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: 7806693
• 负责人: Annette Diane de Kloet
• 金额: $ 3.48万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806693
• 关键词: Acute; Address; Angiotensin II Type 1 Receptor Blockers; 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）：数以百万计的人患有肥胖症和对心血管疾病的易感性。该项目基于这样的观察，即肥胖的关键特征是肾素 - 血管紧张素系统（RAS）的多动症。血管紧张素-LL（Angii）是RAS的效应肽，发挥周围作用，可促进能量储存增加并升高血压。尽管已经对RAS的外围作用进行了广泛的研究，但AngII在能量平衡神经调节中的作用尚不清楚。与周围发生的情况不同，AngII促进了中枢神经系统（CNS）中的负能量平衡。卡托普利（Capteropril）是一种阻止AngII形成的药物（即，转化酶[ACE]抑制剂的血管紧张素，导致血浆ANGI的增加），降低血压并有利于体重减轻。但是，由于卡托普利没有进入大脑以减少CNS ACE活性，因此增加的ANGI通过脑生成的ACE在本地转化为Angii。 CNS AngII增加导致体重降低，部分原因是食物摄入的改变。相比之下，直接施用卡托普利在中枢神经系统中抑制了脑生成的ACE并减少CNS AngII，从而增加了食物摄入量的增加，并暗示CNS RAS通常会影响体重调节体重。但是，尚未明确辨别能量消耗改变的作用和卡托普利诱导的负能量平衡的基本机制。提出的实验将利用大鼠测试总体假设，即AngII通过在下丘脑的副脑核中通过血管紧张素受体类型1（ATI）促进能量平衡来促进能量平衡的神经控制。首先，我们将检验以下假设：系统性ACE抑制（通过卡托普利）会导致食物摄入量减少，能量消耗增加和心血管张力改变，部分原因是增加中央Angii。其次，我们将使用含有ATI反义寡核苷酸的慢病毒载体，以便下调下丘脑旁腔内核核中的AT1表达，从而检验了该ATI种群对于维持基础能量平衡和casteropril诱导的负能量平衡所必需的假设。体重，身体成分，食物摄入，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旁脑核中皮质营养素释放激素的表达将得到评估。拟议的研究的意义在于，它可能导致新的治疗剂的发展以治疗或预防肥胖症，同时还可以防止伴随高血压，糖尿病和中风。