Circadian Rhythms of Glucocorticoid Hormone Actions in Target Tissues: Potential Clinical ImplicationsA Presentation from the European Society for Paediatric Endocrinology (ESPE) New Inroads to Child Health (NICHe) Conference on Stress Response and Child Health in Heraklion, Crete, Greece, 18 to 20 May 2012.

Oct 4, 2012Science signaling

Daily cycles of stress hormone effects in body tissues and possible health impacts

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Abstract

Dysregulation in the clock system and the HPA axis may lead to similar health issues, including obesity and cardiovascular disease.

The hypothalamic-pituitary-adrenal (HPA) axis utilizes glucocorticoids and receptors for signaling in response to environmental stressors.
A circadian clock system regulates internal rhythms by adjusting organism activities to day-night cycles.
The central clock in the brain influences the HPA axis, affecting hormone levels like adrenocorticotropic hormone and cortisol throughout the day.
The HPA axis can modify the circadian rhythms of peripheral clocks in response to stress through the glucocorticoid receptor.
Clock-Bmal1 may impact how peripheral tissues respond to glucocorticoids, potentially counteracting the effects of fluctuating cortisol levels.

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Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self-oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations--including obesity, metabolic syndrome, and cardiovascular disease--by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids.

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