title: Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo.
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-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.
authors.affiliation: Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Sanae
authors.initials: S
authors.lastname: Haga
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Furukawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Teshigawara
authors.forename: Shiyu
authors.initials: S
authors.lastname: Jin
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Iguchi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsu
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: 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
chemical_list: 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