新近研究表明白色脂肪棕色化（Browning）可能是肥胖症治疗的新途径，然而棕色化易于在皮下脂肪诱导，而内脏脂肪棕色化抵抗问题却一直得不到解决。申请人在前期研究中发现，新型转录共调节子TRIP-Br2可介导饮食诱发的肥胖和胰岛素抵抗，选择性诱导内脏脂肪的炎症反应，TRIP-Br2基因敲除小鼠在低脂与高脂饮食喂养以及寒冷暴露后均可诱导内脏脂肪棕色化的发生。目前TRIP-Br2介导内脏脂肪棕色化抵抗的具体机制尚不明确。本课题拟采用TRIP-Br2基因敲除及过表达动物模型和脂肪细胞模型，联合细胞、分子生物学方法以及报告基因和代谢组学技术，明确TRIP-Br2作为介导内脏脂肪棕色化抵抗的新靶点，阐释其对线粒体功能和代谢产物的功能学影响，并重点探讨其调控产热调节子PGC-1a和产热信号通路的潜在作用机制。本课题研究结果将为内脏脂肪棕色化抵抗的基础研究提供实验依据，为肥胖症治疗提供新的分子靶标。

Recent studies showed that browning might be the novel approach for the treatment of obesity. However, the subcutaneous fat is susceptible to induce browning and the problem of visceral fat browning resistant has not been solved yet. In the previous study, we found that the new transcriptional coregulator TRIP-Br2 mediated the diet-induced obesity and insulin resistance, and selectively induced the visceral fat inflammation. In addition, visceral fat browning was induced after fed with low-fat diet or high-fat diet and cold exposure in TRIP-Br2 Knockout mice. To date, the underlying mechanism how TRIP-Br2 mediates visceral fat browning resistance are not well understood. In this study, we are going to use the TRIP-Br2 knockout and overexpress animal models and adipocytes models, combined with cellular and molecular biology, also reporter assay and metabolomics techniques to confirm TRIP-Br2 as a new target mediating visceral fat browning resistance and the functional effects of TRIP-Br2 on mitochondrial function and fatty acid metabolites. Furthermore, we will investigate the underlying mechanism that TRIP-Br2 mediates visceral fat browning resistance through regulating the thermogenic regulator PGC-1a and thermogenic signaling pathway. The findings of our current study will provide the experimental evidences for the basic research of visceral fat browning resistance and discover the novel molecular target for the treatment of obesity.