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 Giguère; Lawrence Kazak

doi:10.1038/s42255-022-00667-w

ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP

Nat Metab. 2022 Nov;4(11):1459-1473. doi: 10.1038/s42255-022-00667-w. Epub 2022 Nov 7.

Authors

Janane F Rahbani¹, Charlotte Scholtes¹, Damien M Lagarde¹, Mohammed F Hussain^{1

2}, Anna Roesler^{1

2}, Christien B Dykstra^{1

2}, Jakub Bunk^{1

2}, Bozena Samborska¹, Shannon L O'Brien^{3

4}, Emma Tripp^{3

4}, Alain Pacis¹, Anthony R Angueira⁵, Olivia S Johansen⁶, Jessica Cinkornpumin², Ishtiaque Hossain², Matthew D Lynes⁷, Yang Zhang⁸, Andrew P White⁹, William A Pastor^{1

2}, Maria Chondronikola^{10

11}, Labros Sidossis¹², Samuel Klein¹³, Anastasia Kralli¹⁴, Aaron M Cypess¹⁵, Steen B Pedersen¹⁶, Niels Jessen^{16

17}, Yu-Hua Tseng⁸, Zachary Gerhart-Hines⁶, Patrick Seale⁵, Davide Calebiro^{3

4}, Vincent Giguère^{1

2}, Lawrence Kazak^{18

19}

Affiliations

¹ Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
² Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
³ Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
⁴ Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham, UK.
⁵ Institute for Diabetes, Obesity & Metabolism and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
⁷ Maine Medical Center Research Institute, Scarborough, ME, USA.
⁸ Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
⁹ Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Nutrition and Radiology, University of California, Davis, Davis, CA, USA.
¹¹ Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
¹² Department of Kinesiology and Health, School of Arts and Sciences, Rutgers University, New Brunswick, NJ, USA.
¹³ Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO, USA.
¹⁴ Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Aarhus N, Denmark.
¹⁷ Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
¹⁸ Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. lawrence.kazak@mcgill.ca.
¹⁹ Department of Biochemistry, McGill University, Montreal, Quebec, Canada. lawrence.kazak@mcgill.ca.

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-Gα_q-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Creatine
Creatine Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding