Activation of SOCS-3 by Resistin

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank Alessandra Tosolini-Borst and Nicole Dudley-Rucker for technical assistance in producing recombinant mouse proteins and Patricia Chui for performing insulin binding assays. IRS-1 phosphospecific antibodies were kindly provided by Roberto Polakiewicz from Cell Signaling. The SOCS F59D cDNA was kindly provided by Irene Nowak and Robert Mooney from the University of Rochester.

This work was supported by grants to C.M.S. (DK K01 DK59896 from NIH and ADA RA117 from the American Diabetes Association), M.A.L. (RO1 DK49780 and PO1 DK49210 from NIH), M.J.B. (RO1 DK56886 from NIH), and the Viral Vector Core of the Penn Diabetes Center (DK19525 from NIH). E.L.W. was supported by a Howard Hughes Predoctoral Fellowship for the Biological Sciences.