Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Cell. 2021 Jun 24;184(13):3502-3518.e33. doi: 10.1016/j.cell.2021.04.037. | PubMed

Olivia Sveidahl Johansen¹, Tao Ma², Jakob Bondo Hansen², Lasse Kruse Markussen³, Renate Schreiber⁴, Laia Reverte-Salisa⁵, Hua Dong⁶, Dan Ploug Christensen⁷, Wenfei Sun⁶, Thorsten Gnad⁵, Iuliia Karavaeva⁸, Thomas Svava Nielsen⁸, Sander Kooijman⁹, Cheryl Cero¹⁰, Oksana Dmytriyeva⁸, Yachen Shen¹¹, Maria Razzoli¹⁰, Shannon L O'Brien¹², Eline N Kuipers⁹, Carsten Haagen Nielsen¹³, William Orchard¹⁴, Nienke Willemsen⁸, Naja Zenius Jespersen¹⁵, Morten Lundh⁸, Elahu Gosney Sustarsic⁸, Cecilie Mørch Hallgren⁸, Mikkel Frost⁸, Seth McGonigle¹⁰, Marie Sophie Isidor⁸, Christa Broholm⁸, Oluf Pedersen⁸, Jacob Bo Hansen¹⁶, Niels Grarup⁸, Torben Hansen⁸, Andreas Kjær¹³, James G Granneman¹⁷, M Madan Babu¹⁸, Davide Calebiro¹², Søren Nielsen¹⁹, Mikael Rydén²⁰, Raymond Soccio¹¹, Patrick C N Rensen⁹, Jonas Thue Treebak⁸, Thue Walter Schwartz², Brice Emanuelli⁸, Alessandro Bartolomucci¹⁰, Alexander Pfeifer⁵, Rudolf Zechner²¹, Camilla Scheele⁸, Susanne Mandrup³, Zachary Gerhart-Hines²²

1. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Embark Biotech ApS, Copenhagen, Denmark; Center for Adipocyte Signaling, University of Southern Denmark, Odense, Denmark.
2. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Embark Biotech ApS, Copenhagen, Denmark.
3. Center for Adipocyte Signaling, University of Southern Denmark, Odense, Denmark; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
4. Institute of Molecular Biosciences, University of Graz, Graz, Austria.
5. Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany.
6. Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland.
7. Embark Biotech ApS, Copenhagen, Denmark.
8. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
9. Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
10. Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
11. Institute for Diabetes, Obesity, and Metabolism, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
12. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham, UK; Institute of Pharmacology and Toxicology and Bio-Imaging Center, University of Würzburg, Würzburg, Germany.
13. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, Copenhagen, Denmark.
14. MRC Laboratory of Molecular Biology, Cambridge, UK.
15. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
16. Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
17. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
18. MRC Laboratory of Molecular Biology, Cambridge, UK; Department of Structural Biology and Center for Data Driven Discovery, St. Jude Children's Research Hospital, Memphis, TN, USA.
19. Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
20. Department of Medicine (H7), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
21. Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria.
22. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Embark Biotech ApS, Copenhagen, Denmark; Center for Adipocyte Signaling, University of Southern Denmark, Odense, Denmark. Electronic address: zpg@sund.ku.dk.

Abstract

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

Presented By Olivia Sveidahl Johansen | ORCID iD