新颖的PGC-1a转录激活剂促进白色脂肪棕色化的作用机制研究和药理活性评价

At present,it is reported that white adipose tissue have the potential of browning. Peroxisome proliferator activated receptor γ coactivator-1 alpha (PGC-1a) has been shown as a key regulator to influence oxidative metabolism and themogenesis. Therefore, we propose，small molecular that stimulate PGC-1a expression in white adipocytes might stimulate brown remodeling of white adipose tissue, ameliorate obesity and metabolic syndrome. Preliminary work, we have established a high throughput screening (HTS) assay that utilized the human PGC-1a promoter to drive luciferase expression. After random screening, we found a series of PGC-1a transcriptional regulaters, representative of these active compounds. The initial pharmacodynamic evaluation in DIO mice of one active compound, Z001, has shown to reducing body weight, reducing fat mass, improved glucose tolerance and browning white fat. These results initially validate the feasibility and rationality of our hypothesis. The project intends to further investigate the mechanism of regulation brown remodeling of white adipose tissue by Z001, further evaluation of its biological activity and find novel structure with new mechanism of anti-obesity and metabolic syndrome lead compounds through the structure optimization.

目前发现白色脂肪组织同时具备棕色化的潜能。过氧化物酶体增殖激活受体γ共激活因子1a(PGC-1a)是调控氧化代谢和热生成的关键因子。我们认为，在白色脂肪组织中上调PGC-1a表达的小分子可能有促进白色脂肪组织棕色化，改善肥胖及代谢综合症的功能。在前期工作中，我们已建立人源PGC-1a启动子驱动的萤光素酶报告基因高通量筛选系统，通过随机筛选获得了一系列PGC-1a小分子转录激活剂，其中代表性活性化合物Z001的初步药效学评价显示该化合物具有降低DIO小鼠体重和脂肪含量、促进白脂棕色化，并改善糖耐量等作用。该研究结果初步证实了我们设想的可行性和合理性。本项目拟进一步考察Z001促进白色脂肪棕色化的作用机制，深入评价其药理学活性，通过结构优化发现结构新颖新作用机制的抗肥胖药物先导化合物。

目前发现白色脂肪组织同时具备棕色化的潜能。过氧化物酶体增殖激活受体γ共激活因子1a(PGC-1a)是调控氧化代谢和热生成的关键因子。我们认为，在白色脂肪组织中上调PGC-1a表达的小分子可能有促进白色脂肪组织棕色化，改善肥胖及代谢综合症的功能。在前期工作中，我们已建立人源PGC-1a启动子驱动的萤光素酶报告基因高通量筛选系统，通过随机筛选获得了一系列PGC-1a小分子转录激活剂，其中包括代表性活性化合物Z001。对Z001的初步药效学评价显示Z001长期给药可以改善高脂诱导胰岛素抵抗小鼠（DIO）的糖脂代谢紊乱，减少白色脂肪组织的大小，提高DIO小鼠的能耗及冷刺激下体温的维持。后续研究表明，Z001是通过促进成熟米色脂肪细胞的产热功能来促进DIO小鼠中皮下脂肪和肾周白色脂肪米色化，改善DIO小鼠的糖耐量。本研究为后续通过结构优化发现结构新颖新作用机制的抗肥胖药物先导化合物提供了理论基础。