FoxO6 integrates insulin signaling with gluconeogenesis in the liver.
FoxO6 integrates insulin signaling with gluconeogenesis in the liver.
复制标题
FOXO6将胰岛素信号传导与肝脏中的糖异生相结合。
作者：
Kim DH;Perdomo G;Zhang T;Slusher S;Lee S;Phillips BE;Fan Y;Giannoukakis N;Gramignoli R;Strom S;Ringquist S;Dong HH
过多的内源性葡萄糖产生导致糖尿病患者的空腹高血糖症。这种效应源于胰岛素对肝脏再生的无效抑制。为了了解其潜在的机制，我们研究了叉头盒O 6（FoxO 6）介导胰岛素对肝脏新生的作用及其对葡萄糖代谢的贡献。我们的特点FoxO 6在培养的肝细胞和饮食性肥胖，胰岛素抵抗，或胰岛素缺乏型糖尿病的啮齿动物模型中的葡萄糖代谢。我们确定了FoxO 6对FoxO 6功能获得与丧失的转基因小鼠和肝脏中选择性FoxO 6消融的糖尿病db/db小鼠的肝脏新生的影响。FoxO 6将胰岛素信号传导整合到肝细胞再生中。在小鼠中，肝脏中FoxO 6活性升高会增强新生血管形成，提高空腹血糖水平，而肝脏FoxO 6耗竭会抑制新生血管形成，导致空腹低血糖。FoxO 6刺激胰岛素生成，而胰岛素会抵消这种作用。胰岛素通过诱导FoxO 6磷酸化并使其转录活性丧失而不改变其在肝细胞中的亚细胞分布的独特机制抑制FoxO 6活性。FoxO 6在胰岛素抵抗的肝脏中变得失调，解释了其在促进胰岛素生成中的无节制活性，并与糖尿病中空腹高血糖症的发病机制相关。这些代谢异常，沿着空腹高血糖，可通过选择性抑制糖尿病小鼠肝脏FoxO 6活性而逆转。我们的数据揭示了一个FoxO 6依赖性途径，肝脏通过该途径协调胰岛素对胰岛素生成的调节，提供了选择性FoxO 6抑制有利于抑制过度的肝脏葡萄糖生成和改善糖尿病血糖控制的概念证明。
Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism. We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver. FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice. Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes.
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影响因子：
15.9
作者：
Bernal-Mizrachi, E;Wen, W;Permutt, MA
通讯作者：
Permutt, MA
影响因子：
56.9
作者：
Monecke, Thomas;Guettler, Thomas;Ficner, Ralf
通讯作者：
Ficner, Ralf
DOI：
10.1016/j.str.2008.06.013
发表时间：
2008-09-10
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Brent MM;Anand R;Marmorstein R
通讯作者：
Marmorstein R
影响因子：
15.9
作者：
Kamagate, Adama;Qu, Shen;Dong, H. Henry
通讯作者：
Dong, H. Henry
影响因子：
15.9
作者：
Foretz, Marc;Hebrard, Sophie;Viollet, Benoit
通讯作者：
Viollet, Benoit