Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.
Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.
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DOI：
10.1016/j.cmet.2008.06.006
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发表时间：
2008-07
期刊：
影响因子：
29
通讯作者：
White MF
中科院分区：
文献类型：
--
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
叉头转录因子Foxo1调节与抗逆性和新陈代谢有关的基因的表达。为了评估Foxo1在肝脏胰岛素抵抗期间代谢紊乱中的作用，我们干扰了缺乏肝脏IRS1和Irs2的小鼠(DKO-小鼠)肝脏中Foxo1的表达。DKO-小鼠体型较小，并患上糖尿病；对DKO-肝脏转录组的分析发现，生长和代谢基因的表达受到干扰，包括Ppargc1a和Igfbp1增加，葡萄糖激酶、Srebp1c、Ghr和Igf1减少。在DKO小鼠中，肝脏特异性缺失Foxo1导致DKO-肝脏转录组显著正常化，对禁食和进食的反应部分恢复，血糖和胰岛素浓度接近正常，体型正常化。这些结果表明，在严重的肝脏胰岛素抵抗时，固有活性的Foxo1对高血糖有重要作用，IRS1/2→PI-3K→Akt→Foxo1胰岛素信号分支在肝脏胰岛素调节的血糖稳态和体细胞生长中起重要作用。
The Forkhead transcription factor Foxo1 regulates expression of genes involved in stress resistance and metabolism. To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO-mice). DKO-mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr and Igf1. Liver-specific deletion of Foxo1 in DKO-mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2→PI-3K→Akt→Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth.
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