1
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.
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.
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- 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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coactivator-1
(PGC-1
