ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis(1). Aside from cAMP signalling downstream of beta-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated alpha(1)-adrenergic receptor (AR) and beta(3)-AR signalling induces the expression of thermogenic genes of the futile creatine cycle(2,3), and that early B cell factors, oestrogen-related receptors and PGC1 alpha are required for this response in vivo. NA triggers physical and functional coupling between the alpha(1)-AR subtype (ADRA1A) and G alpha(q) to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined G alpha(q) and G alpha(s) signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-G alpha(q)-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

Automated summary

The mechanism by which noradrenaline regulates adipocyte thermogenesis is not fully understood. This study reveals that the coordinated signaling of alpha(1)-adrenergic receptor and beta(3)-adrenergic receptor induces the expression of thermogenic genes of the futile creatine cycle. Various factors, such as early B cell factors, estrogen-related receptors, and PGC1 alpha, are required for this response in vivo.