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STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

¹ Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
² Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana
³ Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
⁴ Department of Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana

Corresponding author: Xin-Yuan Fu, PhD, or Akira Moh, MD, PhD, Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Dr. MS 420, Indianapolis, IN 46202. E-mail: xfu{at}iupui.edu or amoh{at}iupui.edu

Abbreviations: DAPI, 4',6-diamidino-2-phenylindole; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; GSK, glycogen synthase kinase; IL, interleukin; IRS, insulin receptor substrate; STAT, signal transducers and activators of transcription; TTR, transthyretin

OBJECTIVE— Glucose homeostasis is achieved by triggering regulation of glycogen synthesis genes in response to insulin when mammals feed, but the underlying molecular mechanism remains largely unknown. The aim of our study was to examine the role of the signal transducers and activators of transcription 3 (STAT3) in insulin signaling.

RESEARCH DESIGN AND METHODS— We generated a strain of mice carrying a targeted disruption of Stat3 gene in the liver (L-Stat3^–/– mice). Hepatocytes of the L-Stat3^–/– mice were isolated to establish cell lines for mechanistic studies. Nuclear translocation and DNA-protein interaction of STAT3 was analyzed with immunofluorescent and chromatin immunoprecipitation methods, respectively. Levels of glucose, insulin, leptin, and glucagon were profiled, and putative downstream molecules of STAT3 were examined in the presence of various stimuli in L-Stat3^–/– and control mice.

RESULTS— STAT3 was found to sensitize the insulin signaling through suppression of GSK-3β, a negative regulator of insulin signaling pathway. During feeding, both mRNA and protein levels of GSK-3β decreased in Stat3^f/+ mice, which reflected the need of hepatocytes for insulin to induce glycogen synthesis. In contrast, the L-Stat3^–/– mice lost this control and showed a monophasic increase in the GSK-3β level in response to insulin. Administration of GSK-3β inhibitors lithium chloride and L803-mts restored glucose homeostasis and rescued the glucose intolerance and impaired insulin response in L-Stat3^–/– mice.

CONCLUSIONS— These data indicate that STAT3 sensitizes insulin signaling by negatively regulating GSK-3β. Inactivation of STAT3 in the liver contributes significantly to the pathogenesis of insulin resistance.

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