Central Renin-Angiotensin System: Metabolism, Fluid Balance, and Hypertension

心血管疾病和代谢性疾病是世界范围内人类健康的快速增长的负担。 目前，美国大约三分之一的成年人患有临床肥胖症， 三是持续性高血压。同时表现出肥胖和肥胖的患者也有很高的重叠性。 高血压总的来说，经济，社会，心理和生产力负担， 心血管和代谢紊乱每年花费美国大约25万亿美元。 参与调节代谢和心血管功能的一种激素系统是 肾素-血管紧张素系统（RAS）。该系统作为典型的激素系统存在于循环中， 也存在于身体的各个器官中，在那里它以旁分泌的方式发挥作用。虽然RAS被发现在 我们已经证明，大脑RAS的过度活跃足以 引起血压、体液平衡和代谢调节的严重紊乱。我们已经确定 特定的，不同的信号传导机制，介导这些表型中的每一个。 目前的建议将狭隘地集中在大脑RAS的代谢调节机制上。 根据我们的初步发现，我们假设大脑RAS通过以下途径刺激产热： 两种机制。首先，通过激活交感神经系统，大脑RAS刺激 棕色脂肪组织内的产热。其次，通过加压素介导的高血压， RAS抑制循环RAS。抑制循环RAS导致血管紧张素 白色脂肪细胞和前脂肪细胞内的AT 2受体信号传导，其导致 褐色脂肪细胞，从而增加产热能力。这些机制一起协同作用， 积极影响新陈代谢率。对这些机制的研究可能会导致识别 代谢疾病的新治疗靶点。

Cardiovascular and metabolic disorders are rapidly growing burdens on tiuman hiealth worldwide. Currently approximately one third ofthe adult population ofthe United States is clinically obese, and one third exhibit sustained hypertension. There is also a high overlap of patients who exhibit both obesity and hypertension. Collectively, the economic, social, psychological, and productivity burdens which result from cardiovascular and metabolic disorders costs the United States roughly quarter of a trillion dollars per year. One hormone system involved in the regulation of both metabolism and cardiovascular function is the Renin-Angiotensin System (RAS). This system exists in the circulation as a classic hormone system, and also within individual orgains ofthe body where it acts in a paracrine fashion. While the RAS is found in many tissues throughout the body, we have demonstrated that hyperactivity of the brain RAS is sufficient to cause gross disturbances in blood pressure, fluid balance, and metabolic regulation. We have identified specific, distinct signaling mechanisms that mediate each of these phenotypes. The current proposal will narrowly focus on the mechanism of metabolic regulation by the brain RAS. Guided by our preliminary findings, we hypothesize that the brain RAS stimulates thermogenesis through two mechanisms. First, via activation of the sympathetic nervous system, the brain RAS stimulates thermogenesis within brown adipose tissue. Second, via a vasopressin-mediated hypertension, the brain RAS suppresses the circulating RAS. Suppression ofthe circulating RAS results in reduced angiotensin AT2 receptor signaling within white adipocytes and preadipocytes, which results in increased formation of brown adipocytes and thus increased thermogenic capacity. Together, these mechanisms synergistically act to positively influence metabolic rate. Examination of these mechanisms will likely lead to the identification of novel therapeutic targets for metabolic diseases.