ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP

Janane F Rahbani, Charlotte Scholtes, Damien M Lagarde, Mohammed F Hussain, Anna Roesler, Christien B Dykstra, Jakub Bunk, Bozena Samborska, Shannon L O'Brien, Emma Tripp, Alain Pacis, Anthony R Angueira, Olivia S Johansen, Jessica Cinkornpumin, Ishtiaque Hossain, Matthew D Lynes, Yang Zhang, Andrew P White, William A Pastor, Maria ChondronikolaLabros 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

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Abstract

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. 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 α1-adrenergic receptor (AR) and β3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, 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 α1-AR subtype (ADRA1A) and Gαq 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 Gαq and Gαs 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-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

Original languageEnglish
JournalNature Metabolism
Volume4
Issue11
Pages (from-to)1459-1473
Number of pages15
ISSN2522-5812
DOIs
Publication statusPublished - Nov 2022

Keywords

  • Adipocytes/metabolism
  • Creatine Kinase/metabolism
  • Creatine/metabolism
  • Energy Metabolism/genetics
  • Thermogenesis/genetics

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