ADRA1A–Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP

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  • 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 Chondronikola
  • Labros Sidossis
  • Samuel Klein
  • Anastasia Kralli
  • Aaron M. Cypess
  • Steen B. Pedersen
  • Niels Jessen
  • Yu Hua Tseng
  • Patrick Seale
  • Davide Calebiro
  • Vincent Giguère
  • Lawrence Kazak

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
Issue number11
Pages (from-to)1459-1473
Publication statusPublished - 2022

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© 2022, The Author(s).

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