Inoue Hiroshi, Ogawa Wataru, Asakawa Akihiro, Okamoto Yasuo, Nishizawa Akihiko, Matsumoto Michihiro, Teshigawara Kiyoshi, Matsuki Yasushi, Watanabe Eijiro, Hiramatsu Ryuji, Notohara Kenji, Katayose Koji, Okamura Hitoshi, Kahn C Ronald, Noda Tetsuo, Takeda Kiyoshi, Akira Shizuo, Inui Akio, Kasuga Masato
Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Cell Metab. 2006 Apr;3(4):267-75. doi: 10.1016/j.cmet.2006.02.009.
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.
信号转导子和转录激活子3（STAT3）通过抑制肝脏中糖异生基因的表达来调节葡萄糖稳态。然而，肝脏STAT3受营养或激素状态调节的机制仍不清楚。在这里，我们表明，通过给予葡萄糖或静脉输注胰岛素使血浆胰岛素浓度升高，会刺激肝脏中STAT3的酪氨酸磷酸化。胰岛素的这种作用是由该激素在大脑中的作用介导的，大脑-胰岛素作用诱导的肝脏白细胞介素-6（IL-6）增加对于STAT3的激活至关重要。在肝脏特异性STAT3缺陷的小鼠或IL-6缺陷的小鼠中，脑室内注射胰岛素诱导的肝脏葡萄糖生成抑制和糖异生基因表达抑制受损。因此，这些结果表明肝脏中的IL-6-STAT3信号传导有助于大脑中的胰岛素作用，从而导致肝脏葡萄糖生成的抑制。
