CarS2 mediated cysteine catabolism drives brown fat development and thermogenesis through persulfidating EBF2 [BAC and L1 differ]

Targeting transcriptional regulatory complex is a promising strategy to activate thermogenic fat and treat obesity. In this study, we focus on identifying critical and special metabolic pathways enriched during brown adipocyte differentiation. By analyzing metabolomics and RNA sequencing results from precursor and mature brown and white adipocytes, we revealed cysteine catabolism pathway is a unique metabolic process that is exclusively increased in the brown adipocyte differentiation. Then, we demonstrated cysteine persulfidation synthase CarS2 is directly induced by EBF2 and mediates cysteine catabolism to produce cysteine persulfide and triggers brown fat protein persulfidation in vitro and in vivo. Loss of CarS2 in thermogenic fat blocks brown and beige fat formation and reduced thermogenesis and energy expenditure in mice. More importantly, CarS2 generates cysteine persulfide and its derivative H2S cell autonomously induces brown adipogenesis and enhances uncoupled respiration by persulfidating EBF2. Mechanistically, the persulfidated EBF2 facilitates its interaction with PPARγ and enhanced the recruitment of the EBF2-PPARγ complex on browning gene promoter, thus driving brown fat development and boosting thermogenic function. Furthermore, the treatment of CarS2 coenzyme PLP or H2S donor elevates brown adipocyte function and ameliorates obesity progression in mice under HFD feeding, indicating a novel metabolite-based strategy for the obesity treatment.