棕色脂肪靶向11β-HSD1抑制剂治疗肥胖的作用机制研究

Obesity has become a global epidemic with complications contributing substantially to health care costs and mortality. In contrast to white adipose tissue (WAT), brown adipose tissue (BAT) plays an active role in energy expenditure. Now it is found that there is still functional brown adipose tissue in adult human, and it plays an important role in maintaining energy balance. Promotion of BAT function in human would offer the possibility of increasing energy expenditure and protection against obesity. In our previous study, we observed a significant increase in the expression of BAT-specific genes and the basal oxygen consumption rate (OCR) in BVT.2733 (a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1)-treated and 11β-HSD1 deficient brown adipocyte, indicating that 11β-HSD1 acts as a vital regulator that controls the brown fat function. Furthermore, we used miRNA microarray analysis of adipocytes treated with glucocorticoids or vehicle, and found that miR-27b was one of the most upregulated miRNAs after glucocorticoids treatment. Further miRNA target prediction by the web site showed that a putative miR-27b target site was identified at a highly evolutionarily conserved octamer seed motif within the 3'UTR of Prdm16. Therefore, miR-27b may mediate its effects by directly targeting Prdm16, a factor that controls both the development of brown fat. In this proposal, we synthesised the specific 11β-HSD1 inhibitor targeted brown adipose tissue, which was already synthesized, to clarify the role of 11β-HSD1 in regulating the brown fat function and provide therapeutic target for obesity and associated disease.

与白色脂肪储存能量相反，棕色脂肪促进能量消耗，目前发现成人体内仍存在着具有功能的棕色脂肪组织，对维持机体能量平衡起关键作用，改善棕色脂肪功能已成为治疗肥胖的新靶点。我们前期研究发现，作为调控糖皮质激素（GC）活性的关键酶，11β-羟化类固醇脱氢酶1（11β-HSD1）是影响棕色脂肪功能的关键因子，并从基因水平、蛋白水平和细胞功能水平均证实抑制棕色脂肪细胞11β－HSD1可显著促进棕色功能。在此基础上，我们利用miRNAs芯片筛选出受GC调控的关键miRNA- - miR-27b，并预测其靶基因为调控棕色脂肪功能的关键核转录因子- - PRDM16。因此，本课题利用特异的棕色脂肪组织靶向多肽（获国家发明专利），创新性地合成棕色脂肪靶向的11β-HSD1抑制剂（已自行合成），研究其对机体代谢的影响，并通过研究miR-27b，搞清11β-HSD1调控棕色脂肪功能的分子机理，为有效干预肥胖提供新手段。

与白色脂肪储存能量相反，棕色脂肪促进能量消耗，目前发现成人体内仍存在着具有功能的棕色脂肪组织，对维持机体能量平衡起关键作用，改善脂肪组织的棕色化功能已成为治疗肥胖的新靶点。我们前期研究发现，作为调控糖皮质激素（GC）活性的关键酶，11β-羟化类固醇脱氢酶1（11β-HSD1）是影响棕色脂肪功能的关键因子，并从基因水平、蛋白水平和细胞功能水平均证实抑制棕色脂肪细胞11β－HSD1可显著促进棕色功能。在此基础上，我们利用miRNAs芯片筛选出受GC调控的关键miRNA : miR-27b，并预测其靶基因为调控棕色脂肪功能的关键核转录因子PRDM16。我们研究发现GC激活BAT中miR-27b的表达，并通过作用于PRDM16抑制了棕色脂肪的功能，表明miR-27b可能作为防治糖皮质激素导致肥胖和代谢紊乱的潜在治疗靶点。