Wang Xu, Liu Shen-Ying, Hu Guo-Sheng, Wang Hao-Yan, Zhang Guo-Liang, Cen Xiang, Xiang Si-Ting, Liu Wen, Li Peng, Ye Haobin, Zhao Tong-Jin
State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Qi Zhi Institute, Shanghai, China.
Life Metab. 2022 May 13;1(1):39-53. doi: 10.1093/lifemeta/loac003. eCollection 2022 Aug.
Brown adipose tissue (BAT) plays a key role in thermogenesis during acute cold exposure. However, it remains unclear how BAT is prepared to rapidly turn on thermogenic genes. Here, we show that damage-specific DNA binding protein 1 (DDB1) mediates the rapid transcription of thermogenic genes upon acute cold exposure. Adipose- or BAT-specific knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes. These mice develop hypothermia when subjected to acute cold exposure at 4 °C and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation. Mechanistically, DDB1 binds the promoters of and and recruits positive transcriptional elongation factor b (P-TEFb) to release promoter-proximally paused RNA polymerase II (Pol II), thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure. Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.
棕色脂肪组织（BAT）在急性冷暴露期间的产热过程中起关键作用。然而，目前尚不清楚BAT如何准备好快速开启产热基因。在此，我们表明损伤特异性DNA结合蛋白1（DDB1）在急性冷暴露时介导产热基因的快速转录。脂肪或BAT特异性敲除小鼠表现出BAT严重变白，产热基因的表达显著降低。这些小鼠在4°C急性冷暴露时会出现体温过低，并且由于脂肪酸氧化不足，在高脂饮食时会出现部分脂肪营养不良。从机制上讲，DDB1与 和 的启动子结合，并募集正性转录延伸因子b（P-TEFb）以释放启动子近端暂停的RNA聚合酶II（Pol II），从而在急性冷暴露时实现产热基因的快速同步转录。因此，我们的研究结果提供了一种BAT如何准备应对急性冷挑战的调节机制。
