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: 9033021
• 负责人: Stephanie W Watts
• 金额: $ 3.58万
• 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/9033021
• 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）的脂肪非常适合影响血管张力。在此提案中，我们为肽的表达和新颖的收缩功能提供了大量证据，该肽通常被认为是在内脏白脂肪组织（WAT）和肝脏中产生的，但与PVAT无关。 Chemerin（Tazarotene诱导的基因，Tig2; Rarres2）是肥胖的生物标志物。循环的化学素水平与BMI密切相关，而化学蛋白水平随体重和脂肪的降低而降低。重要的是，chemerin，ChemR23（G蛋白偶联受体）的一级受体的破坏与小鼠的肥胖和体重的降低有关。化学在血压中的作用尚不清楚。 Chemerin以炎性细胞的激活以及脂肪细胞分化和促炎性细胞因子（IL-1Beta，TNF-Alpha，IL-6）的调节而闻名。我们已经发现了Chemerin在PVAT中的产生和表达，Chemerin以ChemR23依赖性方式刺激血管收缩的能力，而抑制Chemerin Gene表达的抑制可以降低血压，新颖，并在此处进行化学蛋白的未描述作用。重要的是，化学蛋白诱导的收缩会因内皮细胞的丧失，一氧化氮合酶的抑制或通过对激动剂的事先收缩而显着扩增。换句话说，化学蛋白在非肥胖状况中也具有重要的心血管作用。我们的总体假设是，化学是脂肪（包括PVAT）和血压的功能连接器，因此通常合并肥胖和高血压。我们的主要模型是大鼠，其中我们在高血压模型（乙酸乙酸乙酯，NOS抑制）和肥胖（高脂喂养）中具有明显的多功能性。我们专注于肠系膜脉管系统，因为斜视循环控制着大量的心输出量，并且是肥胖症中大量脂肪沉积的部位。我们还将使用人类肠系膜动脉来测试是否存在血管化学蛋白轴并且与人类健康/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AIM 1中，我们检验了化学蛋白诱导ChemR23受体依赖性收缩的假设，并通过功能障碍的内皮扩增。该目标致力于理解化学蛋白诱导的动脉收缩的血管机制，以及化学蛋白对激动剂诱导的收缩的贡献。这与第二个目标配对，致力于测试化学轴轴的生理相关性。在AIM 2中，我们测试ChemR23受体的拮抗作用是通过新的反义寡脱氧核苷酸敲低化学蛋白基因的抑制作用，将减少肥胖或高血压表型的终点，包括血压升高。这样的发现表明，内源性化学蛋白在血管张力和血压中起作用。我们的发现将Chemerin作为动脉基调的关键调节剂，准备 成为肥胖和高血压之间的桥梁。