EndocrinologyAug 10, 2019

Sex Differences in How Removing a Key Clock Gene in the Adrenal Gland Increases Stress Hormone Responses in Mice

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 21, 2026

Abstract

Female Cyp11A1Cre/+::Bmal1Fl/Fl knockout mice exhibit elevated plasma corticosterone following stress, indicating a significant adrenal response.

The adrenal clock is synchronized by the suprachiasmatic nucleus and influences glucocorticoid responses to stress.
Following restraint stress, both female and male knockout mice show increased plasma corticosterone, but plasma ACTH levels remain unchanged.
Elevated plasma corticosterone in female knockout mice occurs specifically during submaximal scruff stress.
Adrenal cells from female knockout mice demonstrate increased corticosterone responses to ACTH without changing the potency of the response.
Gene analysis reveals increased expression of genes involved in cell cycle control and steroid production in female knockout mice.
The findings suggest that adrenal Bmal1 plays a significant role in regulating steroid secretion, especially in females.

Simplified

The circadian glucocorticoid (GC) rhythm is dependent on a molecular clock in the suprachiasmatic nucleus (SCN) and an adrenal clock that is synchronized by the SCN. To determine whether the adrenal clock modulates GC responses to stress, experiments used female and male Cyp11A1Cre/+::Bmal1Fl/Fl knockout [side-chain cleavage (SCC)-KO] mice, in which the core clock gene, Bmal1, is deleted in all steroidogenic tissues, including the adrenal cortex. Following restraint stress, female and male SCC-KO mice demonstrate augmented plasma corticosterone but not plasma ACTH. In contrast, following submaximal scruff stress, plasma corticosterone was elevated only in female SCC-KO mice. Adrenal sensitivity to ACTH was measured in vitro using acutely dispersed adrenocortical cells. Maximal corticosterone responses to ACTH were elevated in cells from female KO mice without affecting the EC50 response. Neither the maximum nor the EC50 response to ACTH was affected in male cells, indicating that female SCC-KO mice show a stronger adrenal phenotype. Parallel experiments were conducted using female Cyp11B2 (Aldosterone Synthase)Cre/+::Bmal1Fl/Fl mice and adrenal cortex-specific Bmal1-null (Ad-KO) mice. Plasma corticosterone was increased in Ad-KO mice following restraint or scruff stress, and in vitro responses to ACTH were elevated in adrenal cells from Ad-KO mice, replicating data from female SCC-KO mice. Gene analysis showed increased expression of adrenal genes in female SCC-KO mice involved in cell cycle control, cell adhesion-extracellular matrix interaction, and ligand receptor activity that could promote steroid production. These observations underscore a role for adrenal Bmal1 as an attenuator of steroid secretion that is most prominent in female mice.

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Disclosure Summary: The authors have nothing to disclose. All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.

PubMed

Sex Differences in How Removing a Key Clock Gene in the Adrenal Gland Increases Stress Hormone Responses in Mice

Abstract

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Competing interests

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Abstract

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Funding

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