Chemerin, Complement, and Insulin Resistance

Chemerin、补体和胰岛素抵抗

• 批准号: 9280789
• 负责人: LAWRENCE L LEUNG
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280789
• 关键词: Adipocytes; Adipose tissue; Affect; Biological Markers; Blood coagulation; Body Weight decreased; C5a anaphylatoxin receptor; CMKLR1 gene; Caloric Restriction; Carboxypeptidase; Cardiovascular Diseases; Chemotactic Factors; Chronic; Cleaved cell; Complement; Complement 3a; Complement 5a; Complement Activation; Development; Diagnostic; Disease; Fat-Restricted Diet; Fatty Liver; Fibrinolysis; Genes; Glucose; Glucose Intolerance; High Fat Diet; Human; Inflammation; Inflammatory; Insulin; Insulin Resistance; Lead; Metabolic syndrome; Metabolism; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Operative Surgical Procedures; Patients; Peptide Hydrolases; Phenotype; Plasma; Play; Population Control; Protein Isoforms; Public Health; Recombinants; Risk; Risk Assessment; Role; Sampling; Serum; Single Nucleotide Polymorphism; Testing; Thinness; Time; Veterans; Visceral; Wild Type Mouse; adipokines; bariatric surgery; cytokine; in vivo; innovation; insight; insulin sensitivity; lipid biosynthesis; mouse model; new therapeutic target; non-diabetic; novel diagnostics; peripheral blood; public health relevance; receptor; subcutaneous; tool

DESCRIPTION (provided by applicant): Metabolic syndrome affects 25% of all Veteran's patients. Chemerin, a chemoattractant and an adipokine, and its receptor CMKLR1, are important in adipogenesis and adipocyte metabolism. CMKLR1-/- mice develop glucose intolerance. Elevated serum chemerin is associated with type 2 diabetes (T2D), and a SNP in the chemerin gene correlates with an increased risk of T2D. Chemerin is secreted as an inactive precursor, and its activation and inactivation is dependent on specific proteolytic cleavages at its C-terminus. We have developed specific ELISAs for the different human and mouse chemerin isoforms. Activated complement C3a and C5a are important in the development of insulin resistance (IR). Carboxypeptidase B2 (CPB2) regulates in vivo complement activity by inactivating both C3a and C5a. CPB2 also activates chemerin. We have utilized CPB2-/- mice in different mouse models of inflammatory disease. We hypothesize that activation of both complement and chemerin are critical in the development of IR and metabolic syndrome in mice and humans. We speculate that the absence of CPB2 will result in increased activation of complement and the development of IR. Specific Aim 1. Determine the levels of C3a, C5a and the different chemerin isoforms in adipose tissues and peripheral blood in a mouse model of obesity. Our preliminary studies show that HFD-fed obese mice have increased levels of chemerin 156S, the most active form of chemerin in mice, in the plasma and subcutaneous adipose tissues. We will examine the time course of complement and chemerin activation over a 24-week HFD-induced obesity study, followed by calorie restriction, in relationship to other inflammatory biomarkers. We will also assess if there is crosstalk between complement and chemerin activation in adipocytes. Specific Aim 2. Determine the levels of C3a, C5a and the different chemerin isoforms in adipose tissues and peripheral blood in humans. 2.1 Obese patients undergoing bariatric surgery and 6-month post-surgery. Our preliminary studies show that patients undergoing bariatric surgery have elevated levels of chem157S, the most active form of chemerin in humans, in the plasma and omental and subcutaneous adipose tissues. They also have elevated C5a levels in adipose tissue. We will examine the levels of complement and different chemerin isoforms in the plasma and adipose tissue of 100 patients undergoing bariatric surgery and 50 nondiabetic control patients. We will correlate these levels with other cytokines and adipokines. 2.2 Assess the potential of chemerin isoforms and complement as a biomarker for IR. Plasma samples will be obtained from patients who are either insulin-resistant (obese or lean), or insulin- sensitive (obese or lean), whose insulin sensitivity or resistance status had been rigorously defined. We will determine the levels of C3a, C5a and chemerin isoforms in 25 samples from each of the four groups to assess whether these parameters can act as a biomarker for IR. Specific Aim 3. Determine if the CPB2-/- mice are predisposed to the development of HFD-induced IR. To test whether CPB2- /- mice are more susceptible to IR, WT and CPB2-/- mice will be placed on HFD or low-fat diet for 8- weeks. IR will be assessed by glucose and insulin intolerance, and hepatic steatosis. If CPB2-/- mice are predisposed to IR, we will attempt to reverse the phenotype using either a C3a or C5a receptor antagonist. Levels of different chemerin isoforms will also be determined. We are the only group that has specific chemerin ELISAs, which permits study of in vivo changes of chemerin levels in humans and mice. This will be the first study to define the role of CPB2 in IR. These studies will provide new information on the activation of complement and chemerin in IR, and may lead to innovative diagnostic tools for the risk assessment of metabolic syndrome and the identification of new therapeutic targets.

