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

描述(申请人提供)：数以百万计的人患有肥胖症和伴随而来的心血管疾病易感性。这个项目是基于观察到肥胖的一个关键特征是肾素-血管紧张素系统(RAS)过度活跃。血管紧张素-11(AngII)是RAS的效应肽，发挥外周效应，促进能量储存增加和血压升高。虽然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。与周围的情况不同，血管紧张素转换酶促进中枢神经系统(CNS)的能量负平衡。卡托普利是一种阻断血管紧张素转换酶(ACE)抑制剂，导致血浆血管紧张素转换酶(ANGI)升高的药物，它可以降低血压，有利于减肥。然而，由于卡托普利不会进入大脑以减少中枢血管紧张素转换酶活性，增加的血管紧张素转换成局部血管紧张素转换成血管紧张素转换酶由脑源性血管紧张素转换酶。CNS Angii增加导致体重下降，这部分是由食物摄入量的变化解释的。相反，将卡托普利直接注入中枢神经系统会抑制脑内产生的血管紧张素转换酶，减少中枢神经系统血管紧张素转换酶，导致食物摄入量增加，暗示中枢神经系统RAS正常影响体重调节。然而，改变能量消耗的作用和卡托普利诱导的能量负平衡的潜在机制(S)还没有明确的认识。拟议的实验将利用大鼠来检验这一总体假设，即Angii通过下丘脑室旁核中的血管紧张素受体1(ATI)促进负能量平衡，在神经控制能量平衡中发挥关键作用。首先，我们将验证这样一种假设，即全身性ACE抑制(通过卡托普利)导致食物摄入量减少，能量消耗增加，心血管张力改变，部分是通过增加中枢血管紧张素Ⅱ来实现的。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AT1的表达，从而验证这样的假设，即ATI群体是维持基础能量平衡和卡托普利诱导的负能量平衡所必需的。将评估体重、身体成分、食物摄入量、能量消耗(间接量热法)、心血管功能(遥测)、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。这项拟议的研究的意义在于，它可能导致开发新的疗法来治疗或预防肥胖症，同时还可以预防伴随而来的高血压、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.