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J. Biol. Chem., Vol. 282, Issue 11, 7991-7996, March 16, 2007

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Adiponectin Sensitizes Insulin Signaling by Reducing p70 S6 Kinase-mediated Serine Phosphorylation of IRS-1^*

Changhua Wang, Xuming Mao, Lixin Wang, Meilian Liu, Michael D. Wetzel, Kun-Liang Guan^¶, Lily Q. Dong, and Feng Liu^||1

From the Departments of Pharmacology, ^||Biochemistry, and Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229 and the ^¶Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109

Adiponectin functions as an insulin sensitizer, and yet the underlying molecular mechanism(s) remains largely unknown. We found that treating C2C12 myotubes with adiponectin or rapamycin enhanced the ability of insulin to stimulate IRS-1 tyrosine phosphorylation and Akt phosphorylation, concurrently with reduced p70 S6 kinase phosphorylation at Thr³⁸⁹ as well as IRS-1 phosphorylation at Ser³⁰² and Ser^636/639. Overexpression of dominant-negative AMP kinase (AMPK), but not dominant-negative p38 MAPK, reduced the insulin-sensitizing effect of adiponectin. Rapamycin, but not adiponectin, enhanced insulin-stimulated Akt phosphorylation in HeLa cells, which lack LKB1, and exogenous expression of LKB1 in HeLa cells rescued the insulin-sensitizing effect of adiponectin. Finally, overexpression of wild-type Rheb (Ras homology-enriched in brain) or the TSC2 mutant lacking the AMPK phosphorylation site (TSC2^S1345A) inhibited the insulin-sensitizing effect of adiponectin in C2C12 cells. These results indicate that activation of the LKB1/AMPK/TSC1/2 pathway alleviates the p70 S6 kinase-mediated negative regulation of insulin signaling, providing a mechanism by which adiponectin increases insulin sensitivity in cells.

Received for publication, January 4, 2007 , and in revised form, January 22, 2007.

^* This work was supported by RO1 Grants from the National Institutes of Health (to F. L., L. Q. D., and K.-L. G.) and a Career Development Award from the American Diabetes Association (to L. Q. D.). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229. E-mail: liuf{at}uthscsa.edu.

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