ADRA1A–Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP
Janane F. Rahbani, Charlotte Scholtes, Damien Lagarde, Mohammed F. Hussain, Anna Roesler, Christien B. Dykstra, Jakub Bunk, Bożena Samborska, Shannon O’Brien, Emma Tripp, Alain Pacis, Anthony R. Angueira, Olivia Sveidahl Johansen, Jessica Cinkornpumin, Ishtiaque Hossain, Matthew D. Lynes, Yang Zhang, Andrew P. White, William A. Pastor, Maria Chondronikola, Labros S. Sidossis, Samuel Klein, Anastasia Kralli, Aaron M. Cypess, Steen B. Pedersen, Niels Jessen, Yu‐Hua Tseng, Zachary Gerhart‐Hines, Patrick Seale, Davide Calebiro, Vincent Giguère, Lawrence Kazak
Abstract
Abstract Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis 1 . Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α 1 -adrenergic receptor (AR) and β 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 PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α 1 -AR subtype (ADRA1A) and Gα 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 Gα q and Gα 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–Gα q –futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.