Sex difference in BAT thermogenesis depends on PGC-1α-ChREBPβ mediated de novo lipogenesis in mice

Abstract Brown adipose tissue (BAT), a thermogenic tissue that plays an important role in systemic energy expenditure, has histological and functional sex differences. BAT thermogenic activity is higher in female mice than in male mice. However, the molecular mechanism underlying this functional sex difference has not been fully elucidated. Herein, we demonstrate the role and mechanism of PGC-1α in this sex difference. Inducible adipocyte-specific PGC-1α knockout (KO) mice displayed decreased BAT thermogenesis only in females. Expression of carbohydrate response-element binding protein beta (Chrebpβ) and downstream de novo lipogenesis (DNL) related genes were both reduced only in female KO mice. BAT-specific knockdown of Chrebpβ reduced the DNL-related gene expression and BAT thermogenesis in female wild-type mice. Furthermore, PGC-1α enhanced the sensitivity of female BAT estrogen signaling, thereby increasing Chrebpβ and its downstream DNL-related gene expression. These findings demonstrate that PGC-1α-ChREBPβ mediated DNL plays a pivotal role in BAT thermogenesis in a sex-dependent manner.