Trends in Endocrinology & Metabolism
ReviewInteractions of the circadian CLOCK system and the HPA axis
Section snippets
Adjustment of internal homeostasis to major changes in circumstance
Virtually all organisms live under the strong influence of day/night cycles created by the 24h rotation of the planet. Organisms sense these regular external changes and synchronize their physical activities, such as behavior, food intake, energy metabolism, sleep, reproductive activity and immune function, to increase their chance for survival [1]. From their early evolution, organisms have developed a highly conserved and sophisticated ubiquitous molecular “clock”, the CLOCK system, which
The circadian CLOCK system
The circadian CLOCK system consists of central and peripheral components. The central component is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and acts as a “master” CLOCK under the strong influence of light/dark input from the eyes, whereas the peripheral components behave as “slave” CLOCKs, functioning virtually in all organs and tissues 1, 2 (Figure 1) (Box 2). The activity of the peripheral CLOCKs is synchronized to that of the central master CLOCK through both humoral
The stress HPA axis
The HPA axis, apart from having circadian activity, also mediates the adaptive response to stressors; it consists of the hypothalamic PVN parvocellular corticotropin-releasing hormone (CRH)- and AVP-secreting neurons, the pituitary corticotrophs, and the adrenal gland cortices. The PVN neurons release CRH and AVP into the hypophyseal portal system located under the median eminence of the hypothalamus in response to stimulatory signals from higher brain regulatory centers. Secreted CRH and AVP
Regulation of the HPA axis by the circadian CLOCK system
Circulating glucocorticoid levels are tightly regulated and fluctuate naturally in a circadian manner, reaching their zenith in the early morning and their nadir in the late evening in diurnal animals, including humans 22, 23. The light-activated central master CLOCK located in the SCN orchestrates this daily rhythmic release of glucocorticoids by influencing the activity of the HPA axis through efferent connections from the SCN to the CRH/AVP-containing neurons of the PVN 6, 18, 24 (Figure 2).
Implications of the CLOCK–HPA axis interaction for the development of metabolic and immune disorders
As evidenced in the previous sections, the CLOCK system and HPA axis influence the activity and function of the CNS and peripheral tissues, whereas the master CLOCK system clearly dictates the circadian activity of the HPA axis. In the following sections, we discuss these mutual interactions and their implications in the development of pathologic conditions, with metabolic and immune disorders as illustrative examples.
Intermediary metabolism handles the turnover of carbohydrates, proteins and
Concluding remarks
The circadian CLOCK and stress systems regulate activity of one another through multilevel interactions to ultimately coordinate homeostasis against the day/night change and various unforeseen random internal and external stressors. As the day/night changes are sterotypic and take place irrevocally, the circadian master CLOCK system controls the stress system, and the stress system adjusts the circadian rhythm of the non-master CNS and peripheral CLOCKs in response to various stressors. Thus,
Acknowledgments
Literary work of this article was funded partly by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
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