Role of hepatic STAT3 in brain-insulin action on hepatic glucose production.
STAT3 regulates glucose homeostasis by suppressing the expression of gluconeogenic genes in the liver. The mechanism by which hepatic STAT3 is regulated by nutritional or hormonal status has remained unknown, however. Here, we show that an increase in the plasma insulin concentration, achieved either by glucose administration or by intravenous insulin infusion, stimulates tyrosine phosphorylation of STAT3 in the liver. This effect of insulin was mediated by the hormone's effects in the brain, and the increase in hepatic IL-6 induced by the brain-insulin action is essential for the activation of STAT3. The inhibition of hepatic glucose production and of expression of gluconeogenic genes induced by intracerebral ventricular insulin infusion was impaired in mice with liver-specific STAT3 deficiency or in mice with IL-6 deficiency. These results thus indicate that IL-6-STAT3 signaling in the liver contributes to insulin action in the brain, leading to the suppression of hepatic glucose production.
Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Hiroshi
H
Inoue
Wataru
W
Ogawa
Akihiro
A
Asakawa
Yasuo
Y
Okamoto
Akihiko
A
Nishizawa
Michihiro
M
Matsumoto
Kiyoshi
K
Teshigawara
Yasushi
Y
Matsuki
Eijiro
E
Watanabe
Ryuji
R
Hiramatsu
Kenji
K
Notohara
Koji
K
Katayose
Hitoshi
H
Okamura
C Ronald
CR
Kahn
Tetsuo
T
Noda
Kiyoshi
K
Takeda
Shizuo
S
Akira
Akio
A
Inui
Masato
M
Kasuga
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004789:Enzyme Activation; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D015309:Glucose Clamp Technique; D005952:Glucose-6-Phosphatase / Q000502:physiology; D006706:Homeostasis; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000032:analysis / Q000502:physiology; D007728:Kupffer Cells / Q000737:chemistry / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010730:Phosphoenolpyruvate Carboxylase / Q000502:physiology; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D007328:Insulin; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D011972:Receptor, Insulin; D005952:Glucose-6-Phosphatase; D010730:Phosphoenolpyruvate Carboxylase; D005947:Glucose