Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior.
Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior.
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DOI：
10.1093/function/zqad001
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发表时间：
2023
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大脑和肌肉 ARNT 样 1 (BMAL1) 是一种核心生物钟蛋白和转录因子，可调节包括血压 (BP) 在内的许多生理功能。雄性整体 Bmal1 敲除 (KO) 小鼠的血压降低约 10mmHg，并且血压节律减弱。 BMAL1 调节血压的机制仍不清楚。肾上腺合成影响血压节律的激素，包括糖皮质激素和盐皮质激素。为了确定肾上腺 BMAL1 对血压调节的作用，使用醛固酮合酶 Cre 重组酶在肾上腺球状带中敲除 Bmal1，产生了肾上腺特异性 Bmal1 (ASCre/+::Bmal1) KO 小鼠。我们证实了 BMAL1 敲除对肾小球带的定位和功效。与同窝 Cre 对照小鼠相比，雄性 ASCre/+::Bmal1 KO 小鼠血压和活动周期/昼夜节律周期（通常为 24 小时）缩短约 1 小时，血压和活动峰值分别延迟约 2 小时和 3 小时。这种差异仅在 KO 小鼠处于代谢笼中时才明显，代谢笼充当应激源，因为与家庭笼相比，代谢笼中的血清皮质酮增加。 ASCre/+::Bmal1 KO 小鼠血清皮质酮的昼夜变化也发生了改变。此外，这些小鼠的饮食行为也发生了改变，它们的夜间/白天食物摄入量比例减弱，但与对照组相比，它们消耗的食物总量没有变化。总体而言，这些数据表明肾上腺 BMAL1 在血压节律和饮食行为的调节中发挥作用。
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 h) by ∼1 h and delayed peak of BP and activity by ∼2 and 3 h, 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.