谷氨酰胺酰基环化酶同工酶（QPCTL）在脂肪发育及体重调节中的作用及机制研究

Obesity is a complex disease characterized by excessive adipose tissue accumulation, in which gene and enviromental factors contribute together. Obesity is the risk foctor for many serious choronic dieseases, such as type 2 diabetes, cardiovascular diaseases and related mortality. Obesity is becoming an epidemic worldwide. To identify the new mechanism of obesity pathogenesis and targets for intervention is imminent. In our previous study, we found that both in exome sequencing in an obese -control cohort and validation in a general population, genetic variations of QPCTL gene significantly associated with increase of body mass index and the risk of obesity. Additionally, we found that QPCTL mRNA and protein expression levels were significantly elevated in the adipose tissue of the obese patients and mouse models as well; meanwhile decreased in the lean mouse models. Moreover, QPCTL expression was increased at late phase of the adipose differentiation process. These results suggest that QPCTL play an important role in the development of obesity by promoting the differentiation of adipose tissues. In the present proposal, based on an established QPCTL transgenic mouse model, we aimed to comprehensively study the effect of QPCTL on modulation of adipose differentiation, weight gain or loss, and energy metabolism in vivo and vitro; to clarify the molecular mechanism of QPCTL in the pathogenesis of adipose differentiation; and finally to confirmed that whether lowing the effect of QPCTL using the inhibitor of QPCTL, PBD150, could reduce adiposity. This study will provide strong evidence for the roles of QPCTL in pathogenesis of obesity, and new mechanism and targets for efficient obesity intervention and prevention.

肥胖系脂肪组织过度堆积所致，已成为多种严重慢性疾病的危险因素，其流行趋势日益严峻，寻找肥胖致病机制及干预靶点迫在眉睫。本研究前期在肥胖队列全外显子组测序及自然人群验证中发现QPCTL遗传位点与肥胖发生风险相关，并且QPCTL在肥胖病人及小鼠脂肪组织表达明显升高，而在偏瘦小鼠模型表达下降，进一步发现QPCTL在脂肪分化成熟后期表达升高，这些结果提示QPCTL极有可能通过促进脂肪分化参与肥胖发生。本项目在已建立QPCTL转基因小鼠模型基础上，拟借助动物模型和原代脂肪前体细胞SVF从体内、体外水平深入研究QPCTL对脂肪分化的调节及对体重、能量代谢的作用；通过各种分子生物学技术阐明QPCTL作用的分子机制，最后利用QPCTL抑制剂PBD150探讨干预QPCTL对肥胖的改善作用。该项目将从临床人群研究和实验室研究两个方面深入阐明QPCTL对肥胖的致病作用和机制，为肥胖干预提供新的靶点。

本课题研究计划以谷氨酰胺酰基环化酶同工酶（QPCTL）的遗传位点为主要研究靶点，以在脂肪发育及体重调节中的作用为切入点，系统深入探讨了肥胖遗传易感基因对脂肪调节及相关代谢异常的相关机制。通过该课题实施，1、建立了10000人40岁以上自然人群研究队列；建立包含身高、体重、血压、腰围、血糖、血脂、胰岛素、糖化血红蛋白、饮食（FFQ）、生活方式等在内的详细的临床表型资料库；留取全血、血清、血浆、DNA、尿液、唾液等生物样本。2、在万人队列中对肥胖、血糖代谢等代谢性状变异位点（100个）进行基因分型。3、完成了QPCTL基因、IRX3基因、GCKR 基因等与肥胖、2型糖尿病、血脂代谢异常的风险相关性研究；QPCTL与环境因素对2型糖尿病或其他代谢性疾病的交互作用；遗传易感性与与环境暴露因素（如BPA）交互作用，显著增加环境暴露糖代谢异常风险。4、证实由34个2型糖尿病遗传易感位点构建的遗传风险评分评分、包括QPCTL、FTO在内的14个肥胖遗传易感评分以及由17个糖化血红蛋白位点构成的遗传风险评分对糖尿病及其早期血管并发症、抑郁等的孟德尔因果关联研究。从分子流行病学角度研究肥胖相关位点与结局的因果关系。5、开展QPCTL、IRX3基因调节脂肪分化的作用机制研究。这些研究对2型糖尿病及其并发症的预防、病理机制探讨及个人化治疗具有非常重要的科学价值和社会意义。该研究成果在功能研究、分子流行病学及临床疾病风险分层和预测方面具有很好的应用前景。