The role of the renin angiotensin system in the CNS regulation of energy balance

描述（由申请人提供）：数百万人患有肥胖症，并伴随心血管疾病的易感性。该项目是基于这样的观察，即肥胖的一个关键特征是肾素-血管紧张素系统（RAS）的过度活跃。血管紧张素-II（ANGII）是RAS的效应肽，发挥外周效应，促进增加能量储存和升高血压。尽管RAS的外周作用已被广泛研究，但ANGII在能量平衡的神经调节中的作用尚不清楚。与外周发生的情况不同，ANGII促进中枢神经系统（CNS）的负能量平衡。卡托普利，一种阻断ANGII形成的药物（即，一种血管紧张素转化酶[ACE]抑制剂，导致血浆ANGI增加，降低血压并有利于体重减轻。然而，由于卡托普利不进入大脑以降低CNS ACE活性，增加的ANGI通过脑产生的ACE局部转化为ANGI II。CNS ANGII增加导致体重减轻，这部分可通过食物摄入的改变来解释。相比之下，直接向CNS中施用卡托普利抑制脑产生的ACE并减少CNS ANGII，导致食物摄入增加，并暗示CNS RAS通常影响体重调节。然而，能量消耗改变的作用和卡托普利诱导的负能量平衡的潜在机制尚未明确识别。所提出的实验将利用大鼠来测试以下总体假设：ANGII通过经由下丘脑室旁核中的1型血管紧张素受体（ATI）促进负能量平衡而在能量平衡的神经控制中起关键作用。首先，我们将检验系统性ACE抑制（通过卡托普利）导致食物摄入减少、能量消耗增加和心血管紧张度改变（部分通过增加中枢ANGII）的假设。其次，我们将使用慢病毒载体含有ATI反义寡核苷酸，以下调AT 1在下丘脑室旁核的表达，从而测试的假设，即ATI人口是必要的，以维持基础能量平衡和卡托普利诱导的负能量平衡。将评估体重、身体组成、摄食量、能量消耗（间接热量测定法）、心血管功能（遥测）、血浆去甲肾上腺素和下丘脑室旁核中促肾上腺皮质激素释放激素的表达。这项研究的意义在于，它可能导致开发新的治疗方法来治疗或预防肥胖，同时预防伴随的高血压，糖尿病和中风。

DESCRIPTION (provided by applicant): Millions of people suffer from obesity and the concomitant susceptibility to cardiovascular disease. This project is based on the observation that a key feature of obesity is hyperactivity of the renin-angiotensin- system (RAS). Angiotensin-ll (ANGII), the effector peptide of the RAS, exerts peripheral effects that promote increased energy storage and elevate blood pressure. Although the peripheral actions of the RAS have been studied extensively, the role of ANGII in the neural regulation of energy balance is unclear. Unlike what occurs in the periphery, ANGII promotes negative energy balance in the central nervous system (CNS). Captopril, a drug that blocks the formation of ANGII (i.e., an angiotensin converting enzyme [ACE] inhibitor, resulting in increased plasma ANGI), reduces blood pressure and favors weight loss. However, because captopril does not enter the brain to reduce CNS ACE activity, the increased ANGI is converted locally to ANGII by brain-generated ACE. Increased CNS ANGII results in decreased body weight that is partially explained by alterations in food intake. In contrast, administration of captopril directly into the CNS inhibits brain-generated ACE and reduces CNS ANGII, resulting in increased food intake and implying that the CNS RAS normally influences body weight regulation. However, the role of altered energy expenditure and the underlying mechanism(s) of captopril-induced negative energy balance have not been unequivocally discerned. The proposed experiments will utilize rats to test the overall hypothesis that ANGII plays a key role in the neural control of energy balance by acting to promote negative energy balance via angiotensin receptor type-1 (ATI) in the paraventricular nucleus of the hypothalamus. First, we will test the hypothesis that systemic ACE inhibition (via captopril) results in decreased food intake, increased energy expenditure and altered cardiovascular tone, in part, by increasing central ANGII. Second, we will use a lentiviral vector containing ATI antisense oligonucleotides in order to downregulate AT1 expression in the hypothalamic paraventricular nucleus and thereby test the hypothesis that this ATI population is necessary for maintaining basal energy balance and for captopril-induced negative energy balance. Body weight, body composition, food intake, energy expenditure (indirect calorimetry), cardiovascular function (telemetry), plasma norepinephrine and the expression of corticotrophin-releasing hormone in the paraventricular nucleus of the hypothalamus will be assessed. The significance of the proposed research is that it may lead to development of novel therapeutics to treat or prevent obesity while also preventing concomitant hypertension, diabetes and stroke.