Interaction between leptin and angiotensin in the pathogenesis of obesity-hypertension

瘦素和血管紧张素在肥胖-高血压发病机制中的相互作用

• 批准号: 10077574
• 负责人: Justin L Grobe
• 金额: $ 38.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077574
• 关键词: Acetates; Adult; American Heart Association; Angiotensin II; Angiotensin II Receptor; Angiotensin Type 1a Receptor; Angiotensinogen; Angiotensins; Animal Model; Autocrine Communication; Basal metabolic rate; Behavior; Blood Pressure; Body Weight; Brain; Brain region; Cardiovascular system; Cells; Centers for Disease Control and Prevention (U.S.); Collaborations; Data; Deoxycorticosterone; Development; Eating; Exhibits; Functional disorder; Gene Deletion; Genes; Genetic; Genetically Modified Animals; Goals; High Fat Diet; Hormones; Hypertension; Hypothalamic structure; Intake; Knockout Mice; Knowledge; Lead; Leptin; Leptin resistance; Maintenance; Measurement; Mediating; Metabolic; Metabolic Control; Methods; Minor; Modeling; Molecular; Molecular Target; Mus; Nerve; Neurons; Obesity; Organism; Overweight; Paracrine Communication; Pathogenesis; Pathway interactions; Peptides; Pharmacology; Phenotype; Physiology; Receptor Activation; Receptor Cross-Talk; Receptor Signaling; Regulation; Renin-Angiotensin System; Rest; Role; Signal Pathway; Signal Transduction; Sodium Chloride; Stimulus; Structure of area postrema; Structure of nucleus infundibularis hypothalami; Subfornical Organ; Sympathetic Nervous System; System; Techniques; Testing; Tissues; United States; Weight Gain; autocrine; blood pressure regulation; cardiovascular health; comorbidity; design; diet-induced obesity; dietary; energy balance; feeding; improved; innovation; leptin receptor; metabolic rate; mouse model; neural circuit; neural network; novel; obesity prevention; paracrine; paraventricular nucleus; receptor; receptor binding; receptor expression; receptor-mediated signaling; response

Project Summary / Abstract The renin-angiotensin system (RAS) exists as a circulating hormone system but also as a local autocrine/paracrine signaling mechanism in tissues such as the brain. The RAS is active in regions of the brain which are recognized contributors to blood pressure control, including the subfornical organ, paraventricular nucleus, area postrema, medulla, and others. Although generally considered a major contributor to metabolic but not cardiovascular control, the arcuate nucleus (ARC) also exhibits expression of the RAS. We and others have determined that the brain RAS strongly contributes to energy balance, especially through the control of sympathetic nervous activity (SNA) and subsequently, resting metabolic rate (RMR). Together these data led to the general hypothesis that the RAS within the ARC may differentially contribute to metabolic versus cardiovascular control. The overall objective of the current proposal is therefore to understand the role of the RAS in the neurocircuitry of the ARC which contributes to metabolic versus cardiovascular control physiology. New unpublished data from our group demonstrate that that the angiotensin II type 1A receptor (AT1A) specifically localized to cells that express the leptin receptor (LepR) are critically involved in the control of RMR and thereby weight gain in response to high fat diet. Importantly AT1A expressed in LepR-expressing cells are also involved in the RMR, but not blood pressure (BP) responses to deoxycorticosterone acetate (DOCA)-salt treatment. Localization and gene profiling studies indicate that AT1A are only expressed in the subset of LepR-expressing cells which also express agouti related peptide (AgRP), but not proopiomelanocortin (POMC). These data lead us to propose three aims. Aim 1 will evaluate the cardiovascular and metabolic consequences of selectively disrupting AT1A expression within AgRP-expressing cells. Aim 2 will examine the role of AT1A in the AgRP neuron in the pathogenesis of selective leptin resistance (SLR). SLR describes the selective loss of metabolic, but not cardiovascular, responses to leptin which occur after prolonged obesity. SLR has been proposed as a possible explanation for the high comorbidity of hypertension and obesity (i.e. – obesity-associated hypertension). Our discovery that the ARC RAS specifically acts to modulate metabolic (but not cardiovascular) sensitivity therefore supports the novel concept that AT1A receptor modulation within AgRP cells may explain the molecular mechanism of SLR. Aim 3 will examine a novel hypothesis that LepR activation in AgRP cells activates a RAS-mediated autocrine signaling pathway, which may represent the molecular mechanism of the cross-talk between the LepR and AT1A in these cells. We will use an array of newly-developed genetically-modified animal models, state-of-the-art methods for the measurement of BP, SNA, and RMR, and well-established collaborations with recognized experts in leptin, SLR and SNA assessments to accomplish the proposed studies. Completion of the project will expand our knowledge of neurocircuitry that controls RMR vs BP and our understanding of obesity-hypertension.

项目摘要 /摘要 肾素 - 血管紧张素系统（RAS）作为循环的马龙系统存在，但也是当地的 组织（例如大脑）中的自分泌/旁分泌信号传导机制。 RAS活跃在 大脑是对血压控制的认可的大脑 室室核，区域poprema，延髓等。尽管通常认为是主要的 促成代谢但非心血管控制的贡献者，弧形核（ARC）也表现出表达 拉斯。我们和其他人已经确定大脑RAS有力地有助于能量平衡， 特别是通过控制交感神经活动（SNA），然后是静息代谢率 （RMR）。这些数据一起导致了一个总体假设，即弧内的RA可能会有所不同 有助于代谢与心血管控制。因此，当前建议的总体目标是 了解RA在弧线的神经记录中的作用，这有助于代谢与 心血管控制生理学。我们小组的新未发表的数据表明，血管紧张素 II型1A受体（AT1A）专门定位于表达瘦素受体（LEPR）的细胞。 参与RMR的控制，从而响应高脂肪饮食而体重增加。重要的是AT1A 在表达LEPR的细胞中表达的也参与了RMR，但没有血压（BP）对 乙酸脱氧核心酮（DOCA） - 盐处理。定位和基因分析研究表明AT1A 仅在表达agouti相关肽（AGRP）的子集中表达 但不是proopiomelanocortin（POMC）。这些数据使我们提出了三个目标。 AIM 1将评估 在AGRP表达中有选择性破坏AT1A表达的心血管和代谢后果 细胞。 AIM 2将检查AT1A在AGRP神经元中的作用在选择性瘦素耐药性的发病机理中 （SLR）。 SLR描述了对瘦素的反应的选择性丧失，但不是心血管的反应 长时间的肥胖症之后。已提出SLR作为对高合并症的可能解释 高血压和肥胖症（即 - 与肥胖相关的高血压）。我们发现弧RAS 专门起作用来调节代谢（但不是心血管）灵敏度，因此支持了新概念 AGRP细胞内的AT1A受体调节可能解释了SLR的分子机制。目标3意志 检查一个新的假设，即AGRP细胞中的LEPR激活激活了RAS介导的自分泌信号传导 途径可能代表LEPR和AT1A之间串扰的分子机制 细胞。我们将使用一系列新开发的一般修饰的动物模型，最先进的方法 为了测量BP，SNA和RMR，以及与公认的专家合作 瘦素，SLR和SNA评估以完成拟议的研究。项目的完成将扩大 我们对控制RMR与BP的神经记录的了解以及我们对肥胖 - 亚型的理解。