Nature Medicine
10, 168 - 174 (2004)
Published online: 11 January 2004; | doi:10.1038/nm980
Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivoHiroshi Inoue1, Wataru Ogawa1, Michitaka Ozaki2, 3, Sanae Haga2, Michihiro Matsumoto1, Kensuke Furukawa1, Naoko Hashimoto1, Yoshiaki Kido1, Toshiyuki Mori1, Hiroshi Sakaue1, Kiyoshi Teshigawara1, Shiyu Jin1, Haruhisa Iguchi4, Ryuji Hiramatsu4, Derek LeRoith5, Kiyoshi Takeda6, Shizuo Akira6
& Masato Kasuga11
Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. 2
Bioengineering Laboratory, Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo 154-8567, Japan. 3
Department of Food and Health Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, 700-8558, Japan. 4
Genomics Science Laboratories, Sumitomo Pharmaceuticals Co. Ltd., Takarazuka, Hyogo 665-0051, Japan. 5
Section on Molecular and Cellular Physiology, Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. 6
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Correspondence should be addressed to Masato Kasuga kasuga@med.kobe-u.ac.jpThe 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- coactivator-1 (PGC-1), 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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