Cooperative roles of the suprachiasmatic nucleus central clock and the adrenal clock in controlling circadian glucocorticoid rhythm

The mammalian circadian timing system consists of the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and subsidiary peripheral clocks in other tissues. Glucocorticoids (GCs) are adrenal steroid hormones with widespread physiological effects that undergo daily oscillations. We previously demonstrated that the adrenal peripheral clock plays a pivotal role in circadian GC rhythm by driving cyclic GC biosynthesis. Here, we show that the daily rhythm in circulating GC levels is controlled by bimodal actions of central and adrenal clockwork. When mice were subjected to daytime restricted feeding to uncouple central and peripheral rhythms, adrenal GC contents and steroidogenic acute regulatory protein expression peaked around zeitgeber time 00 (ZT00), consistent with shifted adrenal clock gene expression. However, restricted feeding produced two distinct peaks in plasma GC levels: one related to adrenal GC content and the other around ZT12, which required an intact SCN. Light pulse-evoked activation of the SCN increased circulating GC levels in both wild-type and adrenal clock-disrupted mutant mice without marked induction of GC biosynthesis. In conclusion, we demonstrate that adrenal clock-dependent steroidogenesis and a SCN-driven central mechanism regulating GC release cooperate to produce daily circulatory GC rhythm.