HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Online-Only Appendix All Versions of this Article: db06-1582v1 57/5/1227    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Moh, A. Articles by Fu, X.-Y. Search for Related Content PubMed PubMed Citation Articles by Moh, A. Articles by Fu, X.-Y. Social Bookmarking                What's this?

STAT3 sensitizes insulin signaling by negatively regulating GSK-3β.

¹Department of Microbiology and Immunology,
²Walther Oncology Center,
³Department of Biology, Indiana University School of Medicine, Indianapolis, IN 46202
⁴Department of Pathology, Yale University School of Medicine, New Haven, CT 06520

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 previously 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 the 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 a 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.

Correspondence: xfu{at}iupui.edu

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?