Liver adenosine monophosphate-activated kinase-α2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin
Liver adenosine monophosphate-activated kinase-α2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin
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DOI：
10.1210/en.2005-0898
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发表时间：
2006-05-01
期刊：
影响因子：
4.8
通讯作者：
Viollet, B
中科院分区：
文献类型：
--
作者：
Andreelli, F;Foretz, M;Viollet, B
AMP激活激酶（AMPK）是一种丝氨酸苏氨酸激酶，其作为燃料传感器在细胞和全身水平上调节能量平衡。我们研究了肝脏AMPK α 2亚型如何影响体内肝脏葡萄糖生成和外周葡萄糖摄取。我们产生了在肝脏中特异性缺失AMPK α 2基因的小鼠（肝脏α 2KO）。肝脏α 2KO小鼠在禁食状态下葡萄糖不耐受和高血糖。高血压与体内评估的内源性葡萄糖产生比对照组高50%相关。然后，我们研究了这种增加的葡萄糖产生是否对胰岛素敏感。当以诱导生理性高胰岛素血症的速率输注胰岛素时，完全抑制肝脏α 2 KO小鼠的内源性葡萄糖产生，表明它们具有正常的胰岛素敏感性。这在体内通过正常胰岛素诱导的Akt磷酸化和在禁食/进食过渡期间肝脏中磷酸烯醇丙酮酸羧激酶、葡萄糖-6磷酸酶和丙酮酸激酶的转录调节得到证实。瘦素和脂联素调节肝脏葡萄糖的产生，因此我们将这些脂肪因子注入肝脏α 2KO小鼠。在缺乏肝脏AMPK α 2的小鼠中，这两种脂肪因子都不能调节肝脏葡萄糖的产生，而在对照小鼠中两者都能调节。总之，我们发现肝脏AMPK α 2亚型对于抑制肝脏葡萄糖产生和维持空腹血糖水平在生理范围内是必不可少的。我们还表明，肝脏葡萄糖的产生，瘦素和脂联素，而不是胰岛素的调节，需要肝脏AMPK α 2活性。
The AMP-activated kinase ( AMPK) is a serine threonine kinase that functions as a fuel sensor to regulate energy balance at both cellular and whole-body levels. Here we studied how hepatic AMPK alpha 2 isoform affects hepatic glucose production and peripheral glucose uptake in vivo. We generated mice deleted for the AMPK alpha 2 gene specifically in the liver (liver alpha 2KO). Liver alpha 2KO mice were glucose intolerant and hyperglycemic in the fasted state. Hyperglycemia was associated with a 50% higher endogenous glucose production than in controls as assessed in vivo. We then investigated whether this increased glucose production was sensitive to insulin. Insulin, when infused at a rate inducing physiological hyperinsulinemia, totally inhibited endogenous glucose production in liver alpha 2KO mice, showing that they had normal insulin sensitivity. This was confirmed in vivo by normal insulin-induced phosphorylation of Akt and transcriptional regulation of the phosphoenolpyruvate carboxykinase, glucose-6 phosphatase, and pyruvate kinase in liver during the fasted/fed transition. Leptin and adiponectin regulate hepatic glucose production, so we then infused these adipokines into liver alpha 2KO mice. Neither of these adipokines regulated hepatic glucose production in mice lacking hepatic AMPK alpha 2, whereas both did so in control mice. In conclusion, we show that the hepatic AMPK alpha 2 isoform is essential for suppressing hepatic glucose production and maintaining fasting blood glucose levels in the physiological range. We also demonstrate that regulation of hepatic glucose production by leptin and adiponectin, but not insulin, requires hepatic AMPK alpha 2 activity.