Stress-Related and Circadian Secretion and Target Tissue Actions of Glucocorticoids: Impact on Health

Abstract

Living organisms are highly complex systems that must maintain a dynamic equilibrium or homeostasis that requires energy to be sustained. Stress is a state in which several extrinsic or intrinsic disturbing stimuli, the stressors, threaten, or are perceived as threatening, homeostasis. To achieve homeostasis against the stressors, organisms have developed a highly sophisticated system, the stress system, which provides neuroendocrine adaptive responses, to restore homeostasis. These responses must be appropriate in terms of size and/or duration; otherwise, they may sustain life but be associated with detrimental effects on numerous physiologic functions of the organism, leading to a state of disease-causing disturbed homeostasis or cacostasis. In addition to facing a broad spectrum of external and/or internal stressors, organisms are subject to recurring environmental changes associated with the rotation of the planet around itself and its revolution around the sun. To adjust their homeostasis and to synchronize their activities to day/night cycles, organisms have developed an evolutionarily conserved biologic system, the "clock" system, which influences several physiologic functions in a circadian fashion. Accumulating evidence suggests that the stress system is intimately related to the circadian clock system, with dysfunction of the former resulting in dysregulation of the latter and vice versa. In this review, we describe the functional components of the two systems, we discuss their multilevel interactions, and we present how excessive or prolonged activity of the stress system affects the circadian rhythm of glucocorticoid secretion and target tissue effects.

Keywords: circadian endocrine rhythms; clock system; glucocorticoid receptor; glucocorticoids; hypothalamic–pituitary–adrenal axis; stress; stress system.

Figure 1

Molecular components of the main and auxiliary transcriptional/translational loops of the circadian clock system. In the main transcription loop, the heterodimer CLOCK/BMAL1 causes upregulation of Pers and Crys. PERs and CRYs undergo phosphorylation by the Csnk1ε/δ and translocate to the nucleus suppressing the transcriptional activity of the CLOCK/BMAL1. Moreover, CLOCK/BMAL1 influences the transcription rate of several other clock-related genes, such as RORα and REV-ERBα, giving rise to an auxiliary transcription loop. AMPK participates in the main transcription loop by phosphorylating CRYs, PERs, and Csnk1ε. SIRT1 functions as a counter-regulatory mechanism for the acetyltransferase activity of the CLOCK by deacetylating BMAL1, PER2, and histone 3. CHRONO, a recently identified BMAL target was found to interact with BMAL1, repressing the main transcription loop via recruitment of histone deacetylase 1. A, acetyl residue on the acetylated molecules; AMPK, adenosine monophosphate-activated protein kinase; BMAL1, brain–muscle–arnt-like protein 1; CHRONO, ChIP-derived repressor of network oscillator; CLOCK, circadian locomotor output cycle kaput; CRYs, cryptochromes; Csnk1ε/δ, casein kinase 1ε/δ; P, phosphate residue on the phosphorylated molecules; PERs, periods; RORα, retinoic acid receptor-related orphan nuclear receptor α; SIRT1, sirtuin 1. Modified from Ref. (32).

Figure 2

Molecular interactions between the hypothalamic–pituitary–adrenal (HPA) axis and the circadian clock system. (A) In the absence of stressors, (B) under acute stressors, and (C) under chronic stressors. (A) In normal conditions, the central suprachiasmatic nucleus (SCN) clock creates the diurnal fluctuation of glucocorticoid concentrations by regulating the activity of the HPA axis through neuronal projections and by influencing the adrenal cortex sensitivity to ACTH through the splanchnic nerves. The peripheral clocks are synchronized to the circadian activity of the central clock through unknown mechanisms and suppress the transcriptional activity of the hGRα by CLOCK-mediated acetylation of the receptor. (B) Under stressful conditions, acute stressors activate the HPA axis leading to increased glucocorticoid concentrations independently of the central clock-mediated circadian regulation of the HPA axis. In peripheral tissues, glucocorticoids phase shift and reset peripheral clocks leading to uncoupling of the latter from the central clock, granted that the GRα protein is not expressed in the SCN. In addition, the transcriptional activity of the hGRα may be influenced by the phase-shifted peripheral clocks by unknown mechanisms. Following termination of the acute stress, the central clock can reset peripheral clocks to their initial phase. (C) In the presence of chronic stressors, the SCN receives indirect glucocorticoid feedback from raphe nuclei, the hypothalamic dorsomedial nucleus, and the paraventricular nucleus. Its activity is also influenced by pro-inflammatory cytokines and BDNF. Chronic stressors trigger the release of glucocorticoids by the adrenal cortex independently of the central clock-mediated diurnal regulation of the HPA axis. This stress-induced glucocorticoid secretion phase shifts and resets peripheral clocks leading to uncoupling of the latter from the central clock. A, acetyl residue on the acetylated molecules; ACTH, adrenocorticotropic hormone; AVP, arginine vasopressin; BDNF, brain-derived neurotrophic factor; BMAL1, brain–muscle–arnt-like protein 1; CLOCK, circadian locomotor output cycle kaput; CRH, corticotropin-releasing hormone; FKBP, FK506-binding protein; GR, glucocorticoid receptor; HSPs, heat shock proteins; PERs, periods.

Figure 3

(A) Circadian pattern of cortisol secretion in normal humans, CS subjects and rotating shift workers (left panel), and the responses of normal and stressed subjects to overnight dexamethasone suppression test. (B) The target tissue sensitivity is lower in the morning and higher at night, mirroring the status of GR acetylation. (A) A population of 284 51-year-old men were examined by obtaining a detailed medical history, by performing anthropometry, and by measuring a series of diurnal salivary cortisol concentrations. Participants were asked to fill in a questionnaire about self-perceived stress and underwent a low-dose overnight dexamethasone suppression test. Normal participants were characterized by increased variance, distant zeniths in the morning and nadirs in the evening, and an appropriate suppression in the morning salivary cortisol concentrations following a low-dose dexamethasone suppression test. On the other hand, CS participants showed a decreased variance, evening nadir elevations and morning zenith decreases of cortisol concentrations, as well as an inadequate response to a low-dose dexamethasone suppression test. We speculate that rotating shift workers might be characterized by a phase-delayed curve of salivary cortisol concentrations, compared to that of normal participants. CS, chronically stressed individuals; D, midnight dexamethasone administration; NS, non-stressed individuals. Modified from Ref. (35, 90).