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Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo

Abstract

The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.

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The authors declare no competing financial interests.

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Acknowledgements

We thank J.E. Darnell Jr. for the STAT-3C-encoding cDNA, T. Noguchi for the Gck probe, H. Shimano for the Srebf1 probe, H. Nakajima for the G6pc probe, N. Iritani for the Fasn probe, D. Accili for the adenovirus encoding hemagglutinin-tagged, wild-type FOXO-1, and D.K. Granner for the HL1C cells. This work was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M.K. and W.O.) and a grant from the Cooperative Link of Unique Science and Technology for Economy Revitalization (to M.K.).

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The authors declare no competing financial interests.

Correspondence to Masato Kasuga.

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Figure 1: Metabolic phenotypes of mice with liver-specific STAT-3 deficiency (L-ST3KO mice).
Figure 2: Euglycemic, hyperinsulinemic clamp analyses, effects of high-fat diet and changes in hepatic gene expression in L-ST3KO mice.
Figure 3: Restoration of STAT-3 expression in livers of L-ST3KO mice.
Figure 4: Effects of IL-6, Ly294002 and dominant-negative or wild-type STAT-3 on gluconeogenic genes, FOXO-1 phosphorylation and Pck1 promoter activity.
Figure 5: Effects of wild-type STAT-3 on PGC-1α-induced expression of PCK-1 and G6PC.
Figure 6: Effects of constitutively active STAT-3 (STAT-3C) on glucose intolerance, gene expression and lipid content in livers of Lepr−/− mice.