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Effects of Pioglitazone on Suppressor of Cytokine Signaling 3 Expression

Potential Mechanisms for Its Effects on Insulin Sensitivity and Adiponectin Expression

¹ The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
² Osaka University Graduate School of Frontier Bioscience, Osaka, Japan
³ Laboratory for Immune Signal, National Institute of Biomedical Innovation, Osaka, Japan

Address correspondence and reprint requests to Isao Usui, MD, PhD, The First Department of Internal Medicine, University of Toyama, 2630 Sugitani Toyama 930-0194, Japan. E-mail: isaousui-tym{at}umin.ac.jp

Abbreviations: GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IRS, insulin receptor substrate; JAK, Janus kinase; MAP, mitogen-activated protein; PPAR, peroxisome proliferator–activated receptor ; SOCS, suppressor of cytokine signaling; TNF-, tumor necrosis factor-; TZD, thiazolidinedione

Pioglitazone is widely used for the treatment of diabetic patients with insulin resistance. The mechanism of pioglitazone to improve insulin sensitivity is not fully understood. Recent studies have shown that the induction of suppressor of cytokine signaling 3 (SOCS3) is related to the development of insulin resistance. Here, we examined whether the insulin-sensitizing effect of pioglitazone affects the SOCS induction. In db/db mice and high-fat–fed mice, expression of SOCS3 mRNA in fat tissue was increased compared with that in lean control mice, and pioglitazone suppressed SOCS3 levels. In 3T3-L1 adipocytes, mediators of insulin resistance such as tumor necrosis factor- (TNF-), interleukin-6, growth hormone, and insulin increased SOCS3 expression, which was partially inhibited by pioglitazone. The ability of pioglitazone to suppress SOCS3 induction by TNF- was greatly augmented by peroxisome proliferator–activated receptor overexpression. SOCS3 overexpression and tyrphostin AG490, a Janus kinase 2 inhibitor, or dominant-negative STAT3 expression partially inhibited adiponectin secretion and was accompanied by decreased STAT3 phosphorylation. Conversely, pioglitazone increased adiponectin secretion and STAT3 phosphorylation in fat tissue of db/db mice and in 3T3-L1 adipocytes. These results suggest that pioglitazone exerts its effect to improve whole-body insulin sensitivity in part through the suppression of SOCS3, which is associated with the increase in STAT3 phosphorylation and adiponectin production in fat tissue.

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