DDB1 prepares brown adipocytes for cold-induced thermogenesis
Received date: 01 Jan 2022
Revised date: 17 Jan 2022
Accepted date: 18 Jan 2022
Copyright
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 Ddb1 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 ℃ and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation. Mechanistically, DDB1 binds the promoters of Ucp1 and Ppargc1a 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.
Key words: brown adipose tissue; thermogenesis; DDB1; RNA polymerase II; promoter-proximal pausing; UCP1; PGC1α
Xu Wang , Shen-Ying Liu , Guo-Sheng Hu , Hao-Yan Wang , Guo-Liang Zhang , Xiang Cen , Si-Ting Xiang , Wen Liu , Peng Li , Haobin Ye , Tong-Jin Zhao . DDB1 prepares brown adipocytes for cold-induced thermogenesis[J]. Life Metabolism, 2022 , 1(1) : 39 -53 . DOI: 10.1093/lifemeta/loac003
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