrative assistance.

These studies were supported by grants from the National Institutes of Health (grants CA65861 to R.J.D. and DK80756 to J.K.K.) and the American Diabetes Association (grant 7-07-RA-80 to J.K.K.). The UMass Mouse Phenotyping Center is supported by the NIDDK Diabetes and Endocrinology Research Center (grant DK52530). R.J.D. is an Investigator of the Howard Hughes Medical Institute.