Trib1调控脂肪棕色化抑制肥胖的机制及三七皂苷R2的干预作用

Advanced researches show that it is a promising strategy to convert white adipose tissue to brown adipose tissue, and an increase in abundance of brown adipocytes is associated with reduced obesity. Journal of clinical investigation and Nature reported that conditional knockout of Trib1 in liver caused severe nonalcoholic fatty liver and conditional knockout of Trib1 in hematopoietic cells inhibited adipogenesis. Our previous study also showed that mRNA expression of Trib1 were highly upregulated when adipocyte differentiation, the mRNA expression of which was the most in iWAT. Both previous studies and our results suggest that Trib1 may possess potential ability to regulate fatty metabolism. Promoting browning of white adipose by inhibiting Trib1 in adipocytes might be a new strategy to fight against obesity. Thus, this research will employ mice model with Trib1 knockout in adipose tissue, RNA-seq, and gene function determination to investigate the regulatory effects of Trib1 on browning of white adipose and molecular pathway underlying the effect of Trib1 on white adipocytes. Based on the Trib1 research, it will be confirmed that Notoginsenoside R2 facilitates browning of white adipose via inhibition of Trib1 expression, to protect against obesity. The present study may provide novel insight into potential new therapeutic targets for combating the ever increasing epidemics of obesity.

最新研究发现促进储能型的白色脂肪转化成代谢活跃的棕色脂肪，可有效地防治肥胖。JCI和Nature等国际权威杂志报道，肝脏中条件性敲除Trib1可造成严重的脂肪肝；干扰骨髓细胞中Trib1可抑制脂肪细胞的形成。我们前期研究也发现Trib1在脂肪细胞分化时表达显著升高，且在白色脂肪中表达最高。提示Trib1在脂肪细胞分化过程中发挥重要的作用，我们提出通过调控Trib1促进脂肪棕色化可能成为抵抗肥胖的新途径的假说。本研究拟采用转基因动物模型、RNA测序和基因功能鉴定和染色质免疫共沉淀等技术，深入研究Trib1在脂肪棕色化的关键作用及分子机理，为肥胖的防治寻找新的靶标，并基于前期的工作基础确认三七皂苷R2调控脂肪功能与促进脂肪棕色化与抑制Trib1的表达有关，确证其作用的信号通路和靶分子，探索三七皂苷R2抵抗肥胖新的分子机制。

研究指出促进棕色脂肪发育及白色脂肪棕色化成为防治肥胖的新策略。寻找调控脂肪棕色化的靶标至关重要。前期研究发现Trib1与脂肪代谢有密切的关系，我们也发现该蛋白在棕色脂肪中高表达，我们提出调控Trib1表达可促进脂肪棕色化的假说。本研究体内采用Trib1基因敲除模型、4℃冷刺激等动物模型，体外采用3T3-L1前脂细胞模型、原代脂肪模型; 并结合RNA测序、基因过表达和Co-IP技术，深入研究Trib1在脂肪棕色化的关键作用和分子机理。同时采用动物和细胞模型，研究三七中NGR2对脂肪棕色化调控作用，探索三七皂苷R2抵抗肥胖的新机制。