Role of the brain Renin-Angiotensin Sys. in Cardiovas and Metabolic Regulation

大脑中的肾素-血管紧张素系统(RAS)被公认为是高血压的重要决定因素 通过对动脉压、液体稳态和交感神经的作用来调节心血管 活动，并与高血压有牵连。越来越多的证据提出了一个概念，即 大脑和外周的RAS也调节能量消耗。然而，准确的中央和 血管紧张素II(Ang)调节能量稳态的外周机制 大脑的产生和活动、涉及的神经回路以及它与其他途径的整合 控制摄食和能量动态平衡仍然是未知的。同样，目前还不清楚 血管紧张素转换酶调节心血管和代谢作用的机制和传出通路 相似的或不同的。在前一次融资期间，我们报告了推动这一概念的令人信服的数据 大脑中血管紧张素能信号的激活会导致能量消耗的增加。我们的 总体假设是，有不同的中枢机制控制心血管和 脑RAS激活后的代谢输出，以及脑内Ang的局部合成 动脉压、水摄入量和能量消耗通过重叠但不连续的血管紧张素依赖 机制和传出途径。我们进一步假设，脂肪RAS到AT2R 调节大脑RAS对脂肪组织的作用，饮食诱导的肥胖(DIO)钝化 脑血管紧张素转换酶激活对能量消耗的影响 AT2R依赖机制。该提案的目的是解决以下假设。1)和 SFO和PVN的产生和血管紧张素能信号是动脉的关键介质 压力、水摄入量和能量消耗对外源性和内源性脑RAS的反应 2)脑RAS活性增加的影响受脂肪RAS活性的调节 DIO诱导并介导AT2R依赖机制；3)内质网应激 SFO和PVN在动脉血压、水摄入量和能量消耗中起重要作用。 对大脑RAS活性增加的反应。我们将利用令人振奋的新的初步数据，以及 利用概念上的进步和该项目研究人员在遗传学方面的独特专业知识， 神经控制机制，神经解剖学，以及复杂的心血管和代谢表型。 一个独特的优势是与其他项目进行了广泛的智力和技术互动。

The renin-angiotensin system (RAS) in the brain is well recognized as an important determinant of cardiovascular regulation, through its actions on arterial pressure, fluid homeostasis and sympathetic nerve activity, and has been implicated in hypertension. Growing evidence has advanced the concept that the RAS, both in the brain and periphery also regulates energy expenditure. However, the precise central and peripheral mechanisms by which angiotensin II (ANG) regulates energy homeostasis, its sites of production and action in the brain, the neural circuitry involved, and its integration with other pathways controlling feeding and energy homeostasis remain undefined. Similarly, it remains unclear if the mechanisms and efferent pathways regulating the cardiovascular versus metabolic actions of ANG are similar or distinct. During the previous funding period we reported compelling data advancing the concept that activation of angiotensinergic signaling in the brain results in increased energy expenditure. Our overall hypothesis is that there are differential central mechanisms controlling the cardiovascular and metabolic outputs following brain RAS activation, and that local synthesis of ANG in the brain controls arterial pressure, water intake, and energy expenditure through overiapping yet discrete ANG-dependent mechanisms and efferent pathways. We further hypothesize that the adipose RAS through AT2R modulates the actions of the brain RAS on adipose tissue, and that diet-induced obesity (DIO) blunts the effects of brain RAS activation on energy expenditure by stimulating the adipose RAS acting through an AT2R-dependent mechanism. The aims ofthe proposal are to address the following hypotheses. 1) ANG production and angiotensinergic signaling in the SFO and PVN are critical mediators of the arterial pressure, water intake, and energy expenditure responses to exogenous and endogenous brain RAS activation; 2) The effects of increased brain RAS activity are modulated by the activity ofthe adipose RAS induced by DIO and mediated by an AT2R-dependent mechanism; 3) Endoplasmic reticulum (ER) stress in the SFO and PVN plays an important role in the arterial pressure, water intake, and energy expenditure responses to increased brain RAS activity. We will capitalize on exciting new preliminary data, and leverage conceptual advances and the unique expertise of the investigators in this program in genetics, neural control mechanisms, neuroanatomy, and sophisticated cardiovascular and metabolic phenotyping. A distinctive strength is the extensive intellectual and technical interactions with the other projects.