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Molecular and Cellular Biology, February 2005, p. 1569-1575, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1569-1575.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation of SOCS-3 by Resistin{dagger}

Claire M. Steppan,1* Juan Wang,1 Eileen L. Whiteman,1,2 Morris J. Birnbaum,1,2 and Mitchell A. Lazar1*

Division of Endocrinology, Diabetes, and Metabolism, Penn Diabetes Center and The Cox Institute,1 Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania2

Received 14 May 2004/ Returned for modification 29 June 2004/ Accepted 10 November 2004

Resistin is an adipocyte hormone that modulates glucose homeostasis. Here we show that in 3T3-L1 adipocytes, resistin attenuates multiple effects of insulin, including insulin receptor (IR) phosphorylation, IR substrate 1 (IRS-1) phosphorylation, phosphatidylinositol-3-kinase (PI3K) activation, phosphatidylinositol triphosphate production, and activation of protein kinase B/Akt. Remarkably, resistin treatment markedly induces the gene expression of suppressor of cytokine signaling 3 (SOCS-3), a known inhibitor of insulin signaling. The 50% effective dose for resistin induction of SOCS-3 is ~20 ng/ml, close to levels of resistin in serum. Association of SOCS-3 protein with the IR is also increased by resistin. Inhibition of SOCS function prevented resistin from antagonizing insulin action in adipocytes. SOCS-3 induction is the first cellular effect of resistin that is independent of insulin and is a likely mediator of resistin's inhibitory effect on insulin signaling in adipocytes.

* Corresponding author. Present address for Claire M. Steppan: Pfizer Inc., PRGD, MS220-3145, Eastern Point Rd., Groton, CT 06340. Phone: (860) 686-2717. Fax: (860) 715-4610. E-mail: claire.m.steppan{at}pfizer.com. Mailing address for Mitchell A. Lazar: University of Pennsylvania School of Medicine, CRB 611, 415 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-0198. Fax: (215) 898-5408. E-mail: lazar{at}mail.med.upenn.edu.

* Corresponding author. Present address for Claire M. Steppan: Pfizer Inc., PRGD, MS220-3145, Eastern Point Rd., Groton, CT 06340. Phone: (860) 686-2717. Fax: (860) 715-4610. E-mail: claire.m.steppan{at}pfizer.com. Mailing address for Mitchell A. Lazar: University of Pennsylvania School of Medicine, CRB 611, 415 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-0198. Fax: (215) 898-5408. E-mail: lazar{at}mail.med.upenn.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2005, p. 1569-1575, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1569-1575.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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