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

H Inoue, W Ogawa, M Ozaki, S Haga, M Matsumoto… - Nature medicine, 2004 - nature.com
H Inoue, W Ogawa, M Ozaki, S Haga, M Matsumoto, K Furukawa, N Hashimoto, Y Kido…
Nature medicine, 2004nature.com
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-lox P 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 …
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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