Chem.283, Issue 2, 708-715, January 11, 2008 This Article All Versions of this Article: 283/2/708 _most recent_ Services Google Scholar PubMed REGULATION OF INTERLEUKIN-6-INDUCED HEPATIC INSULIN RESISTANCE BY MAMMALIAN TARGET OF RAPAMYCIN THROUGH THE STAT3-SOCS3 PATHWAY JEONG-HO KIM, JAE EUN KIM1, HUI-YU LIU, WENHONG CAO, AND JIE CHEN2 From the Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 and Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 2770 The proinflammatory cytokine interleukin (IL)-6 has been proposed to be one of the mediators that link obesity-derived chronic inflammation with insulin resistance.Through the mammalian target of rapamycin (mTOR) has been found to impact insulin sensitivity under various pathological conditions, through serine phosphorylation and inhibition of insulin receptor substrate by the downstream effector of mTOR, ribosomal S6 kinase 1 (S6K1).An involvement of mTOR in IL-6-induced insulin resistance has not yet been reported.We show that rapamycin, the inhibitor of mTOR signaling, rescues insulin signaling and glycogen synthesis from IL-6 inhibition in HepG2 hepatocarcinoma cells as well as in mouse primary hepatocytes.S6K1 in these cells, but unexpectedly, S6K1 is not involved in IL-6 inhibition of insulin signaling, since the effect of IL-6 persists in cells with drastically reduced S6K1 levels induced by RNA interference, suggesting that the function of mTOR signaling is through a mechanism different from the prevailing model of S6K1 phosphorylation of insulin receptor substrate-1.Find that the phosphorylation of STAT3 on Ser727 and STAT3 transcriptional activity are regulated by mTOR upon IL-6 stimulation and that STAT3 is required for IL-6 inhibition of insulin signaling.IL-6-induced SOCS3 expression is inhibited by rapamycin, and ectopic expression of SOCS3 blocks the ability of rapamycin to enhance insulin sensitivity in the presence of IL-6.We propose that mTOR plays a key role in IL-6-induced hepatic insulin resistance by regulating STAT3 activation and subsequent SOCS3 expression.Received for publication, October 16, 2007 , and in revised form, November 9, 2007.This work was supported by National Institutes of Health Grants R01AR48914 (to J.And R01DK76039 (to W.A grant from the American Diabetes Association (to J.And a grant from the American Heart Association (to W. The costs of publication of this article were defrayed in part by the payment of page charges.Must therefore be hereby marked "_advertisement_" in accordance with 18 U.Section 1734 solely to indicate this fact.1 Present address: Wyeth Research Oncology, 401 N.Rd.NY 10965.2 To whom correspondence should be addressed: 601 S.Ave.IL 61801.Read more Responsiveness of the adult attention-deficit/hyperactivity disorder quality of life scale (aaqol)
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