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

Oct 16, 2018Endocrinology

The adrenal gland’s internal clock helps stop light from disrupting daily stress hormone rhythms

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Abstract

Targeted deletion of the core clock gene Bmal1 in mice led to a loss of adrenal clock function and disrupted glucocorticoid rhythms under altered light cycles.

Deletion of Bmal1 during adrenal transdifferentiation resulted in dampened mPER2Luc rhythms in adrenal slices.
Corticosterone rhythms were maintained in control mice under 12:12-hour light-dark cycles but were disrupted in knockout mice under 3.5:3.5-hour light cycles.
Most control mice exhibited persistent circadian corticosterone rhythms under altered light conditions, while knockout mice did not.
Knockout mice showed signs of hyperadrenocorticism, indicated by increased peak corticosterone levels and total daily output.
Dysregulated adrenal gene analysis in knockout mice identified potential candidates related to cholesterol metabolism and steroid production.

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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.

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

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