Chemerin As a Link Between Obesity and Blood Pressure

凯莫林作为肥胖和血压之间的联系

• 批准号: 8892233
• 负责人: Stephanie W Watts
• 金额: $ 44.54万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-17 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892233
• 关键词: Acetates; Adipocytes; Adipose tissue; Agonist; Animals; Arteries; Biological Markers; Blood Pressure; Blood Vessels; Body Weight decreased; Body fat; Brown Fat; Cardiac Output; Cardiovascular Diseases; Cardiovascular system; Cells; Cerebrum; Contracts; Data; Deoxycorticosterone; Deposition; Diabetes Mellitus; Diastolic blood pressure; Disease; Endothelial Cells; Endothelium; Engineering; Environment; Fatty acid glycerol esters; Feeds; Foxes; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression; Genes; Gray unit of radiation dose; Health; Human; Hypertension; Individual; Inflammation; Inflammatory; Interleukin-6; Link; Literature; Liver; Medial; Mesenteric Arteries; Mesentery; Modeling; Mus; Nitric Oxide Synthase; Non obese; Obesity; Peptides; Phenotype; Physiological; Play; Positioning Attribute; Predisposition; Process; Production; Rattus; Regulation; Reporting; Risk Factors; Role; Site; Source; Splanchnic Circulation; Stroke; Tazarotene; Techniques; Testing; Therapeutic; Thoracic aorta; Tissues; Tumor Necrosis Factor-alpha; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilator Agents; Visceral; Work; adipocyte differentiation; blood pressure reduction; constriction; cytokine; endothelial dysfunction; feeding; high risk; human CMKLR1 protein; human TNF protein; in vivo; macrophage; migration; monocyte; novel; paracrine; public health relevance; receptor; subcutaneous

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.

描述（由申请人提供）： 血管周围脂肪组织（PVAT）是位于影响血管张力的理想位置的脂肪。在这个建议中，我们提供了大量的证据，表达和新的收缩功能的肽，通常被讨论为产生内脏白色脂肪组织（WAT）和肝脏，但从来没有与PVAT。Chemerin（他扎罗汀诱导基因，TIG 2; RARRES 2）是肥胖的生物标志物。循环chemerin水平与BMI密切相关，chemerin水平随着体重和脂肪的减少而降低。重要的是，chemerin的主要受体ChemR 23（G蛋白偶联受体）的破坏与小鼠的肥胖和体重减少有关; chemerin在血压中的作用尚不清楚。Chemerin最为人所知的是激活炎性细胞，调节脂肪细胞分化和脂肪细胞中促炎细胞因子（IL-1 β，TNF-α，IL-6）的产生。我们已经发现了PVAT中chemerin的产生和表达，chemerin以ChemR 23依赖性方式刺激血管收缩的能力，以及chemerin基因表达的抑制降低血压，chemerin的新的和未描述的作用。重要的是，chemerin诱导的收缩随着内皮细胞的损失、一氧化氮合酶的抑制或通过对激动剂的预先收缩而显著放大。换句话说，chemerin在非肥胖条件下也具有重要的心血管作用。我们的总体假设是chemerin是脂肪（包括PVAT）和血压的功能连接器，因此将肥胖和高血压结合在一起，因此通常是共病的。我们的主要模型是大鼠，其中我们在高血压（醋酸脱氧皮质酮，NOS抑制）和肥胖（高脂肪喂养）模型中具有显著的通用性。我们集中在肠系膜血管，因为内脏循环控制了相当大一部分的心输出量，是网站的显着脂肪沉积在肥胖症。我们还将使用人类肠系膜动脉来测试血管chemerin轴是否存在以及是否与人类健康/疾病相关。一系列的实验技术（基因，组织和整个动物）使我们能够研究两个目标。在目的1中，我们检验了Chemerin诱导ChemR 23受体依赖性收缩并被功能障碍的内皮放大的假设。该目的致力于理解chemerin诱导的动脉收缩的血管机制，以及chemerin对激动剂诱导的收缩的贡献。这与第二个目标配对，致力于测试chemerin轴的生理相关性。在目标2中，我们测试了ChemR 23受体的拮抗作用或新的反义寡脱氧核苷酸敲低chemerin基因是否会降低肥胖或高血压表型的终点，包括血压升高。这一发现表明内源性chemerin在血管张力和血压中起作用。我们的发现将chemerin作为动脉张力的关键调节剂， 成为肥胖和高血压之间的桥梁。