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，并伴有心血管疾病的易感性。这个项目是基于观察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- 2 （ANGII）是RAS的效应肽，发挥外周效应，促进能量储存增加和升高血压。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。与外周不同，ANGII促进中枢神经系统（CNS）的负能量平衡。卡托普利是一种阻断ANGII形成的药物（即血管紧张素转换酶[ACE]抑制剂，导致血浆ANGI增加），可以降低血压，有利于减肥。然而，由于卡托普利不进入大脑以降低中枢神经系统ACE活性，增加的ANGI通过脑生成的ACE局部转化为ANGII。中枢神经系统ANGII增加导致体重下降，部分原因是食物摄入量的改变。相反，卡托普利直接进入中枢神经系统抑制脑生成的ACE并降低中枢神经系统ANGII，导致食物摄入量增加，这表明中枢神经系统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负能量平衡的潜在机制尚未明确。本实验将利用大鼠来验证ANGII通过下丘脑室旁核的血管紧张素受体1型（ATI）促进负能量平衡，在能量平衡的神经控制中起关键作用的整体假设。首先，我们将测试系统性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张力改变的假设，部分是通过增加中枢ANGII。其次，我们将使用含有ATI反义寡核苷酸的慢病毒载体来下调下丘脑室旁核中AT1的表达，从而验证ATI群体对于维持基础能量平衡和卡托普利诱导的负能量平衡是必要的这一假设。评估体重、身体组成、食物摄入、能量消耗（间接量热法）、心血管功能（遥测法）、血浆去甲肾上腺素和下丘脑室旁核促肾上腺皮质激素释放激素的表达。这项研究的重要意义在于，它可能会导致新的治疗方法的发展，以治疗或预防肥胖，同时也预防伴随的高血压、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.