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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases
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FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases

机译：FoxO转录因子通过抑制蛋白磷酸酶激活Akt并减弱心脏中的胰岛素信号传导

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摘要

Insulin resistance and metabolic syndrome are rapidly expanding public health problems. Acting through the PI3K/Akt pathway, insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO transcription factors, a class of highly conserved proteins important in numerous physiological functions. However, even as FoxO is a downstream target of insulin, FoxO factors also control upstream signaling elements governing insulin sensitivity and glucose metabolism. Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity. FoxO-activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition. We reported previously that FoxO factors attenuate cardiomyocyte calcineurin (PP2B) activity. We now show that calcineurin forms a complex with Akt and inhibition of calcineurin enhances Akt phosphorylation. In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions. Repression of Akt-PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO-dependent increases in Akt phosphorylation and kinase activity. Resveratrol, an activator of Sirti, increases the transcrip-tional activity of FoxO1 and triggers Akt phosphorylation in heart. Importantly, FoxO-mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin-triggered glucose uptake. Also, inactivation of the gene coding for FoxO3 enhances insulin-dependent Akt phosphorylation. Taken together, this study demonstrates that changes in FoxO activity have a dose-responsive repressive effect on insulin signaling in cardiomyocytes through inhibition of protein phosphatases, which leads to altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism.
机译：胰岛素抵抗和代谢综合征正在迅速扩大公共卫生问题。胰岛素和胰岛素样生长因子-1（IGF-1）通过PI3K / Akt途径起作用，使FoxO转录因子失活，FoxO转录因子是一类高度保守的蛋白，在许多生理功能中都很重要。但是，即使FoxO是胰岛素的下游靶标，FoxO因子也控制着控制胰岛素敏感性和葡萄糖代谢的上游信号传导元件。在这里，我们报告说，心肌细胞中FoxO1或FoxO3的持续激活会增加基础水平的Akt磷酸化和激酶活性。 FoxO激活的Akt直接与FoxO相互作用并使其磷酸化，从而提供反馈抑制作用。我们以前曾报道过FoxO因子减弱心肌钙调神经磷酸酶（PP2B）的活性。我们现在显示钙调神经磷酸酶与Akt形成复合物，抑制钙调神经磷酸酶可增强Akt磷酸化。此外，FoxO活性抑制蛋白磷酸酶2A（PP2A），并破坏Akt-PP2A和Akt-钙调神经磷酸酶的相互作用。 Akt-PP2A / B相互作用和磷酸酶活性的抑制至少部分地导致Akt磷酸化和激酶活性的FoxO依赖性增加。白藜芦醇是Sirti的活化剂，可增加FoxO1的转录活性并触发心脏中的Akt磷酸化。重要的是，FoxO介导的Akt活性增加减少了胰岛素信号传导，这表现为Akt磷酸化减少，Glut4膜移位减少以及胰岛素触发的葡萄糖摄取减少。同样，FoxO3编码基因的失活增强了胰岛素依赖性Akt磷酸化。两者合计，这项研究表明FoxO活性的变化通过抑制蛋白磷酸酶对心肌细胞中的胰岛素信号传导具有剂量反应性的抑制作用，从而导致Akt活化改变，胰岛素敏感性降低和葡萄糖代谢受损。

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