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

肾素血管紧张素系统在中枢神经系统能量平衡调节中的作用

• 批准号: 8115108
• 负责人: Annette Diane de Kloet
• 金额: $ 1.41万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115108
• 关键词: Acute; Address; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antisense Oligonucleotides; Behavior; Blood Pressure; Body Composition; Body Weight; Body Weight decreased; Brain; Captopril; Cardiac Output; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cell Nucleus; Cerebral Ventricles; Consumption; Corticotropin-Releasing Hormone; Development; Diabetes Mellitus; Dose; Eating; Energy Metabolism; Enzyme Inhibition; Heart Rate; Homeostasis; Human; Hyperactive behavior; Hypertension; Hypothalamic structure; Indirect Calorimetry; Laboratories; Lateral; Lead; Lentivirus Vector; Measures; Neuraxis; Neurons; Norepinephrine; Obesity; Peptides; Peptidyl-Dipeptidase A; Peripheral; Pharmaceutical Preparations; Plasma; Play; Population; Predisposition; Rattus; Receptor, Angiotensin, Type 1; Regulation; Renin; Renin-Angiotensin System; Research; Rodent; Role; Stroke; Telemetry; Testing; base; energy balance; enzyme activity; improved; insulin signaling; neuroregulation; novel therapeutics; paraventricular nucleus; prevent; relating to nervous system; research study

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.

描述（由申请人提供）：数百万人患有肥胖症并容易患心血管疾病。该项目基于这样的观察：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-II (ANGII) 是 RAS 的效应肽，发挥外周作用，促进能量储存增加和血压升高。尽管 RAS 的外周作用已被广泛研究，但 ANGII 在能量平衡神经调节中的作用尚不清楚。与外周发生的情况不同，ANGII 会促进中枢神经系统 (CNS) 的负能量平衡。卡托普利是一种阻断 ANGII（即血管紧张素转换酶 [ACE] 抑制剂，导致血浆 ANGI 增加）形成的药物，可降低血压并有利于减肥。然而，由于卡托普利不会进入大脑来降低 CNS ACE 活性，因此增加的 ANGI 通过大脑生成的 ACE 在局部转化为 ANGII。中枢神经系统 ANGII 增加会导致体重减轻，部分原因是食物摄入量的变化。相比之下，直接向中枢神经系统施用卡托普利会抑制大脑生成的 ACE 并减少中枢神经系统 ANGII，从而导致食物摄入量增加，这意味着中枢神经系统 RAS 通常会影响体重调节。然而，能量消耗改变的作用和卡托普利引起的负能量平衡的潜在机制尚未明确认识。拟议的实验将利用大鼠来测试总体假设，即 ANGII 通过下丘脑室旁核中的 1 型血管紧张素受体 (ATI) 促进负能量平衡，从而在能量平衡的神经控制中发挥关键作用。首先，我们将检验这样的假设：全身性 ACE 抑制（通过卡托普利）会导致食物摄入减少、能量消耗增加和心血管张力改变，部分原因是增加中枢 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，从而检验 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所必需的假设。将评估体重、身体成分、食物摄入量、能量消耗（间接热量测定）、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，它可能会导致开发新的疗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。