Role of hepatic STAT3 in brain-insulin action on hepatic glucose production

Hiroshi Inoue, Wataru Ogawa, Akihiro Asakawa, Yasuo Okamoto, Akihiko Nishizawa, Michihiro Matsumoto, Kiyoshi Teshigawara, Yasushi Matsuki, Eijiro Watanabe, Ryuji Hiramatsu, Kenji Notohara, Koji Katayose, Hitoshi Okamura, C. Ronald Kahn, Tetsuo Noda, Kiyoshi Takeda, Shizuo Akira, Akio Inui, Masato Kasuga

Research output: Contribution to journalArticlepeer-review

182 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)267-275
Number of pages9
JournalCell Metabolism
Issue number4
Publication statusPublished - Apr 2006

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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