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Overexpression of Suppressor of Cytokine Signaling 3 in Adipose Tissue Causes Local but Not Systemic Insulin Resistance

From the Division of Endocrinology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Jeffrey S. Flier, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Finard 202, Boston, MA 02215. E-mail: jflier{at}bidmc.harvard.edu

Abbreviations: ELISA, enzyme-linked immunosorbent assay; FAS, fatty acid synthase; GPDH, glycerol-3-phosphate dehydrogenase; GTT, glucose tolerance test; HA, hemagglutinin; IRS, insulin receptor substrate; ITT, insulin tolerance test; PPAR, peroxisome proliferator–activated receptor; SOCS, suppressor of cytokine signaling; SREBP, sterol response element–binding protein; TNF-, tumor necrosis factor-

In adipocytes, suppressor of cytokine signaling (SOCS)3 deficiency increases insulin-stimulated insulin receptor substrate (IRS)-1 and -2 phosphorylation, IRS-associated phosphatidylinositol 3 kinase activity, and insulin-stimulated glucose uptake. Moreover, SOCS3 is required for tumor necrosis factor- full inhibition of insulin-stimulated IRS-1 and -2 phosphorylation, phosphatidylinositol 3 kinase activity, and glucose uptake. Whether SOCS3 also inhibits adipocyte insulin signaling in vivo and whether this action further affects systemic insulin sensitivity is not clear. We therefore generated a transgenic mouse (aP2-SOCS3 mouse) overexpressing SOCS3 in adipose tissue. Overexpression of SOCS3 in adipocytes decreases IRS1 protein levels and subsequent insulin-stimulated IRS-1 and -2 phosphorylation, decreases p85 binding to IRS-1, and leads to decreased insulin-stimulated glucose uptake in adipocytes. This impaired insulin signaling in adipose tissue of aP2-SOCS3 mice causes decreased lipogenesis and blocks insulin’s antilipolytic action. However, because of decreased energy partitioning in adipose tissue, aP2-SOCS3 mice are resistant to diet-induced obesity and are protected against systemic insulin resistance caused by a high-fat diet. Therefore, overexpression of SOCS3 in adipocytes causes local adipocyte insulin resistance, but it is not sufficient to cause systemic insulin resistance.

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