BMPs拮抗因子PRDC在米色脂肪分化及肥胖发生中作用机制研究

Recent epidemiological studies suggest that the incidence of obesity is increasing. Previous studies shown that BMP signaling pathway plays a very important role in adipogenesis. Based on the previous study，we found that the natural BMP inhibitor PRDC was significantly lower expressed in the white adipose tissue of obese patients and mouse models than normal people and mice,respectively.PRDC has been showed to be a regulator of adipogenesis in vitro, but the molecular mechanism and its in vivo involvement is not clear. Thus we have established the adipose tissue specific PRDC knockout and PRDC transgenic mouse model, which is now ready for use. By using this mouse model, in the present study, we will demonstrate the significant role and underlying mechanism of PRDC, the inhibitor member of BMP signaling, in adipogenesis and body weight regulation in vivo. These results suggest that PRDC may regulate adipogenesis and obesity by inhibiting canonical BMP signaling pathway. In this study, we will use PRDC knockout and PRDC transgenic mouse model as well as primary cells, and analyze the phenotypes of mice and cells after PRDC overexpression or knockdown, to demonstrate the important role of PRDC in fat development and body weight control. Lastly, we will compare the serum PRDC level between obese patients and normal individuals to establish the correlation of PRDC and obesity. Altogether, our study will provide a new candidate for the pathogenesis and therapy of obesity.

最新的流行病学证据表明，肥胖症在我国呈加剧流行趋势。肥胖的致病机制及干预研究是亟待解决的课题。研究表明BMP信号通路在脂肪发育过程中发挥非常重要作用。本研究在既往研究基础上发现，BMP拮抗剂PRDC在肥胖患者和肥胖小鼠脂肪组织中表达明显降低。原代脂肪前体细胞诱导分化试验表明PRDC调节米色脂肪形成，提示PRDC有可能通过调节脂肪分化参与肥胖发生。基于此，我们构建了PRDC转基因小鼠和脂肪组织特异性的PRDC基因敲除小鼠，本项目拟借助此基因修饰小鼠模型及体外分子生物学实验，通过表型观察、PRDC过表达或下调干预试验，从体内外水平阐明PRDC通过BMP信号通路参与米色脂肪分化与体重调节的作用机制；同时本课题将检测肥胖和正常人群的血清PRDC水平，建立PRDC与肥胖指标如BMI、皮下内脏脂肪面积等之间的相关性。这将在肥胖发生机制方面提出一个全新的分泌因子，并可能为肥胖干预提供一个新靶点

棕/米色脂肪可通过线粒体解耦连蛋白增加产热抵抗肥胖发生，鉴定调控白色脂肪棕色化的新脂肪因子对于认知肥胖具有重要科学意义。骨形成蛋白信号通路（BMPs）在棕色脂肪发育中起重要调控作用，但目前尚未有关于BMPs拮抗因子PRDC（又名GREM2）在肥胖中的研究报道。 本研究共招募222例正常对照人群和349例肥胖患者，检测血清PRDC水平并分析其与肥胖的相关性。结果显示,与正常对照人群相比，肥胖患者血清PRDC水平明显升高，且与BMI、体脂含量、腰臀比等肥胖指标呈正相关。进一步研究表明,PRDC在内脏脂肪中高表达，切除内脏脂肪后小鼠血清PRDC水平明显下降。体外研究表明，内脏原代脂肪前体细胞中加入PRDC纯化蛋白后可能通过BMP/SMAD信号通路抑制其向米色脂肪分化。其次，我们构建了PRDC转基因小鼠及脂肪组织特异性PRDC基因敲除小鼠。研究结果显示，PRDC转基因小鼠内脏脂肪棕色化能力下降；而PRDC脂肪特异性敲除小鼠内脏脂肪棕色化能力增强。更重要的是，脂肪组织特异性PRDC敲除小鼠的体重及内脏脂肪含量较对照组下降。 综上，本研究首次定义一个全新的脂肪因子PRDC，揭示PRDC与肥胖的关系，并初步探讨其通过棕色化调控肥胖发生发展的机制，这对于肥胖的分子诊断及靶向治疗有重要价值。