Journal
NATURE METABOLISM
Volume 4, Issue 11, Pages 1459-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-022-00667-w
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Funding
- Canadian Institutes of Health Research (CIHR) [PJT-159529, PJT-180557]
- Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant
- Canadian Foundation for Innovation John R. Evans Leaders Fund [37919]
- CIHR postdoctoral fellowship [MFE-176528]
- Rolande and Marcel Gosselin Graduate studentship
- Canderel studentship
- Wellcome Trust Senior Research Fellowship [212313/Z/18/Z]
- National Institutes of Health grant [K01DK111714]
- MRC IMPACT PhD studentship
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The mechanism by which noradrenaline regulates adipocyte thermogenesis is not fully understood. This study reveals that the coordinated signaling of alpha(1)-adrenergic receptor and beta(3)-adrenergic receptor induces the expression of thermogenic genes of the futile creatine cycle. Various factors, such as early B cell factors, estrogen-related receptors, and PGC1 alpha, are required for this response in vivo.
Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis(1). Aside from cAMP signalling downstream of beta-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated alpha(1)-adrenergic receptor (AR) and beta(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 PGC1 alpha are required for this response in vivo. NA triggers physical and functional coupling between the alpha(1)-AR subtype (ADRA1A) and G alpha(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 G alpha(q) and G alpha(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-G alpha(q)-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
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