The Adrenal Clock Prevents Aberrant Light-Induced Alterations in Circadian Glucocorticoid Rhythms

Abstract

The glucocorticoid (GC) rhythm is entrained to light-dark (LD) cycles via a molecular clock in the suprachiasmatic nucleus (SCN) and is maintained by an adrenal clock synchronized by SCN-dependent signals. Targeted deletion of the core clock gene Bmal1 can disrupt adrenal clock function. The requirement of the adrenal clock to stabilize the circadian GC rhythm during exposure to aberrant LD cycles was determined using novel aldosterone synthase (AS)Cre/+::Bmal1Fl/Fl mice in which Bmal1 deletion occurred during postnatal adrenal transdifferentiation. To examine whether adrenal Bmal1 deletion results in loss of the adrenal clock, mice were crossed with mPER2::Luciferase (mPER2Luc/+) mice. Adrenals from ASCre/+::Bmal1+/+::PER2Luc/+ [control (CTRL)] mice show mPER2Luc rhythms ex vivo, whereas slices from ASCre/+::Bmal1Fl/Fl::PER2Luc/+ [knockout (KO)] mice show dampened rhythms. To monitor corticosterone rhythmicity, mice were implanted with subcutaneous microdialysis probes and sampled at 60-minute intervals for up to 3 days under 12:12-hour [τ (T) 24] LD or 3.5:3.5-hour (T7) LD cycles. Corticosterone rhythms were entrained to T24 LD in CTRL and KO mice. Under T7 LD, circadian corticosterone rhythms persisted in most CTRL mice but not KO mice. Hyperadrenocorticism also was observed in KO mice under T7 LD, reflected by increased corticosterone peak amplitude, total daily corticosterone, and responses to ACTH. Analysis of dysregulated adrenal genes in KO mice exposed to aberrant light identified candidates involved in cholesterol metabolism and trafficking, including steroidogenic acute regulatory protein, which could increase steroidogenesis. Our results show that the adrenal clock functions to buffer steroidogenic responses to aberrant light and stabilize circadian GC rhythmicity.

Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation

“…This sexually dimorphic response could partly be explained by the unequal hM3Dq expression at 20 weeks of age in males and females ( Figure 1B). Notably, previous mouse models that have used the AS-Cre mouse line to drive adrenal cortex-specific Cre expression have exhibited similar sex differences (49,50).…”

Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy

“…Interestingly, melatonin seems to directly inhibit ACTHstimulated steroidogenesis (Campino et al 2011). In mice with a selective knockout of Bmal in the adrenocortical cell, basal steroidogenesis and stress-induced response were maintained (Dumbell et al 2016), albeit with an exaggerated response, especially in females, and the animals were more vulnerable to light-induced timeshift, suggesting that the adrenal clock machinery acts to buffer steroidogenic responses and stabilize circadian glucocorticoid rhythmicity (Engeland et al 2018(Engeland et al , 2019.…”

Prolonged treatment with the synthetic glucocorticoid methylprednisolone affects adrenal steroidogenic function and response to inflammatory stress in the rat

“…In turn, GR activity can be regulated by clock proteins, including CLOCK and Cryptochrome 1 and 2 (Cry1 and Cry2) (Nader et al, 2009;Lamia et al, 2011) via non-genomic mechanisms. With regard to a link between clock genes and adrenal steroidogenic pathways, studies in mice have shown that the expression of StAR is regulated by the activity of the CLOCK-BMAL complex (Son et al, 2008;Leliavski et al, 2014) and mutation in the Bmal gene in the adrenal gland leads to loss of corticosterone circadian rhythm in mice housed in altered light cycle (Son et al, 2008;Engeland et al, 2018). In light of this, we hypothesised that the changes in the expression of steroidogenic genes observed in MP-T and in MP-W rats may be associated with changes in adrenal clock genes expression.…”