棕色脂肪活性调控新基因Star-PAP在肥胖发生中的基础研究

Fine mapping genetic factors underlying the development of obesity has been the hottest topic in recent years. Using whole-exome sequencing strategy, we identified that low-frequency variants in Star-PAP were more frequent in young morbid obesity than lean controls (P=1.67×10-7) from Genetics of Obesity in Chinese Youngs (GOCY) study. Most of the variants accelerated proteins’ degradation and further extensively changed the expression profile of preadipocytes in vitro. The activity of browning adipocytes induced from primary adipocyte progenitors were blocked with Star-PAP knockdown. In vivo data also showed that Star-PAP overexpression or deficiency changed the activity and genes expression of brown adipose tissues of transgenic or global knockout mice. We plan to construct a brown tissue-specific knockout mice, further analyze phenotypes of the three genetic-modified mice models, and explore the potential molecular candidates in the project, which will provide us a novel pathogenic gene of obesity and candidate target for clinical intervention.

如何发现肥胖新的致病基因已成为肥胖研究领域最为挑战且具有吸引力的科学问题。申请人利用本中心已建成中国青少年早发性肥胖队列及对照开展了较大样本的全外显子测序工作并发现了新基因Star-PAP低频变异在肥胖组中明显富集（P=1.67×10-7），体外功能试验表明这些变异致蛋白降解加速、蛋白表达量下降，进而改变前体脂肪细胞的表达谱；在脂肪前体细胞中特异性基因沉默Star-PAP后，米色（类棕色）脂肪活性明显减弱。为进一步证明Star-PAP可能通过调节米色脂肪活性进而调控肥胖发生，现已构建转基因和全身性Star-PAP杂合突变小鼠并开展了相关表型分析，本申请项目拟进一步借助类/棕色脂肪特异性基因敲除小鼠模型及体外试验，阐明Star-PAP缺失促发肥胖的分子机制。这将是肥胖研究中的一项重要发现，对于肥胖症的病因及临床干预均具有重要科学意义。

本研究对Star-PAP基因的胰岛素敏感性进行了深入的研究和分析，阐明了Star-PAP在胰岛素敏感性中的作用，并揭示了HO1可能是Star-PAP调控胰岛素敏感性的靶基因，为糖尿病的预防和治疗提出新的思路。同时我们还构建了糖尿病的临床大数据库，利用糖尿病大数据开展了真实世界研究工作，在2019年报道了利用41万2型糖尿病患者人群的23种常见癌症类型的风险情况，研究结果显示：男性和女性2型糖尿病患者的总体癌症标准化发病率(SIRs)分别为1.34和1.62。