ADRA1A-Gα signalling potentiates adipocyte thermogenesis through CKB and TNAP

Janane F. Rahbani, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Charlotte Scholtes, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Damien M. Lagarde, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Mohammed F. Hussain, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Anna Roesler, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Christien B. Dykstra, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Jakub Bunk, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Bozena Samborska, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Shannon L. O'Brien, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
Emma Tripp, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
Alain Pacis, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Anthony R. Angueira, Institute for Diabetes, Obesity & Metabolism and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Olivia S. Johansen, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Jessica Cinkornpumin, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Ishtiaque Hossain, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Matthew D. Lynes, MaineHealth Institute for ResearchFollow
Yang Zhang, Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
Andrew P. White, Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
William A. Pastor, Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Maria Chondronikola, Department of Nutrition and Radiology, University of California, Davis, Davis, CA, USA.
Labros Sidossis, Department of Kinesiology and Health, School of Arts and Sciences, Rutgers University, New Brunswick, NJ, USA.
Samuel Klein, Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO, USA.
Anastasia Kralli, Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Document Type

Article

Publication Date

11-7-2022

Institution/Department

MaineHealth Institute for Research

Journal Title

Nature metabolism

MeSH Headings

Creatine, Alkaline Phosphatase, Thermogenesis, Energy Metabolism, Adipocytes, Receptors, Adrenergic, Norepinephrine, Creatine Kinase, Estrogens

Abstract

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis. 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 α-adrenergic receptor (AR) and β-AR signalling induces the expression of thermogenic genes of the futile creatine cycle, 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 α-AR subtype (ADRA1A) and Gα 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 and Gα 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-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

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