Combined a- and ß-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle.

Noradrenaline regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signaling downstream of ß-adrenergic receptor (ßAR) activation, how noradrenaline promotes thermogenic output is still not fully understood. Here, we show that coordinated a1-adrenergic receptor (a1AR) and ß3AR signaling induces the expression of thermogenic genes of the futile creatine cycle, and that EBFs, ERRs, and PGC1a are required for this response in vivo. Noradrenaline triggers physical and functional coupling between the a1AR subtype (ADRA1A) to Gaq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase b (CKB) and tissue-nonspecific alkaline phosphatase (TNAP). Combined Gaq and Gas signaling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and CKB is required for this effect. Thus, the ADRA1A-Gaq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis. Overall design: Comparative ATACseq profiling analysis for brown adipose tissue (either 30°C or 6°C) with saline solution or PBZ injections.