STAT3 sensitizes insulin signaling by negatively regulating glycogen synthase kinase-3 beta.
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.


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-3beta, a negative regulator of insulin signaling pathway. During feeding, both mRNA and protein levels of GSK-3beta 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-3beta level in response to insulin. Administration of GSK-3beta 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-3beta. Inactivation of STAT3 in the liver contributes significantly to the pathogenesis of insulin resistance.
Moh
Akira
A
Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Dr. MS 420, Indianapolis, IN 46202, USA. amoh@iupui.edu
Zhang
Wenjun
W
Yu
Sidney
S
Wang
Jun
J
Xu
Xuming
X
Li
Jiliang
J
Fu
Xin-Yuan
XY
D000818:Animals; D018929:Cell Culture Techniques; D002843:Chromatin / Q000235:genetics / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011228:Prealbumin / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection
D002843:Chromatin; D007328:Insulin; D011228:Prealbumin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3