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Science 322 (5907): 1539-1543

Copyright © 2008 by the American Association for the Advancement of Science

A Stress Signaling Pathway in Adipose Tissue Regulates Hepatic Insulin Resistance

Guadalupe Sabio,1,2 Madhumita Das,2 Alfonso Mora,2 Zhiyou Zhang,3 John Y. Jun,3,4 Hwi Jin Ko,3 Tamera Barrett,2 Jason K. Kim,3 Roger J. Davis1,2*

Abstract: A high-fat diet causes activation of the regulatory protein c-Jun NH2-terminal kinase 1 (JNK1) and triggers development of insulin resistance. JNK1 is therefore a potential target for therapeutic treatment of metabolic syndrome. We explored the mechanism of JNK1 signaling by engineering mice in which the Jnk1 gene was ablated selectively in adipose tissue. JNK1 deficiency in adipose tissue suppressed high-fat diet–induced insulin resistance in the liver. JNK1-dependent secretion of the inflammatory cytokine interleukin-6 by adipose tissue caused increased expression of liver SOCS3, a protein that induces hepatic insulin resistance. Thus, JNK1 activation in adipose tissue can cause insulin resistance in the liver.

1 Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
4 Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

* To whom correspondence should be addressed. E-mail: roger.davis{at}umassmed.edu

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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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