锌指蛋白ZNF638调控棕色和米色脂肪产热的作用和机制研究

Obesity is a major risk factor for metabolic diseases. It has been shown that brown and beige fat activation could prevent obesity by promoting thermogenesis and energy expenditure. However, the molecular mechanism of brown and beige fat thermogenesis is still largely unknown. We identified a novel component of thermogenic transcriptional complex, Zinc finger protein ZNF638. Preliminary data showed that ZNF638 was abundent in adipose tissues and its level was highly induced byβ-adrenergic signaling pathway. ZNF638 fat-conditional knockout mice showed impaired thermogenic capacity, reduced energy expenditure and were prone to obesity under high fat diet. Conversely, ZNF638 overexpression in iWAT promoted white fat browning, increased energy expenditure and prevented diet-induced obesity in mice. Mechanistically, ZNF638 could cooperate with PGC1ɑ/PPARs thermogenic transcriptional complex and promote thermogenesis. Based on these results, we will further elucidate the role and mechanism of ZNF638 in regulation of brown and beige fat thermogenesis and energy metabolism using ZNF638 fat-conditional KO mice and ZNF638 iWAT-OE mice. Our work would provide novel therapeutic targets and potential molecular basis for combating obesity and matebolic diseases.

肥胖是代谢综合征的重大风险因素。研究表明，激活的棕色和米色脂肪促进产热和机体能量代谢，抵抗肥胖。然而调控成熟棕色和米色脂肪细胞产热的分子机制尚不清楚。我们前期鉴定出产热转录复合物新组分ZNF638，初步研究发现ZNF638在脂肪组织中高表达，并受β-肾上腺素信号通路调控。ZNF638脂肪特异性敲除小鼠产热能力下降，代谢减低，倾向于高脂饮食诱发的肥胖。相反，在米色脂肪过表达ZNF638能诱导白色脂肪棕色化和促进产热。机制研究表明，ZNF638可能通过协同PGC1ɑ/PPARs产热转录复合物调控产热。基于以上发现，本项目将以ZNF638脂肪特异性敲除小鼠和ZNF638米色脂肪过表达小鼠为主要研究模型，借助原代细胞分离和诱导分化等细胞和分子生物学技术平台，阐明ZNF638调控棕色和米色脂肪产热基因UCP1转录，促进产热和能量代谢的分子机制，为治疗肥胖提供新的分子靶点和理论基础。

肥胖是代谢综合征的重大风险因素。研究表明，激活的棕色和米色脂肪促进产热和机体能量代谢，抵抗肥胖。然而调控成熟棕色和米色脂肪细胞产热的分子机制尚不清楚。本项目以ZNF638脂肪特异性敲除小鼠和ZNF638米色脂肪过表达小鼠为主要研究模型，借助原代细胞分离和诱导分化等细胞和分子生物学技术平台，研究发现ZNF638在脂肪组织中高表达，并受β-肾上腺素信号通路调控。ZNF638脂肪特异性敲除小鼠产热能力下降，代谢减低，倾向于高脂饮食诱发的肥胖。相反，在米色脂肪过表达ZNF638能诱导白色脂肪棕色化和促进产热。机制研究表明，ZNF638可能通过协同PGC1ɑ/PPARs产热转录复合物调控产热，为治疗肥胖提供新的分子靶点和理论基础。同时，我们系统性研究了脂肪和肝脏中脂质代谢的关键调控分子，在转录调控和转录后调控层面鉴定和阐明了了非酒精性脂肪肝发生发展过程中FOXA3和YTHDC2等关键因子的脂质代谢调控的作用和机制。为未来靶向脂质代谢调控改善代谢性疾病奠定重要基础。