糖皮质激素差异调控脂肪祖细胞米色化的细胞特异性研究

Visceral obesity is responsible for various diseases. Glucocorticoid plays a key role at fat redistribution and visceral fat accumulation. Visceral obesity is consistent with much lower beiging of visceral fat than that of subcutaneous fat. .We have found that GR inhibits the lipid beiging by regulating miR-27b expression via binding to the miR-27b promoter. Our study confirmed that visceral fat expression of miR-27b higher than subcutaneous fat. While visceral fat contained more PDGFRα+ progenitor cells, subcutaneous fat has a higher proportion of CD137+ progenitor cells. GC inhibited beiging of PDGFRα+ cells but had no effect on CD137+ cells, while miR-27b can suppress the beiging of both. Therefore, we hypothesized that the different effects of GC on the beiging of PDGFRα+ cells and CD137+ cells are related to the cell specificity of GR for miR-27b transcriptional regulation. In this proposal, we intend to work innovatively on the binding of GR to DNA, the methylation and acetylation of GRE binding to GR, and the role of GR-related transcriptional regulation complex through gene sequencing and ATAC-seq motif analysis. Therefore to study the distinct effects of GC among different adipose progenitor cells, defining the underlying mechanism of visceral obesity, and providing new means for the treatment of visceral obesity.

内脏肥胖是致病根源，糖皮质激素在脂肪重新分布、内脏脂肪蓄积起关键作用，内脏脂肪米色化远低于皮下脂肪与内脏肥胖有关。我们研究已确定GR通过与miR-27b启动子结合调控miR-27b表达抑制脂肪米色化，我们现证实内脏脂肪miR-27b表达高于皮下脂肪，内脏脂肪PDGFRα+祖细胞比例高而皮下脂肪CD137+祖细胞比例高，且GC抑制PDGFRα+祖细胞米色化而对CD137+祖细胞无影响，但miR-27b则能抑制两者米色化，因此我们假设GC差异调控PDGFRα+祖细胞与CD137+祖细胞米色化与GR对miR-27b转录调控的细胞特异性有关，本课题通过基因测序及ATAC-seq motif定位调控位点分析，创新性地从GR与DNA的结合力、与GR结合的GRE位点甲基化及乙酰化以及GR相关转录调控复合体的作用研究GC影响不同脂肪祖细胞的转录差异，明确内脏肥胖根本原因，为治疗内脏肥胖提供新手段。

内脏肥胖是致病根源，糖皮质激素在脂肪重新分布、内脏脂肪蓄积起关键作用，内脏脂肪米色化远低于皮下脂肪与内脏肥胖有关。受糖皮质激素和脂肪祖细胞异质性的累积证据的启发，我们观察到，在内脏脂肪组织中占主导地位的PDGFRα+祖细胞是糖皮质激素敏感的米色脂肪祖细胞，而在皮下脂肪组织中占主导地位的CD137+祖细胞是糖皮质激素不敏感的米色脂肪祖细胞。已有研究证明miR-27b抑制脂肪细胞米色化，糖皮质激素刺激后，PDGFRα+祖细胞中miR-27b的表达显著增加。通过ATAC-seq、BS-seq和dCas9-Tet1/Dnmt3a对CpG甲基化的精确编辑，发现 TEAD1在PDGFRα+祖细胞中具有独特的低甲基化，是糖皮质激素受体的关键共作用因子。糖皮质激素通过miR-27b抑制PDGFRα+祖细胞向米色脂肪分化， TEAD1协同GR转录激活miR-27b。因此，我们的研究为内脏肥胖的机制和高脂饮食诱导的肥胖中脂肪特异性分化体病理生理学提供了新的干预靶点。