Effect Of Glucocorticoids On Circadian Regulation Of Mammanlian Peripheral Clocks

Glucocorticoids secreted by the adrenal cortex are a class of steroid hormones, playing important physiological functions in regulating the body homeostasis and metabolism, It is widely applied in clinic which shows severe side effect in long-term administration. Thus, it is full of importance and necessity to start chronopharmacological study of glucocorticoids in clinical application. Rhythmic secreted glucocorticoids are controlled by SCN, which is not only an output of SCN, but also a transfer of the resetting signals from SCN to peripheral clocks, that prevent disorganized internal circadian rhythm. Few studies have addressed the function of glucocorticoids in reentrainment during jet lag. Here, we first analysed rhythmic secretion of glucocorticoids in male Wistar rats, and then investigated the effect of glucocorticoid-stimulation on the expression of peripheral clock (liver and heart) genes and hepatic glucose metabolic genes at different time of day. We also explored the role of glucocorticoids in adapting the jet lag.The results obtained here indicated that glucocorticoids were not essential for maintaining circadian rhythm in normal condiction, but the lack of glucocorticoids would cause attenuated amplitude of peripheral clock genes and hepatic glucose metabolic genes. Glucocorticoid-stimulation could remarkably induce the expression of peripheral clock genes and hepatic glucose metabolic genes in a tissue-and gene-specific mannar, the effect of which depended on the time of stimulation. The expression phases of circadian and glucose metabolic genes were shifted after glucocorticoids injection for7days, which were delayed in peak time injection group, and advanced in valley time injection group. When the administration of glucocorticoids was processed at the middle time of peak and valley, the internal circadian rhythm was minimum disturbed, which indicated the best time for the clinical administration of glucocorticoids.Injection of glucocorticoids at different time would effectively regulate the speed of phase resetting of liver and heart clocks under experimental jet lag. Glucocorticoids administration at the expected new peak or valley time after jet lag would accelerate or decelerate the circadian reentrainment, respectively. In addition, timed administration of glucocorticoids could substantially alter the day/night activity reentrainment. Therefore, it might be an attractive therapeutic alternative during jet lag to modulate the glucocorticoids rhythm by timed inhibiting or facilitating glucocorticoids synthesis, considering its minor side effects.