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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >FOXO and insulin signaling regulate sensitivity of the circadian clock to oxidative stress
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FOXO and insulin signaling regulate sensitivity of the circadian clock to oxidative stress

机译：FOXO和胰岛素信号调节生物钟对氧化应激的敏感性

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摘要

Circadian rhythms can be regulated by many environmental and endogenous factors. We show here a sensitivity of circadian clock function to oxidative stress that is revealed in flies lacking the foxo gene product. When exposed to oxidative stress, wild-type flies showed attenuated clock gene cycling in peripheral tissues, whereas foxo mutants also lost behavioral rhythms driven by the central clock. FOXO is expressed predominantly in the fat body, and transgenic expression in this tissue rescued the mutant behavioral phenotype, suggesting that foxo has non-cell-autonomous effects on central circadian clock function. Overexpression of signaling molecules that affect FOXO activity, such as the insulin receptor or Akt, in the fat body also increased susceptibility of the central clock to oxidative stress. Finally, foxo mutants showed a rapid decline in rest:activity rhythms with age, supporting the idea that the increase of oxidative stress contributes to age-associated degeneration of behavioral rhythms and indicating the importance of FOXO in mitigating this deterioration. Together these data demonstrate that metabolism affects central clock function and provide a link among insulin signaling, oxidative stress, aging, and circadian rhythms.
机译：昼夜节律可由许多环境和内源性因素调节。我们在这里显示了昼夜节律的时钟功能对氧化应激的敏感性，这在缺乏foxo基因产物的果蝇中显示出来。当暴露于氧化应激时，野生型果蝇在外围组织中的时钟基因循环减弱，而狐狸突变体也失去了由中心时钟驱动的行为节律。 FOXO主要在脂肪体内表达，并且在该组织中的转基因表达挽救了突变的行为表型，表明foxo对中枢生物钟功能具有非细胞自主作用。在脂肪体内影响FOXO活性的信号分子（例如胰岛素受体或Akt）的过度表达也增加了中心钟对氧化应激的敏感性。最后，foxo突变体显示出随着年龄的增长，其休息：活动节律迅速下降，支持了氧化应激增加导致行为节律与年龄相关的退化的观点，并表明了FOXO在减轻这种恶化中的重要性。这些数据一起证明，代谢会影响中枢时钟功能，并在胰岛素信号传导，氧化应激，衰老和昼夜节律之间提供联系。

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