ChREBP-β regulates thermogenesis in brown adipose tissue.

Brown adipose tissue (BAT) plays a critical role in energy expenditure by uncoupling protein 1 (UCP1)-mediated thermogenesis. Carbohydrate response element-binding protein (ChREBP) is one of the key transcription factors regulating de novo lipogenesis (DNL). As a constitutively active form, ChREBP-beta is expressed at extremely low levels. Up to date, its functional relevance in BAT remains unclear. In this study, we show that ChREBP-beta inhibits BAT thermogenesis. BAT ChREBP-beta mRNA levels were elevated upon cold exposure, which prompted us to generate a mouse model overexpressing ChREBP-il specifically in BAT using the Cre/LoxP approach. ChREBP-beta overexpression led to a whitening phenotype of BAT at room temperature, as evidenced by increased lipid droplet size and decreased mitochondrion content. Moreover, BAT thermogenesis was inhibited upon acute cold exposure, and its metabolic remodeling induced by long-term cold adaptation was significantly impaired by ChREBP-beta overexpression. Mechanistically, ChREBP-beta overexpression downregulated expression of genes involved in mitochondrial biogenesis, autophagy, and respiration. Furthermore, thermogenic gene expression (e.g. Dio2, UCP1) was markedly inhibited in BAT by the overexpressed ChREBP-beta. Put together, our work points to ChREBP-beta as a negative regulator of thermogenesis in brown adipocytes.