ADRA1A–Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Metabolism |
| Vol/bind | 4 |
| Udgave nummer | 11 |
| Sider (fra-til) | 1459-1473 |
| ISSN | 2522-5812 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We thank all members of the Kazak laboratory for critical reading of the manuscript. We thank J. Estall for providing Ppargc1afl/flmice. This work was supported by Canadian Institutes of Health Research (CIHR) project grants (PJT-159529 and PJT-180557), a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, and the Canadian Foundation for Innovation John R. Evans Leaders Fund (37919; to L.K.); a CIHR postdoctoral fellowship (MFE-176528; to J.F.R.); a Canderel studentship and a Rolande and Marcel Gosselin Graduate studentship (to M.F.H.); a Canderel studentship (to C.B.D.); a Wellcome Trust Senior Research Fellowship (212313/Z/18/Z; to D.C.); a National Institutes of Health grant (K01DK111714; to M.D.L.); and an MRC IMPACT PhD studentship (to E.T.). L.K. is a Canada Research Chair in adipocyte biology.
Funding Information:
We thank all members of the Kazak laboratory for critical reading of the manuscript. We thank J. Estall for providing Ppargc1a mice. This work was supported by Canadian Institutes of Health Research (CIHR) project grants (PJT-159529 and PJT-180557), a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, and the Canadian Foundation for Innovation John R. Evans Leaders Fund (37919; to L.K.); a CIHR postdoctoral fellowship (MFE-176528; to J.F.R.); a Canderel studentship and a Rolande and Marcel Gosselin Graduate studentship (to M.F.H.); a Canderel studentship (to C.B.D.); a Wellcome Trust Senior Research Fellowship (212313/Z/18/Z; to D.C.); a National Institutes of Health grant (K01DK111714; to M.D.L.); and an MRC IMPACT PhD studentship (to E.T.). L.K. is a Canada Research Chair in adipocyte biology. fl/fl
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© 2022, The Author(s).
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