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

项目摘要/摘要 肾素-血管紧张素系统(RAS)既是一种循环系统，也是一种局部的 脑等组织中的自分泌/旁分泌信号机制。RAS在以下地区活跃 大脑是公认的对血压控制有贡献的器官，包括穹隆下器官， 室旁核、最后区、延髓等。尽管普遍被认为是一个主要的 作为代谢而非心血管控制的贡献者，弓状核(ARC)也表达 RAS。我们和其他人已经确定，大脑RAS对能量平衡有很大贡献， 特别是通过控制交感神经活动(SNA)和随后的静息代谢率 (RMR)。这些数据一起导致了一个普遍的假设，即ARC内的RAS可能不同 有助于新陈代谢控制而不是心血管控制。因此，当前提案的总体目标是 为了了解RAS在ARC神经回路中的作用，ARC参与代谢与 心血管控制生理学。来自我们小组的新的未发表的数据表明，血管紧张素 I型1A型受体(AT1a)特异性地定位于表达瘦素受体(Lepr)的细胞 参与控制RMR，从而对高脂肪饮食的体重增加做出反应。重要的是AT1a 在表达Lepr的细胞中也参与了RMR，但不参与血压(BP)的反应 脱氧皮质酮醋酸酯(DOCA)-盐处理。定位和基因图谱研究表明AT1a 仅在也表达刺鼠相关肽(AgRP)的Lepr表达细胞亚群中表达， 但不包括前阿片黑素皮质素(POMC)。这些数据让我们提出了三个目标。目标1将评估 选择性干扰AgRP表达中AT1a表达对心血管和代谢的影响 细胞。目的2研究AT1a在选择性瘦素抵抗的AgRP神经元中的作用 (单反)。SLR描述了对瘦素的选择性代谢反应的丧失，但不是心血管反应的丧失 在长期肥胖之后。SLR已被提出作为一种可能的解释，以解释高共病 高血压和肥胖(即肥胖相关的高血压)。我们的发现是ARC RAS 特定作用于调节新陈代谢(但不是心血管)敏感性，因此支持这一新概念 AT1a受体在AgRP细胞内的调节可能解释了SLR的分子机制。目标3将 验证一种新的假说，即AgRP细胞中Lepr的激活激活了RAS介导的自分泌信号 途径，这可能代表了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转基因动物模型，最先进的方法 用于BP、SNA和RMR的测量，以及与公认的专家在 瘦素、SLR和SNA评估以完成拟议的研究。该项目的竣工规模将扩大 我们对控制RMR和BP的神经回路的知识，以及我们对肥胖-高血压的理解。

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 New unpublished data from our group demonstrate that that the angiotensin II type 1A receptor (AT1A) specifically localized to cells that express the leptin receptor (LepR)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.