TY - JOUR
T1 - Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo
AU - Inoue, Hiroshi
AU - Ogawa, Wataru
AU - Ozaki, Michitaka
AU - Haga, Sanae
AU - Matsumoto, Michihiro
AU - Furukawa, Kensuke
AU - Hashimoto, Naoko
AU - Kido, Yoshiaki
AU - Mori, Toshiyuki
AU - Sakaue, Hiroshi
AU - Teshigawara, Kiyoshi
AU - Jin, Shiyu
AU - Iguchi, Haruhisa
AU - Hiramatsu, Ryuji
AU - LeRoith, Derek
AU - Takeda, Kiyoshi
AU - Akira, Shizuo
AU - Kasuga, Masato
N1 - Funding Information:
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.).
PY - 2004/2
Y1 - 2004/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=11144357516&partnerID=8YFLogxK
U2 - 10.1038/nm980
DO - 10.1038/nm980
M3 - Article
C2 - 14716305
AN - SCOPUS:11144357516
SN - 1078-8956
VL - 10
SP - 168
EP - 174
JO - Nature Medicine
JF - Nature Medicine
IS - 2
ER -