Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior

Abstract

Brain and muscle ARNT-like 1 (BMAL1) is a core circadian clock protein and transcription factor that regulates many physiological functions, including blood pressure (BP). Male global Bmal1 knockout (KO) mice exhibit ∼10 mmHg reduction in BP, as well as a blunting of BP rhythm. The mechanisms of how BMAL1 regulates BP remains unclear. The adrenal gland synthesizes hormones, including glucocorticoids and mineralocorticoids, that influence BP rhythm. To determine the role of adrenal BMAL1 on BP regulation, adrenal-specific Bmal1 (ASCre/+::Bmal1) KO mice were generated using aldosterone synthase Cre recombinase to KO Bmal1 in the adrenal gland zona glomerulosa. We confirmed the localization and efficacy of the KO of BMAL1 to the zona glomerulosa. Male ASCre/+::Bmal1 KO mice displayed a shortened BP and activity period/circadian cycle (typically 24 hours) by ∼1 hour and delayed peak of BP and activity by ∼2 and 3 hours, respectively, compared with littermate Cre- control mice. This difference was only evident when KO mice were in metabolic cages, which acted as a stressor, as serum corticosterone was increased in metabolic cages compared with home cages. ASCre/+::Bmal1 KO mice also displayed altered diurnal variation in serum corticosterone. Furthermore, these mice have altered eating behaviors where they have a blunted night/day ratio of food intake, but no change in overall food consumed compared with controls. Overall, these data suggest that adrenal BMAL1 has a role in the regulation of BP rhythm and eating behaviors.

Chrono‐nutrition for hypertension

“…activity and BP rhythm periods that were shortened by 1 hour. 61 Furthermore, the peaks in BP and activity rhythms were delayed by two and 3 hours respectively. 61 These mice also had altered eating behaviour with a reduction in nighttime food intake and an increase in daytime intake.…”

“…In conditions where ACTH or cortisol production is abnormal, such as Addison's disease or Cushing's Syndrome, the circadian rhythm of BP is disrupted 58–60 . The impact of the adrenal gland on circadian rhythms has been further explored in adrenal specific BMAL1 KO mice 61 . These mice displayed activity and BP rhythm periods that were shortened by 1 hour 61 .…”

“…The impact of the adrenal gland on circadian rhythms has been further explored in adrenal specific BMAL1 KO mice 61 . These mice displayed activity and BP rhythm periods that were shortened by 1 hour 61 . Furthermore, the peaks in BP and activity rhythms were delayed by two and 3 hours respectively 61 .…”

“…[58][59][60] The impact of the adrenal gland on circadian rhythms has been further explored in adrenal specific BMAL1 KO mice. 61 These mice displayed BOHMKE ET AL. activity and BP rhythm periods that were shortened by 1 hour.…”

BMAL1 in the Adrenal Gland: It’s About Time—A Perspective on “Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior”

“…In a timely investigation, Costello et al generated an adrenal-specific BMAL1 KO mouse to study the influence of the adrenal gland on blood pressure regulation and blood pressure rhythms. 9 Given that female kidney-specific BMAL1 KO mice do not exhibit changes in blood pressure or blood pressure rhythms, Costello et al focused on males. This study found that KO of BMAL1 in the zona glomerulosa of the adrenal cortex resulted in a shortened blood pressure and activity period, and a delayed peak of both blood pressure and activity.…”