干预GPR1通路对实验性小鼠脂肪累积的影响

The Effects of Experimental Mice Adipose Accumulation by Targeting GPR1 Pathway

一直以来,肥胖是令人担忧和烦恼的健康问题,可导致包括2型糖尿病在内的代谢综合征发生.与肥胖相关疾病的发病机制是多因子影响的结果,但是,越来越多的证据表明,脂肪组织分泌的细胞因子(脂联素、瘦素、TNF-α等)的改变,以及局部的炎症反应对于这些疾病的发生具有重要作用.Chemerin(也被称为他扎罗汀诱导基因2或者视黄酸受体反应子2),是近年来发现的一种脂肪细胞因子,是G蛋白偶联受体1(GPR1)的配体,在调节代谢、先天免疫等方面具有重要的作用.为了研究Chemerin及其受体GPR1对小鼠脂肪累积的影响,本课题组通过高脂饲料喂养,成功建立小鼠肥胖模型,利用si RNA干扰技术沉默小鼠和分化前3T3-L1细胞中Chemerin或GPR1基因的表达发现:a.Chemerin及其受体GPR1在高脂饲料喂养小鼠的腹股沟脂肪以及肩胛下脂肪中的表达高于正常饲料组;b.沉默C57BL/6小鼠体内Chemerin或GPR1基因的表达后,肝脏以及腹股沟脂肪组织中脂质的累积受到抑制;c.3T3-L1细胞在体外分化成熟过程中,Chemerin和GPR1也呈高表达的趋势,沉默分化前3T3-L1细胞中Chemerin或GPR1基因的表达后,3T3-L1细胞向脂肪细胞的分化受到影响,降低了脂肪细胞中脂质的累积以及与脂质代谢相关基因的表达,改变了成熟脂肪细胞中新陈代谢功能.这些结果提示,Chemerin及其受体GPR1可能在小鼠脂肪累积中具有调控作用.综上所述,Chemerin/GPR1可能是一种调节脂肪组织中脂质累积的潜在信号通路,为肥胖症等代谢紊乱疾病的治疗提供了可能的作用靶点.

Obesity is considered to be a trouble and risk factor to interfere health and it’s a potential risk for type Ⅱdiabetes,cardiovascular diseases,and hypertension.Although the pathologic mechanisms of those diseases related to obesity are resulted from multifactor,increasing evidence demonstrated that altered adipokines（adiponectin,leptin,TNF-α） secreted by adipose tissue,and local inflammatory responses play important role in pathogenesis of the disease.The Chemerin（RARRES2 or TIG2）,an adipokine has been discovered recently,serves as a ligand for the G protein-coupled receptor1（GPR1） and has a significant role in metabolism and innate immunity.To investigate the effect of Chemerin and its receptor GPR1 in lipid accumulation of mice,we established obesity mice model successfully by given high-fat diet.Knockdown of Chemerin or GPR1 expression in C57BL/6 mice and pre-differentiation 3T3-L1 cells by si RNA interfering technology,we discovered that Chemerin and its receptor GPR1 were expressed in inguinal fat tissue and subscapular fat tissue.Meanwhile,the lipid accumulation in liver and inguinal fat tissue was inhibited by knockdown of Chemerin or GPR1 expression in C57BL/6 mice.Cultured3T3-L1 adipocytes secrete Chemerin,which recruits GPR1 signaling in adipocytes and stimulates chemotaxis of GPR1-expressing cells.Small interfering RNA（si RNA） targeted knockdown of Chemerin or GPR1 expression in3T3-L1 cells impaired differentiation of 3T3-L1 cells into adipocytes,reduced the lipid accumulation in adipocytes and the expression of adipocyte genes and altered metabolic functions in mature adipocytes.So,Chemerin and its receptor may play an important role in regulating lipid accumulation.In summary,Chemerin/GPR1 may be a potential signal pathway that regulates lipid accumulation in adipocytes,and provides a potential therapeutic target for metabolism disorder disease linking obesity.