Melanocortin MC4R receptor is required for energy expenditure but not blood pressure effects of angiotensin II within the mouse brain.
Melanocortin MC4R receptor is required for energy expenditure but not blood pressure effects of angiotensin II within the mouse brain.
复制标题
黑皮质素 MC4R 受体是小鼠大脑内能量消耗所必需的，但血管紧张素 II 的血压作用并非如此。
DOI：
10.1152/physiolgenomics.00015.2022
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发表时间：
2022
影响因子：
4.6
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中科院分区：
文献类型：
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作者：
Oliveira,Vanessa;Riedl,RuthA;Claflin,KristinE;Mathieu,NataliaM;Ritter,McKenzieL;Balapattabi,Kirthikaa;Wackman,KelseyK;Reho,JohnJ;Brozoski,DanielT;Morgan,DonaldA;Cui,Huxing;Rahmouni,Kamal;Burnett,ColinML;Nakagawa,Pablo;
脑肾素-血管紧张素系统（RAS）涉及血压（BP）、液体摄入和能量消耗（EE）的控制。下丘脑弓状核内的血管紧张素II（ANG II）有助于控制静息代谢率（RMR），从而通过其对Agouti相关肽（AgRP）神经元的作用控制EE，这也有助于瘦素控制EE。首先，我们确定，虽然瘦素刺激EE在控制同窝出生的小鼠，与转基因激活的大脑RAS（sRA）表现出增加EE和瘦素没有加性效应，夸大EE在这些小鼠。这些发现使我们假设瘦素和血管紧张素II在大脑刺激EE通过一个共同的机制。由于AgRP信号传导到黑皮质素MC 4 R受体有助于瘦素的代谢作用，我们进行了一系列研究，检查RMR，液体摄入量和BP对ANG II的反应，通过转录阻断（Mc 4 r-TB）使MC 4 R表达缺陷的小鼠。这些小鼠通过慢性醋酸脱氧皮质酮（DOCA）-盐处理对内源性脑RAS激活的RMR刺激具有抗性，而液体和电解质效应保持完整。这些小鼠也对通过急性脑室内（ICV）注射ANG II刺激RMR具有抗性，而对ICV ANG II的BP反应保持完整。总的来说，这些数据表明，脑内ANG II控制RMR和EE的作用依赖于MC 4 R信号传导，而流体稳态和BP反应独立于MC 4 R信号传导。
The brain renin-angiotensin system (RAS) is implicated in control of blood pressure (BP), fluid intake, and energy expenditure (EE). Angiotensin II (ANG II) within the arcuate nucleus of the hypothalamus contributes to control of resting metabolic rate (RMR) and thereby EE through its actions on Agouti-related peptide (AgRP) neurons, which also contribute to EE control by leptin. First, we determined that although leptin stimulates EE in control littermates, mice with transgenic activation of the brain RAS (sRA) exhibit increased EE and leptin has no additive effect to exaggerate EE in these mice. These findings led us to hypothesize that leptin and ANG II in the brain stimulate EE through a shared mechanism. Because AgRP signaling to the melanocortin MC4R receptor contributes to the metabolic effects of leptin, we performed a series of studies examining RMR, fluid intake, and BP responses to ANG II in mice rendered deficient for expression of MC4R via a transcriptional block (Mc4r-TB). These mice were resistant to stimulation of RMR in response to activation of the endogenous brain RAS via chronic deoxycorticosterone acetate (DOCA)-salt treatment, whereas fluid and electrolyte effects remained intact. These mice were also resistant to stimulation of RMR via acute intracerebroventricular (ICV) injection of ANG II, whereas BP responses to ICV ANG II remained intact. Collectively, these data demonstrate that the effects of ANG II within the brain to control RMR and EE are dependent on MC4R signaling, whereas fluid homeostasis and BP responses are independent of MC4R signaling.