描述（由申请人提供）： 代谢综合征影响25%的退伍军人患者。Chemerin是一种趋化因子和脂肪因子，其受体CMKLR 1在脂肪形成和脂肪细胞代谢中起重要作用。CMKLR 1-/-小鼠发生葡萄糖耐受不良。血清chemerin升高与2型糖尿病（T2 D）相关，chemerin基因中的SNP与T2 D风险增加相关。Chemerin作为无活性前体分泌，其活化和失活依赖于其C-末端的特异性蛋白水解裂解。我们已经开发了不同的人类和小鼠chemerin亚型的特异性ELISA。活化的补体C3 a和C5 a在胰岛素抵抗（IR）的发展中是重要的。羧肽酶B2（CPB 2）通过灭活C3 a和C5 a来调节体内补体活性。CPB 2也激活chemerin。我们在不同的炎症性疾病小鼠模型中使用了CPB 2-/-小鼠。我们假设补体和趋化蛋白的激活在小鼠和人类IR和代谢综合征的发展中是至关重要的。我们推测，CPB 2的缺乏将导致补体激活增加和IR的发展。测定肥胖小鼠模型中脂肪组织和外周血中C3 a、C5 a和不同chemerin亚型的水平。我们的初步研究表明，HFD喂养的肥胖小鼠在血浆和皮下脂肪组织中具有增加的chemerin 156 S水平，chemerin 156 S是小鼠中最活跃的chemerin形式。我们将在一项为期24周的HFD诱导的肥胖研究中检查补体和chemerin激活的时间过程，随后进行热量限制，与其他炎症生物标志物的关系。我们还将评估脂肪细胞中补体和趋化蛋白激活之间是否存在串扰。具体目标2。测定人体脂肪组织和外周血中C3 a、C5 a和不同chemerin亚型的水平。2.1接受减肥手术和术后6个月的肥胖患者。我们的初步研究表明，接受减肥手术的患者在血浆、网膜和皮下脂肪组织中chem 157 S水平升高，chem 157 S是人体中最活跃的chemerin形式。他们还具有脂肪组织中升高的C5 a水平。我们将检查100例接受减肥手术的患者和50例非糖尿病对照患者的血浆和脂肪组织中补体和不同chemerin亚型的水平。我们将这些水平与其他细胞因子和脂肪因子相关联。2.2评估chemerin亚型和补体作为IR生物标志物的潜力。血浆样品将从胰岛素抵抗（肥胖或瘦）或胰岛素敏感（肥胖或瘦）的患者获得，其胰岛素敏感性或抵抗状态已被严格定义。我们将确定来自四个组中的每个组的25个样品中的C3 a、C5 a和chemerin同种型的水平，以评估这些参数是否可以作为IR的生物标志物。确定CPB 2-/-小鼠是否倾向于发展HFD诱导的IR。为了测试CPB 2- /-小鼠是否对IR更敏感，将WT和CPB 2-/-小鼠置于HFD或低脂饮食8周。IR将通过葡萄糖和胰岛素不耐受以及肝脂肪变性进行评估。如果CPB 2-/-小鼠易患IR，我们将尝试使用C3 a或C5 a受体拮抗剂逆转表型。还将测定不同chemerin亚型的水平。我们是唯一一个拥有特异性chemerin ELISA的团队，可以研究人类和小鼠体内chemerin水平的变化。这将是第一个研究，以确定CPB 2在IR中的作用。这些研究将提供新的信息激活的补体和chemerin在IR中，并可能导致创新的诊断工具，代谢综合征的风险评估和识别新的治疗靶点。