Development of metabolic syndrome is associated with hyperactivity of the HPA axis characterized by elevated levels of circulating adrenal hormones including cortisol and aldosterone. However, the molecular mechanism leading to the dysregulation of the HPA axis is not well elucidated. In this study, we found that insulin regulates adrenal steroidogenesis by increasing the expression and activity of steroidogenic factor 1 (SF-1) both in vitro and in vivo and this insulin effect was partly through inhibition of FoxO1. Specifically, insulin increased the protein and RNA levels of SF-1 and steroidogenic target genes. Further, adrenal SF-1 expression was significantly increased by hyperactivation of insulin signaling in mice. Together with the elevated SF-1 expression in adrenal glands, hyperactivation of insulin signaling led to increased aldosterone and corticosterone levels. On the other hand, suppressing the insulin signaling using streptozotocin markedly reduced the expression of adrenal SF-1 in mice. In addition, overexpression of FoxO1 significantly suppressed SF-1 and its steroidogenic target genes implying that the positive effect of insulin on SF-1 activity might be through suppression of FoxO1 in the adrenal gland. Taken together, these results indicate that insulin regulates adrenal steroidogenesis through coordinated control of SF-1 and FoxO1.

中文翻译：

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胰岛素通过稳定SF-1活性来调节肾上腺类固醇生成。

代谢综合征的发生与HPA轴功能亢进有关，其特征是循环肾上腺激素（包括皮质醇和醛固酮）水平升高。但是，导致HPA轴失调的分子机制尚不清楚。在这项研究中，我们发现胰岛素通过增加体内和体外类固醇生成因子1（SF-1）的表达和活性来调节肾上腺类固醇生成，这种胰岛素作用部分是通过抑制FoxO1来实现的。具体而言，胰岛素增加了SF-1和类固醇生成靶基因的蛋白质和RNA水平。此外，在小鼠中，胰岛素信号的过度激活会显着增加肾上腺SF-1的表达。再加上肾上腺中SF-1的表达升高，胰岛素信号的过度活化导致醛固酮和皮质酮水平升高。另一方面，使用链脲佐菌素抑制胰岛素信号转导显着降低了小鼠肾上腺SF-1的表达。此外，FoxO1的过表达显着抑制了SF-1及其类固醇生成靶基因，这暗示胰岛素对SF-1活性的积极作用可能是通过抑制肾上腺中的FoxO1来实现的。综上所述，这些结果表明胰岛素通过对SF-1和FoxO1的协调控制来调节肾上腺类固醇生成。FoxO1的过表达显着抑制了SF-1及其类固醇生成靶基因，这暗示胰岛素对SF-1活性的积极作用可能是通过抑制肾上腺中的FoxO1来实现的。综上所述，这些结果表明胰岛素通过对SF-1和FoxO1的协调控制来调节肾上腺类固醇生成。FoxO1的过表达显着抑制了SF-1及其类固醇生成靶基因，这暗示胰岛素对SF-1活性的积极作用可能是通过抑制肾上腺中的FoxO1来实现的。综上所述，这些结果表明胰岛素通过对SF-1和FoxO1的协调控制来调节肾上腺类固醇生成。