Glucocorticoid regulation of the circadian clock modulates glucose homeostasis
Glucocorticoid regulation of the circadian clock modulates glucose homeostasis
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DOI：
10.1073/pnas.0909733106
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发表时间：
2009-10-13
影响因子：
11.1
通讯作者：
Feldman, Brian J.
中科院分区：
文献类型：
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作者：
So, Alex Y. -L.;Bernal, Teresita U.;Feldman, Brian J.
昼夜节律钟基因受糖皮质激素的调节，然而，这种调节是直接的还是间接的作用，以及这种调节的生理后果尚不清楚。在这里，我们确定了糖皮质激素反应元件（GRES）在多个时钟基因，并表明3直接调节糖皮质激素受体。我们确定，一个GRE内的核心时钟基因Per2的节奏表达过程中连续占用和必要的糖皮质激素调节该基因在体内。我们进一步证明，具有跨越该GRE的基因组缺失的小鼠表达升高的瘦素水平，并且在糖皮质激素治疗时免受葡萄糖耐受不良和胰岛素抵抗的影响，但不免受肌肉萎缩的影响。我们的结论是Per2是一个特定的糖皮质激素调节途径的组成部分，糖皮质激素的外周时钟的调节是选择性地需要糖皮质激素的一些行动。
Circadian clock genes are regulated by glucocorticoids; however, whether this regulation is a direct or secondary effect and the physiological consequences of this regulation were unknown. Here, we identified glucocorticoid response elements (GREs) at multiple clock genes and showed that 3 were directly regulated by the glucocorticoid receptor. We determined that a GRE within the core clock gene Per2 was continuously occupied during rhythmic expression and essential for glucocorticoid regulation of that gene in vivo. We further demonstrated that mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. We conclude that Per2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.