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: 8755829
• 负责人: Stephanie W Watts
• 金额: $ 33.92万
• 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/8755829
• 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; 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）是一种非常适合影响血管张力的脂肪。在这项提案中，我们为一种肽的表达和新颖的收缩功能提供了实质性证据，这种肽通常被讨论为在内脏白色脂肪组织 (WAT) 和肝脏中产生，但从未与 PVAT 相关。 Chemerin（他扎罗汀诱导基因，TIG2；RARRES2）是肥胖的生物标志物。循环中的凯莫瑞水平与体重指数密切相关，并且凯莫瑞水平随着体重和脂肪的减少而降低。重要的是，凯莫瑞主要受体 ChemR23（G 蛋白偶联受体）的破坏与小鼠肥胖和体重的减少有关。凯莫瑞在血压中的作用尚不清楚。 Chemerin 因激活炎症细胞、调节脂肪细胞分化以及脂肪细胞中促炎细胞因子（IL-1β、TNF-α、IL-6）的产生而闻名。我们发现了凯莫瑞在 PVAT 中的产生和表达、凯莫瑞以 ChemR23 依赖性方式刺激血管收缩的能力，以及抑制凯莫瑞基因表达可降低血压，这是凯莫瑞的新颖且尚未描述的作用。重要的是，凯莫瑞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激动剂的预先收缩而显着放大。换句话说，凯莫瑞在非肥胖情况下也具有重要的心血管作用。我们的总体假设是，凯莫林是脂肪（包括 PVAT）和血压的功能性连接器，因此将肥胖和高血压结合在一起，因此通常是共病。我们的主要模型是大鼠，我们在高血压（醋酸脱氧皮质酮，NOS 抑制）和肥胖（高脂肪喂养）模型中具有显着的多功能性。我们关注肠系膜脉管系统，因为内脏循环控制着相当一部分心输出量，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血管凯莫瑞轴是否存在以及与人类健康/疾病相关。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，我们测试了这样的假设：Chemerin 诱导 ChemR23 受体依赖性收缩，并通过功能失调的内皮细胞放大。该目标致力于了解凯莫瑞诱导的动脉收缩的血管机制，以及凯莫瑞对激动剂诱导的收缩的贡献。这与第二个目标配对，致力于测试凯莫瑞轴的生理相关性。在目标 2 中，我们测试了 ChemR23 受体的拮抗作用或新的反义寡脱氧核苷酸敲低凯莫瑞基因是否会减少肥胖或高血压表型的终点，包括血压升高。这一发现表明内源性凯莫瑞在血管张力和血压中发挥作用。我们的研究结果表明凯莫林是动脉张力的关键调节剂，有望 成为肥胖和高血压之间的桥梁。