ADRA1A–Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP

• Published in: Nature metabolism Vol. 4; no. 11; pp. 1459 - 1473
• Main Authors: Rahbani, Janane F., Scholtes, Charlotte, Lagarde, Damien M., Hussain, Mohammed F., Roesler, Anna, Dykstra, Christien B., Bunk, Jakub, Samborska, Bozena, O’Brien, Shannon L., Tripp, Emma, Pacis, Alain, Angueira, Anthony R., Johansen, Olivia S., Cinkornpumin, Jessica, Hossain, Ishtiaque, Lynes, Matthew D., Zhang, Yang, White, Andrew P., Pastor, William A., Chondronikola, Maria, Sidossis, Labros, Klein, Samuel, Kralli, Anastasia, Cypess, Aaron M., Pedersen, Steen B., Jessen, Niels, Tseng, Yu-Hua, Gerhart-Hines, Zachary, Seale, Patrick, Calebiro, Davide, Giguère, Vincent, Kazak, Lawrence
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2022
• Subjects: 45/77; 59/57; 631/443/319/2723; 631/45; 631/80/304; 64/110; 64/60; 82/80; Adipocytes - metabolism; Biomedical and Life Sciences; Creatine - metabolism; Creatine Kinase - metabolism; Energy Metabolism - genetics; Letter; Life Sciences; Thermogenesis - genetics
• ISSN: 2522-5812
• DOI: 10.1038/s42255-022-00667-w

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. Rahbani et al. show that the α 1 -adrenergic receptor potentiates thermogenesis in thermogenic adipocytes, acting via Gα q signalling, creatine kinase B and tissue-non-specific alkaline phosphatase.