CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice
CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice
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CLOCK 和 BMAL1 通过 SIRT1 调节雄性小鼠的肌肉胰岛素敏感性
DOI：
10.1210/en.2015-2027
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发表时间：
2016-06-01
期刊：
影响因子：
4.8
通讯作者：
Zhai, Qiwei
中科院分区：
文献类型：
--
作者：
Liu, Jun;Zhou, Ben;Zhai, Qiwei
在人和动物模型中，昼夜节律失调都会导致胰岛素抵抗，而骨骼肌是对胰岛素最大的器官反应。然而，生物钟如何调节肌肉的胰岛素敏感性和潜在的分子机制在很大程度上仍不清楚。在这里，我们显示了昼夜节律运动输出周期kaput(CLOCK)和脑和肌肉芳烃受体核转运子样蛋白(BMAL)-1，这两个核心的昼夜节律转录因子在胰岛素抵抗的C2C12肌管和小鼠骨骼肌中下调。此外，CLOCK(Delta 19/Delta 19)小鼠骨骼肌中的胰岛素信号被减弱，而小干扰RNA敲除CLOCK或BMAL1可诱导C2C12肌管中的胰岛素抵抗。Clock和BMAL1的异位表达一致地提高了C2C12肌管对胰岛素的敏感性。此外，Clock和BMAL1在C2C12肌管和小鼠骨骼肌中调节胰岛素敏感性的重要调节因子sirtuin1(SIRT1)的表达，Sirt1启动子中的两个E-box元件负责其在肌肉细胞中的Clock和BMAL1依赖的转录。进一步的研究表明，Clock和BMAL1通过SIRT1调节肌肉的胰岛素敏感性。此外，我们发现，在持续黑暗中维持的小鼠肌肉中BMAL1和SIRT1减少，补充白藜芦醇激活SIRT1并改善胰岛素敏感性。所有这些数据表明，Clock和BMAL1通过SIRT1调节肌肉的胰岛素敏感性，SIRT1的激活可能是一种潜在的有价值的策略，可以减轻与昼夜节律失调相关的肌肉胰岛素抵抗。
Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of Clock(Delta 19/Delta 19) mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK-and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment.