The adrenal peripheral clock: glucocorticoid and the circadian timing system

The mammalian circadian timing system is organized in a hierarchy, with the master clock residing in the suprachiasmatic nucleus (SCN) of the hypothalamus and subsidiary peripheral clocks in other brain regions as well as peripheral tissues. Since the local oscillators in most cells contain a similar molecular makeup to that in the central pacemaker, determining the role of the peripheral clocks in the regulation of rhythmic physiology and behavior is an important issue. Glucocorticoids (GCs) are a class of multi-functional adrenal steroid hormones, which exhibit a robust circadian rhythm, with a peak linked with the onset of the daily activity phase. It has long been believed that the production and secretion of GC is primarily governed through the hypothalamus-pituitary-adrenal (HPA) neuroendocrine axis in mammals. Growing evidence, however, strongly supports the notion that the periodicity of GC involves the integrated activity of multiple regulatory mechanisms related to circadian timing system along with the classical HPA neuroendocrine regulation. The adrenal-intrinsic oscillator as well as the central pacemaker plays a pivotal role in its rhythmicity. GC influences numerous biological processes, such as metabolic, cardiovascular, immune and even higher brain functions, and also acts as a resetting signal for the ubiquitous peripheral clocks, suggesting its importance in harmonizing circadian physiology and behavior. In this review, we will therefore focus on the recent advances in our understanding of the circadian regulation of adrenal GC and its functional relevance.