A WAT-to-BAT communication facilitates sustained activation of BAT thermogenesis during cold exposure [RNA-Seq]

BAT activation for thermogenesis is a physiological mechanism that maintains body temperature during cold exposure. However, how BAT is dynamically activated and preserve its sustained activation in cold is not completely understood. In this study, we identified soluble ST2 (sST2) mediates a WAT-to-BAT endocrine mechanism, which is required for constant BAT activation during cold exposure. Specific depletion of sST2 isoform blocks the alternative thermogenesis upon BAT denervation and leads to cold sensitive in a prolong cold exposure. Mechanistically, sST2 is induced and secreted from eWAT by the Adrb1/2 signaling driven Creb1 activation. The secreted sST2 directly binds to the Adrb3 receptor in BAT and in synergy with NE to induce BAT thermogenesis, which is independent of IL33. Additionally, supplement of sST2 induces beige fat formation in mice and humans. Therefore, our study demonstrated eWAT derived adipokine sST2 functions on BAT activation as a novel mechanism in sustained activation of thermogenesis of BAT in cold exposure. More importantly, sST2 may serve as an emerging therapeutic approach in combine with b3 receptor agonist for obesity treatment.