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J. Biol. Chem., Vol. 280, Issue 52, 42731-42737, December 30, 2005

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p38 Mitogen-activated Protein Kinase Plays a Stimulatory Role in Hepatic Gluconeogenesis^*

Wenhong Cao1, Qu Fan Collins, Thomas C. Becker¶, Jacques Robidoux, Edgar G. Lupo, Jr., Yan Xiong2, Kiefer W. Daniel, Lisa Floering, and Sheila Collins||

From the Endocrine Biology Program, CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709 and ^¶The Sarah W. Stedman Center for Nutrition and Metabolism, Division of Endocrinology, Department of Medicine, and ^||Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27708

Hepatic gluconeogenesis is essential for maintaining blood glucose levels during fasting and is the major contributor to postprandial and fasting hyperglycemia in diabetes. Gluconeogenesis is a classic cAMP/protein kinase A-dependent process initiated by glucagon, which is elevated in the blood during fasting and in diabetes. In this study, we have shown that p38 mitogen-activated protein kinase (p38) was activated in liver by fasting and in primary hepatocytes by glucagon or forskolin. Fasting plasma glucose levels were reduced upon blockade of p38 with either a chemical inhibitor or small interference RNA in mice. In examining the mechanism, inhibition of p38 suppressed gluconeogenesis in liver, along with expression of key gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Peroxisome proliferator-activated receptor coactivator 1 and cAMP-response element-binding protein have been shown to be important mediators of hepatic gluconeogenesis. We have shown that inhibition of p38 prevented transcription of the PPAR coactivator 1 gene as well as phosphorylation of cAMP-response element-binding protein. Together, our results from in vitro and in vivo studies define a model in which cAMP-dependent activation of genes involved in gluconeogenesis is dependent upon the p38 pathway, thus adding a new player to our evolving understanding of this physiology.

Received for publication, June 8, 2005 , and in revised form, November 1, 2005.

^* This work was supported by an Investigator Development Fund from the CIIT Centers for Health Research (to W. C.), American Heart Association Grant SDG-0530244N (to W. C.), and National Institutes of Health Grant R01-DK53092 (to S. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Visiting scholar from the Dept. of Pharmacology, Xiang-Ya Medical School, Central South University of China.

¹ To whom correspondence should be addressed: CIIT Centers for Health Research, 6 Davis Dr., P. O. Box 12137, Research Triangle Park, NC 27709. E-mail: wcao{at}ciit.org.

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