棕色脂肪和肠道菌群在时间限制性饮食重塑机体糖脂代谢中的作用以及机制

多项临床研究表明，时间限制性饮食（TRF）对于肥胖以及相关代谢疾病有显著改善作用，但其作用机制尚不明确。我们的结果表明，TRF可以显著改善高脂饮食（HFD）诱导的代谢紊乱，其中因为HFD而降低的小鼠耗氧量以及棕色脂肪（BAT）关键产热蛋白UCP1的表达水平也得到了恢复。另外TRF改变了肠道菌群组成，而通过移植TRF组菌群即可模拟TRF带来的代谢改善。以上结果提示我们，BAT和肠道菌群在TRF重塑机体糖脂代谢中发挥了重要作用。本项目将重点关注BAT和肠道菌群在TRF重塑糖脂代谢过程中发挥的具体作用以及分子机制。首先我们将采用宏基因组学方法和脂质代谢组学方法研究肠道微生物多样性以及菌群结构等，探寻并鉴定出发挥关键作用的菌种及其次级代谢产物，并由细胞以及多种动物模型验证，最后全面解析TRF-肠道菌群-次级代谢产物-BAT这一代谢轴的分子作用机理，为开发可以模拟TRF作用的靶向药物提供理论依据。

Several clinical studies have reported that time-restricted feeding (TRF) can significantly improve obesity and related metabolic diseases, but its mechanism is still unclear. Our results indicated that TRF can significantly improve the metabolic disorders induced by high-fat diet (HFD), and elevate the oxygen consumption and the expression level of UCP1, the key protein of brown adipose tissue (BAT). In addition, TRF treatment changed the composition of intestinal microbiota, and the metabolic improvement brought by TRF could be simulated by fecal microbiota transplantation from TRF group. These results suggest that BAT and intestinal microbiota play an important role in the remodeling of glucose and lipid metabolism driven by TRF. This project will focus on the specific roles and molecular mechanisms of BAT and intestinal microbiota in the remodeling of glycolipid metabolism by TRF diet. Firstly, we will apply whole genomic sequencing and lipidomic techniques to clarify the effects of TRF on microbial diversity and community structure and identify key microbiota and related secondary metabolite(s). In addition, we will validate the curative effects of screened microbiota and secondary metabolite(s) in our cells and animal models. Finally we will perform comprehensive analysis to figure out the molecular mechanisms of TRF - intestinal microbiota - secondary metabolites – BAT axis to provide theory basis for developing safe and convenient targeted pharmacologic therapies that mimic the effects of TRF.