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.

项目总结/摘要 肾素-血管紧张素系统（RAS）作为循环激素系统存在，但也作为局部激素系统存在。 自分泌/旁分泌信号传导机制在组织如脑中。RAS活跃于 脑，其被认为是血压控制的贡献者，包括穹窿下器官， 室旁核、最后区、髓质等。虽然通常被认为是主要的 弓状核（ARC）是代谢控制的贡献者，但不是心血管控制的贡献者，弓状核（ARC）也表现出表达 RAS。我们和其他人已经确定，大脑RAS对能量平衡有很大的贡献， 特别是通过控制交感神经活动（SNA）和随后的静息代谢率 （RMR）。这些数据共同导致了一个普遍的假设，即ARC内的RAS可能与ARC内的RAS之间存在差异。 有助于代谢和心血管控制。因此，本提案的总体目标是 了解RAS在ARC神经回路中的作用，这有助于代谢与 心血管控制生理学我们小组未发表的新数据表明，血管紧张素 II型1A受体（AT 1A）特异性定位于表达瘦素受体（LepR）的细胞， 参与控制RMR，从而控制高脂饮食引起的体重增加。重要的是AT 1A 在表达LepR的细胞中表达的LepR也参与RMR，但不参与血压（BP）对 醋酸脱氧皮质酮（DOCA）-盐处理。定位和基因分析研究表明，AT 1A 仅在也表达AgRP相关肽（AgRP）的LepR表达细胞亚群中表达， 而不是阿黑皮素原（POMC）。这些数据使我们提出了三个目标。目标1将评估 选择性破坏AgRP表达细胞内AT 1A表达的心血管和代谢后果 细胞目的2：探讨AgRP神经元中AT 1A在选择性瘦素抵抗发病机制中的作用 （SLR）. SLR描述了选择性的代谢损失，但不是心血管，对瘦素的反应， 在长期肥胖之后。SLR已被提出作为高并发症的可能解释， 高血压和肥胖（即肥胖相关的高血压）。我们发现ARC RAS 特异性调节代谢（但不调节心血管）敏感性，因此支持新概念 AgRP细胞内AT 1A受体的调节可能解释SLR的分子机制。目标3将 检验一种新的假说，即AgRP细胞中的LepR激活激活RAS介导的自分泌信号传导 这可能代表了这些细胞中LepR和AT 1A之间串扰的分子机制。 细胞我们将使用一系列新开发的转基因动物模型， 用于BP，SNA和RMR的测量，并与公认的专家建立了良好的合作关系， 瘦素、SLR和SNA评估以完成所提议的研究。该项目的完成将扩大 我们对控制RMR与BP的神经回路的了解以及我们对肥胖高血压的了解。