Peripheral circadian clocks are diversely affected by adrenalectomy

Glucocorticoids are considered to synchronize the rhythmicity of clock genes in peripheral tissues; however, the role of circadian variations of endogenous glucocorticoids is not well defined. In the present study, we examined whether peripheral circadian clocks were impaired by adrenalectomy. To achieve this, we tested the circadian rhythmicity of core clock genes (Bmal1, Per1-3, Cry1, RevErbα, Rora), clock-output genes (Dbp, E4bp4) and a glucocorticoid- and clock-controlled gene (Gilz) in liver, jejunum, kidney cortex, splenocytes and visceral adipose tissue (VAT). Adrenalectomy did not affect the phase of clock gene rhythms but distinctly modulated clock gene mRNA levels, and this effect was partially tissue-dependent. Adrenalectomy had a significant inhibitory effect on the level of Per1 mRNA in VAT, liver and jejunum, but not in kidney and splenocytes. Similarly, adrenalectomy down-regulated mRNA levels of Per2 in splenocytes and VAT, Per3 in jejunum, RevErbα in VAT and Dbp in VAT, kidney and splenocytes, whereas the mRNA amounts of Per1 and Per2 in kidney and Per3 in VAT and splenocytes were up-regulated. On the other hand, adrenalectomy had minimal effects on Rora and E4bp4 mRNAs. Adrenalectomy also resulted in decreased level of Gilz mRNA but did not alter the phase of its diurnal rhythm. Collectively, these findings suggest that adrenalectomy alters the mRNA levels of core clock genes and clock-output genes in peripheral organs and may cause tissue-specific modulations of their circadian profiles, which are reflected in changes of the amplitudes but not phases. Thus, the circulating corticosteroids are necessary for maintaining the high-amplitude rhythmicity of the peripheral clocks in a tissue-specific manner.糖皮质激素（glucocorticoids）被认为可同步外周组织（peripheral tissues）中时钟基因的节律性，但内源性糖皮质激素的昼夜节律波动的生理作用尚未得到充分阐明。本研究中，我们探究了肾上腺切除术（adrenalectomy）是否会对外周昼夜时钟造成损伤。为此，我们检测了肝脏、空肠、肾皮质、脾细胞及内脏脂肪组织（visceral adipose tissue, VAT）中核心时钟基因（core clock genes：Bmal1、Per1-3、Cry1、RevErbα、Rora）、时钟输出基因（clock-output genes：Dbp、E4bp4）以及糖皮质激素与时钟共同调控基因Gilz的昼夜节律性。肾上腺切除术未改变时钟基因节律的时相，但显著调控了时钟基因的mRNA水平，且该效应存在组织依赖性。具体而言，肾上腺切除术对内脏脂肪组织、肝脏和空肠中的Per1 mRNA水平具有显著抑制作用，但对肾脏与脾细胞无此效果。类似地，肾上腺切除术下调了脾细胞和内脏脂肪组织中的Per2、空肠中的Per3、内脏脂肪组织中的RevErbα，以及内脏脂肪组织、肾脏和脾细胞中的Dbp的mRNA水平；而肾脏中的Per1与Per2、内脏脂肪组织与脾细胞中的Per3的mRNA含量则出现上调。此外，肾上腺切除术对Rora和E4bp4的mRNA水平影响极小。肾上腺切除术还导致Gilz mRNA水平降低，但未改变其昼夜节律的时相。综上，上述研究结果表明，肾上腺切除术可改变外周器官中核心时钟基因及时钟输出基因的mRNA水平，并可能对它们的昼夜节律特征产生组织特异性调控，这种调控体现在振幅而非时相的变化中。因此，循环中的糖皮质激素对于以组织特异性方式维持外周时钟的高振幅节律性是必需的。