MC4R及其与Wnt通路交互作用诱导脂肪细胞差异分化的机制研究

项目名称： MC4R及其与Wnt通路交互作用诱导脂肪细胞差异分化的机制研究

项目编号： No.81500671

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 裴舟

作者单位： 复旦大学

项目金额： 18万元

中文摘要： MC4R基因突变可致儿童重度肥胖，我们的家系研究表明此种肥胖难以用饮食、运动等常规方法取得干预成效。MC4R参与肥胖形成的机制，既往主要侧重于下丘脑神经核群机制，我们预实验研究发现，MC4R在小鼠白色、棕色脂肪组织中存在差异表达，在不同种类的前脂肪细胞系分化过程中亦存在差异性表达，由此推测MC4R也参与外周脂肪细胞分化，且侧重于白色脂肪细胞。经MC4R拮抗剂处理后的斑马鱼下丘脑中Wnt信号表达下调，由此推测MC4R与Wnt通路在中枢神经系统存在交互作用。本课题拟：1.通过采用MC4R激动剂、抑制剂进一步研究MC4R对外周白色、棕色脂肪细胞分化的影响，以及在分化过程中MC4R与Wnt通路的交互作用。2.通过构建MC4R-/-斑马鱼模型，结合已有的Wnt-/-斑马鱼，进一步探究MC4R与Wnt在肥胖形成过程中的中枢交互作用，为肥胖早期干预提供思路和研究方向。

中文关键词： 肥胖；脂肪细胞分化；黑素皮质素受体-4；；Wnt通路；斑马鱼

英文摘要： Our study on families with deficient MC4R gene showed that obesity stemmed from the deficient MC4R could not be successfully managed by diet and exercise. Previous studies discovered that MC4R expressed in nucleus of the hypothalamus is a key regulator of appetite. However, the function of MC4R in peripheral adipose tissues is not clear. After we investigated the expression of MC4R in white adipose tissue and brown adipose tissue, we discovered that MC4R is exclusively expressed in white adipose tissue and, the expression levels of MC4R during preadipocyte differentiation was in a time-dependent manner. Our results indicated that MC4R is involved in white adipogenesis. In addition, we found MC4R antagonist treated zebrafish had deceased Wnt expression in the hypothalamus. Therefore, MC4R pathway is likely to cross-talk with Wnt pathway. In our proposed study, we will investigate: 1) the Wnt-dependent effect of MC4R agonist and antagonist on the differentiation of white and brown adipose tissues, 2) the role of MC4R in the central nervous system using MC4R knockout and Wnt knockout zebrafish. Our study can provide evidence for the function of MC4R, its interaction with Wnt pathway in adipogenesis and therefore construct a molecular basis for early obesity interventions.

英文关键词： obesity;adipocyte differentiation;MC4R;Wnt pathway;zebrafish