Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
J Endocrinol. 2020 Aug;246(2):R13-R31. doi: 10.1530/JOE-20-0066.
The circadian rhythm derives from the integration of many signals that shape the expression of clock-related genes in a 24-h cycle. Biological tasks, including cell proliferation, differentiation, energy storage, and immune regulation, are preferentially confined to specific periods. A gating system, supervised by the central and peripheral clocks, coordinates the endogenous and exogenous signals and prepares for transition to activities confined to periods of light or darkness. The fluctuations of cortisol and its receptor are crucial in modulating these signals. Glucocorticoids and the autonomous nervous system act as a bridge between the suprachiasmatic master clock and almost all peripheral clocks. Additional peripheral synchronizing mechanisms including metabolic fluxes and cytokines stabilize the network. The pacemaker is amplified by peaks and troughs in cortisol and their response to food, activity, and inflammation. However, when the glucocorticoid exposure pattern becomes chronically flattened at high- (as in Cushing's syndrome) or low (as in adrenal insufficiency) levels, the system fails. While endocrinologists are well aware of cortisol rhythm, too little attention has been given to interventions aimed at restoring physiological cortisol fluctuations in adrenal disorders. However, acting on glucocorticoid levels may not be the only way to restore clock-related activities. First, a counterregulatory mechanism on the glucocorticoid receptor itself controls signal transduction, and second, melatonin and/or metabolically active drugs and nutrients could also be used to modulate the clock. All these aspects are described herein, providing some insights into the emerging role of chronopharmacology, focusing on glucocorticoid excess and deficiency disorders.
昼夜节律源于许多信号的整合，这些信号以 24 小时周期来塑造与时钟相关的基因表达。生物任务，包括细胞增殖、分化、能量储存和免疫调节，优先局限于特定的时间段。一个门控系统，由中枢和外周时钟监督，协调内源性和外源性信号，并为过渡到局限于光或暗时间段的活动做准备。皮质醇及其受体的波动在调节这些信号方面至关重要。糖皮质激素和自主神经系统作为视交叉上核主时钟与几乎所有外周时钟之间的桥梁。其他外周同步机制包括代谢通量和细胞因子，稳定了这个网络。皮质醇的峰值和低谷及其对食物、活动和炎症的反应放大了起搏器。然而，当糖皮质激素暴露模式在高水平（如库欣综合征）或低水平（如肾上腺功能不全）时变得慢性平坦时，系统就会失效。尽管内分泌学家非常了解皮质醇节律，但对旨在恢复肾上腺疾病中生理皮质醇波动的干预措施关注甚少。然而，作用于糖皮质激素水平可能不是恢复与时钟相关活动的唯一方法。首先，糖皮质激素受体本身的一个反馈调节机制控制信号转导，其次，褪黑素和/或代谢活跃的药物和营养物质也可以用于调节时钟。本文描述了所有这些方面，提供了一些关于时间药理学新兴作用的见解，重点关注糖皮质激素过多和缺乏障碍。
