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 Chondronikola; Labros Sidossis; Samuel Klein; Anastasia Kralli; Aaron M. Cypess; Steen B. Pedersen; Niels Jessen; Yu-Hua Tseng; Zachary Gerhart-Hines; Patrick Seale; Davide Calebiro; Vincent Giguere; Lawrence Kazak

doi:10.1038/S42255-022-00667-W

ADRA1A-Gα_q 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 Giguere, Lawrence Kazak^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 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 α₁-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–Gαq–futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

Original language	English
Pages (from-to)	1459–1473
Number of pages	15
Journal	Nature Metabolism
Volume	4
Issue number	11
DOIs	https://doi.org/10.1038/S42255-022-00667-W
Publication status	Published - 7 Nov 2022

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Rahbani, J. F., Scholtes, C., Lagarde, D. M., Hussain, M. F., Roesler, A., Dykstra, C. B., Bunk, J., Samborska, B., O'Brien, S. L., Tripp, E., Pacis, A., Angueira, A. R., Johansen, O. S., Cinkornpumin, J., Hossain, I., Lynes, M. D., Zhang, Y., White, A. P., Pastor, W. A., ... Kazak, L. (2022). ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP. Nature Metabolism, 4(11), 1459–1473. https://doi.org/10.1038/S42255-022-00667-W

@article{c21759adb97b44c5bd386351e242a8d8,

title = "ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP",

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.",

author = "Rahbani, {Janane F.} and Charlotte Scholtes and Lagarde, {Damien M.} and Hussain, {Mohammed F.} and Anna Roesler and Dykstra, {Christien B.} and Jakub Bunk and Bozena Samborska and O'Brien, {Shannon L.} and Emma Tripp and Alain Pacis and Angueira, {Anthony R.} and Johansen, {Olivia S.} and Jessica Cinkornpumin and Ishtiaque Hossain and Lynes, {Matthew D.} and Yang Zhang and White, {Andrew P.} and Pastor, {William A.} and Maria Chondronikola and Labros Sidossis and Samuel Klein and Anastasia Kralli and Cypess, {Aaron M.} and Pedersen, {Steen B.} and Niels Jessen and Yu-Hua Tseng and Zachary Gerhart-Hines and Patrick Seale and Davide Calebiro and Vincent Giguere and Lawrence Kazak",

year = "2022",

month = nov,

day = "7",

doi = "10.1038/S42255-022-00667-W",

language = "English",

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journal = "Nature Metabolism",

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Rahbani, JF, Scholtes, C, Lagarde, DM, Hussain, MF, Roesler, A, Dykstra, CB, Bunk, J, Samborska, B, O'Brien, SL, Tripp, E, Pacis, A, Angueira, AR, Johansen, OS, Cinkornpumin, J, Hossain, I, Lynes, MD, Zhang, Y, White, AP, Pastor, WA, Chondronikola, M, Sidossis, L, Klein, S, Kralli, A, Cypess, AM, Pedersen, SB, Jessen, N, Tseng, Y-H, Gerhart-Hines, Z, Seale, P, Calebiro, D, Giguere, V & Kazak, L 2022, 'ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP', Nature Metabolism, vol. 4, no. 11, pp. 1459–1473. https://doi.org/10.1038/S42255-022-00667-W

TY - JOUR

T1 - ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP

AU - Rahbani, Janane F.

AU - Scholtes, Charlotte

AU - Lagarde, Damien M.

AU - Hussain, Mohammed F.

AU - Roesler, Anna

AU - Dykstra, Christien B.

AU - Bunk, Jakub

AU - Samborska, Bozena

AU - O'Brien, Shannon L.

AU - Tripp, Emma

AU - Pacis, Alain

AU - Angueira, Anthony R.

AU - Johansen, Olivia S.

AU - Cinkornpumin, Jessica

AU - Hossain, Ishtiaque

AU - Lynes, Matthew D.

AU - Zhang, Yang

AU - White, Andrew P.

AU - Pastor, William A.

AU - Chondronikola, Maria

AU - Sidossis, Labros

AU - Klein, Samuel

AU - Kralli, Anastasia

AU - Cypess, Aaron M.

AU - Pedersen, Steen B.

AU - Jessen, Niels

AU - Tseng, Yu-Hua

AU - Gerhart-Hines, Zachary

AU - Seale, Patrick

AU - Calebiro, Davide

AU - Giguere, Vincent

AU - Kazak, Lawrence

PY - 2022/11/7

Y1 - 2022/11/7

N2 - 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.

AB - 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.

UR - https://publons.com/wos-op/publon/56123768/

U2 - 10.1038/S42255-022-00667-W

DO - 10.1038/S42255-022-00667-W

M3 - Article

VL - 4

SP - 1459

EP - 1473

JO - Nature Metabolism

JF - Nature Metabolism

IS - 11

ER -

ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP

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ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP