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首页> 外文期刊>Cell metabolism >Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.
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Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.

机译：胰岛素信号使肝Foxo1失活是适应性营养稳态和内分泌生长调节所必需的。

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摘要

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 --> PI3K --> Akt --> Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth.
机译：前叉转录因子Foxo1调节与抗逆性和代谢有关的基因的表达。若要评估Foxo1对肝胰岛素抵抗过程中代谢失调的贡献，我们破坏了缺乏肝Irs1和Irs2的小鼠（DKO小鼠）肝脏中Foxo1的表达。 DKO小鼠体积小，发展为糖尿病。 DKO-肝转录组的分析确定了生长和代谢基因的表达受干扰，包括增加的Ppargc1a和Igfbp1，减少的葡萄糖激酶，Srebp1c，Ghr和Igf1。 DKO小鼠中肝脏特异性Foxo1的缺失导致DKO-肝转录组显着正常化，并且对禁食和进食，血糖和胰岛素浓度接近正常以及体型正常化的反应部分恢复。这些结果表明，在严重肝胰岛素抵抗期间，组成型活性Foxo1显着促成高血糖，并且胰岛素信号的Irs1 / 2-> PI3K-> Akt-> Foxo1分支在很大程度上负责肝胰岛素调节的葡萄糖稳态和体细胞生长。

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