Chemerin As a Link Between Obesity and Blood Pressure

描述(申请人提供)：血管周围脂肪组织(PVAT)是一种完全可以影响血管张力的脂肪。在这个提案中，我们提供了大量证据来证明一种多肽的表达和新的收缩功能，这种多肽通常被认为是在内脏白色脂肪组织(WAT)和肝脏中产生的，但从未与PVAT相关。Chmerin(他扎罗汀诱导基因，TIG2；RARRES2)是肥胖的生物标志物。循环中的趋化蛋白水平与BMI密切相关，并且随着体重和脂肪的减少，血液中的趋化蛋白水平会降低。重要的是，趋化蛋白的主要受体ChemR23(G蛋白偶联受体)的破坏与小鼠肥胖和体重的减少有关；趋化蛋白在血压中的作用尚不清楚。Chmerin最广为人知的作用是激活炎症细胞，调节脂肪细胞分化，并在脂肪细胞中产生促炎细胞因子(IL-1β、TNF-α、IL-6)。我们已经发现趋化蛋白在PVAT中的产生和表达，趋化蛋白以一种依赖于ChemR23的方式刺激血管收缩的能力，以及抑制趋化蛋白基因表达降低血压，这是趋化蛋白的新颖和未知的作用。重要的是，随着内皮细胞的丧失、一氧化氮合酶的抑制或预先给予激动剂的收缩，趋化蛋白诱导的收缩显著放大。换句话说，趋化蛋白在非肥胖条件下也有重要的心血管作用。我们的总体假设是，趋化蛋白是脂肪(包括PVAT)和血压的功能连接点，因此将肥胖和高血压联系在一起，因此通常是共存的。我们的主要模型是大鼠，在高血压(脱氧皮质酮醋酸酯，一氧化氮合酶抑制)和肥胖(高脂肪喂养)模型中，我们有显著的多功能性。我们关注肠系膜血管系统，因为内脏循环控制着相当一部分的心输出量，也是肥胖患者大量脂肪沉积的部位。我们还将使用人的肠系膜动脉来测试血管趋化素轴是否存在，以及是否与人类健康/疾病有关。一系列实验技术(基因、组织和整个动物)使我们能够研究两个目标。在目标1中，我们验证了Chmerin诱导ChemR23受体依赖的收缩并被功能障碍的内皮放大的假说。本研究旨在了解趋化蛋白诱导动脉收缩的血管机制(S)，以及趋化蛋白在激动剂诱导的收缩中的作用。这与第二个目标相匹配，致力于测试趋化蛋白轴的生理相关性。在目标2中，我们测试了ChemR23受体的拮抗或新型反义寡核苷酸敲除趋化蛋白基因是否会减少肥胖或高血压表型的终点，包括血压升高。这样的发现将证明内源性趋化蛋白在血管紧张性和血压中发挥作用。我们的发现使趋化蛋白成为动脉张力的关键调节器，有望 成为肥胖和高血压之间的桥梁。

DESCRIPTION (provided by applicant): Perivascular adipose tissue (PVAT) is fat perfectly situated to influence vascular tone. In this proposal, we provide substantial evidence for the expression and novel contractile function of a peptide that is typically discussed as being produced within visceral white adipose tissue (WAT) and the liver, but never associated with PVAT. Chemerin (tazarotene induced gene, TIG2; RARRES2) is a biomarker for adiposity. Circulating chemerin levels associate strongly with BMI, and chemerin levels are reduced with reduction of weight and fat. Importantly, disruption of the primary receptor for chemerin, ChemR23 (G protein coupled receptor), is associated with reduced adiposity and body mass in mice; the role of chemerin in blood pressure is not known. Chemerin is best known for activation of inflammatory cells, and regulation of adipocyte differentiation and production of pro-inflammatory cytokines (IL-1beta, TNF-alpha, IL-6) in the adipocyte. We have discovered the production and expression of chemerin in PVAT, the ability of chemerin to stimulate blood vessel contraction in a ChemR23-dependent manner, and that suppression of chemerin gene expression reduces blood pressure, novel and here-to undescribed actions of chemerin. Importantly, chemerin- induced contraction is significantly amplified with loss of the endothelial cell, inhibition of nitric oxide synthase or by prior contraction to an agonist. In other words, chemerin also has important cardiovascular effects in non-obese conditions. Our overall hypothesis is that chemerin is a functional connector of fat (including PVAT) and blood pressure and thus unites obesity and hypertension, so commonly comorbid. Our primary model is the rat, in which we have significant versatility in models of hypertension (deoxycorticosterone acetate, NOS-inhibited) and obesity (high fat fed). We focus on the mesenteric vasculature, because the splanchnic circulation controls a considerable portion of cardiac output and is the site at which significant fat is deposited in obesity. We will also use human mesenteric arteries to test whether the vascular chemerin axis exists and is relevant to human health/disease. A range of experimental techniques (gene, tissue and whole animal) allows us to study two Aims. In Aim 1, we test the hypothesis that Chemerin induces ChemR23 receptor-dependent contraction and is amplified by dysfunctional endothelium. This aim is dedicated to understanding the vascular mechanism(s) of chemerin-induced contraction in arteries, as well as contributions of chemerin to agonist-induced contraction. This is paired with a second aim, dedicated to testing the physiological relevance of the chemerin axis. In Aim 2, we test whether antagonism of the ChemR23 receptor, or knockdown of chemerin gene by new antisense oligodeoxynucleotides, will reduce endpoints of the obese or hypertensive phenotype, including elevated blood pressure. Such a finding would argue that endogenous chemerin plays a role in vascular tone and blood pressure. Our findings place chemerin as a critical regulator of arterial tone, poised to be a bridge between obesity and hypertension.