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

Hiroshi Inoue, Wataru Ogawa, Michitaka Ozaki, Sanae Haga, Michihiro Matsumoto, Kensuke Furukawa, Naoko Hashimoto, Yoshiaki Kido, Toshiyuki Mori, Hiroshi Sakaue, Kiyoshi Teshigawara, Shiyu Jin, Haruhisa Iguchi, Ryuji Hiramatsu, Derek LeRoith, Kiyoshi Takeda, Shizuo Akira, Masato Kasuga

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273 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)168-174
Number of pages7
JournalNature Medicine
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Inoue, H., Ogawa, W., Ozaki, M., Haga, S., Matsumoto, M., Furukawa, K., Hashimoto, N., Kido, Y., Mori, T., Sakaue, H., Teshigawara, K., Jin, S., Iguchi, H., Hiramatsu, R., LeRoith, D., Takeda, K., Akira, S., & Kasuga, M. (2004). Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nature Medicine, 10(2), 168-174. https://doi.org/10.1038/nm980