配体依赖的辅助抑制因子调控脂肪分化与代谢的作用及机制研究

脂肪细胞的功能紊乱是许多代谢性疾病发生发展过程中的一个核心事件，因此探索脂肪组织的生物学功能，阐明各种生理病理条件下脂肪细胞分化和代谢的调控机制具有深刻的意义。越来越多的证据表明，核受体辅助因子对于脂肪分化、脂质代谢以及能量代谢的调控至关重要。我们最近的研究发现配体依赖的辅助抑制因子LCOR具有抑制脂肪细胞分化的作用。我们还发现LCOR在脂肪细胞分化早期控制着C/EBPa和PPARg的表达，而脂肪分化早期调控因子C/EBPb是LCOR的结合蛋白。我们预测LCOR可能通过调控C/EBPb的转录活性，影响C/EBPa和PPARg的表达水平以及脂肪细胞的分化能力。我们计划深入研究LCOR调控脂肪细胞分化的分子机理，研究LCOR调控转录的表观遗传机制，利用LCOR脂肪特异敲除小鼠探索LCOR对机体能量代谢的调控作用。本项目研究将揭示肥胖及肥胖相关疾病的病理机制，为治疗相关疾病提供新的思路和靶标。

Since adipocyte dysfunction is a key event in the development and progression of multiple metabolic diseases, it is important to explore the biological function of adipose tissues and clarify the molecular mechanism of the adipocyte differentiation and metabolism under various physiological and pathological conditions. Growing evidence indicates that nuclear receptor cofactors play critical roles in adipogenesis, lipid metabolism and energy metabolism. Recently, we discovered that ligand-depend corepressor (LCOR) is a suppressor of adipogenesis. Further investigation suggested that LCOR regulates the transcription of CCAAT enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferative-activated receptor gamma (PPARgamma) during early adipogenesis. Subsequently, we identified C/EBPbeta, a key regulator of early adipogenesis, as a LCOR binding protein. We hypothesized that LCOR regulates the expression of C/EBPalpha and PPARgamma and determine the ability of adipocyte differentiation through interfering with the transcriptional activity of C/EBPbeta. In this project, we aim to understand the molecular mechanism of adipogenesis mediated by LCOR and the epigenetic regulation of gene transcription controlled by LCOR. Meanwhile, we would like to explore the regulatory role of LCOR in energy metabolism by using adipose-specific LCOR knockout mice. This study will unveil the pathogenesis of obesity and obesity-related diseases and provide new ideas and targets for clinical treatment.