MCB Accepts, published online ahead of print on 19 October 2009

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Mol. Cell. Biol. doi:10.1128/MCB.01162-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Role of muscle JNK1 in obesity-induced insulin resistance

Guadalupe Sabio, Norman J. Kennedy, Julie Cavanagh-Kyros, Dae Young Jung, Hwi Jin Ko, Helena Ong, Tamera Barrett, Jason K. Kim, and Roger J. Davis^*

Howard Hughes Medical Institute, Program in Molecular Medicine, and the Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

^* To whom correspondence should be addressed. Email: Roger.Davis{at}Umassmed.Edu.

Obesity caused by feeding a high fat diet (HFD) is associated with increased activation of cJun 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 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 (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.