骨代谢平衡受到多重复杂因素影响，我们前期发现核受体ERRα调控新靶基因Gls，影响线粒体谷氨酰胺回补代谢，促进间充质干细胞成骨分化。然而在高脂饮食诱导的肥胖小鼠模型中，却发现ERRα抑制剂增加骨密度、防止骨丢失，进而发现ERRα可能调控脂肪因子leptin启动子的表达，据此我们提出新的假说：ERRα通过调控脂肪因子介导脂肪与骨组织间对话。本项目拟构建ERRα脂肪组织特异性敲除小鼠，结合高脂饮食、脂肪组织移植、leptin替代等动物实验方法，采用启动子点突变、染色质免疫共沉淀、慢病毒表达等分子技术，阐明ERRα转录调控leptin等脂肪因子的新分子机制，揭示核受体ERRα调控骨代谢的新作用方式。明确ERRα通过调控脂肪因子介导脂肪与骨组织间对话的作用机制，对研究骨代谢紊乱与肥胖等代谢性疾病的关联机制具有重要的科学创新意义和临床参考价值。

Bone metabolism is subjected to the complex influences of multiple factors. Our previous work illustrated that nuclear hormone receptor ERRa governs the expression of a novel target gene glutaminase (Gls), affecting mitochondrial glutamine metabolism and enhancing energy; thus, promoting the osteogenic differentiation of mesenchymal stem cells (MSCs). Paradoxically, high-fat-diet induced obese mice treated with an ERRa inverse agonist were found to have increased bone density and reduced bone loss. On the other hand, we recently discovered that ERRa can induce the expression of several adipokines including leptin. Based on these new evidences, we propose a novel hypothesis: ERRa regulates adipokines such as leptin mediating the tissue crosstalk between fat and bone. We aim to test this hypothesis by generating fat tissue specific ERRa knockout mice, challenging with high-fat-diet, replacing with wild type fat tissue by transplantation, and supplementing with recombinant leptin to assess the role of ERRa in the tissue cross talk between fat and bone. In addition, we will employ techniques such as enhancer/promoter mutation, chromatin immunoprecipitation, adenovirus-mediated overexpression to illustrate how ERRa additionally fine tunes bone metabolism through governing the expression of adipokines such as leptin, highlighting how obesity and metabolic dysregulation affects ERRa function and thus bone metabolism.