Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity.
Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity.
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DOI：
10.1016/j.cmet.2012.03.002
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发表时间：
2012-05-02
期刊：
影响因子：
29
通讯作者：
Tabas I
中科院分区：
文献类型：
--
作者：
Ozcan L;Wong CC;Li G;Xu T;Pajvani U;Park SK;Wronska A;Chen BX;Marks AR;Fukamizu A;Backs J;Singer HA;Yates JR 3rd;Accili D;Tabas I
肝脏葡萄糖生成（HGP）对葡萄糖稳态至关重要，但其潜在机制尚未完全阐明。在本研究中，我们发现一种钙敏感酶CaMKII在原代hcc中以钙和ip3r依赖的方式被cAMP和胰高血糖素激活，在体内被胰高血糖素和禁食激活。CaMKII的遗传缺陷或抑制通过影响fox01的磷酸化来阻断其核易位，损害空腹和胰高血糖素/ camp诱导的糖原分解和糖异生，降低血糖水平，而组成型活性CaMKII具有相反的作用。重要的是，CaMKII缺乏对葡萄糖代谢的抑制作用被组成核FoxO1的转导所消除，这表明CaMKII缺乏的作用需要FoxO1的核排除。在肥胖的情况下，同样的途径也涉及到过量的HGP。这些结果揭示了钙介导的信号通路参与FoxO1核定位和肝脏葡萄糖稳态。
Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary HCs and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects. Importantly, the suppressive effect of CaMKII deficiency on glucose metabolism is abrogated by transduction with constitutively nuclear FoxO1, indicating that the effect of CaMKII deficiency requires nuclear exclusion of FoxO1. This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis.
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影响因子：
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