Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo.
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-gamma coactivator-1 alpha (PGC-1 alpha), 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.
Inoue
Hiroshi
H
Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Ogawa
Wataru
W
Ozaki
Michitaka
M
Haga
Sanae
S
Matsumoto
Michihiro
M
Furukawa
Kensuke
K
Hashimoto
Naoko
N
Kido
Yoshiaki
Y
Mori
Toshiyuki
T
Sakaue
Hiroshi
H
Teshigawara
Kiyoshi
K
Jin
Shiyu
S
Iguchi
Haruhisa
H
Hiramatsu
Ryuji
R
LeRoith
Derek
D
Takeda
Kiyoshi
K
Akira
Shizuo
S
Kasuga
Masato
M
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D004041:Dietary Fats; D018014:Gene Transfer Techniques; D005943:Gluconeogenesis / Q000235:genetics* / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D001786:Blood Glucose; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D007328:Insulin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1