title: Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors.
abstract: Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors. Because BAT therapies based on cold exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A2A receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Gnad
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany [2] Research Training Group 1873, University of Bonn, 53127 Bonn, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Scheibler
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Ivar
authors.initials: I
authors.lastname: von Kügelgen
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Scheele
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Kilić
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Glöde
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Hoffmann
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany [2] Research Training Group 1873, University of Bonn, 53127 Bonn, Germany.
authors.forename: Laia
authors.initials: L
authors.lastname: Reverte-Salisa
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Horn
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Samet
authors.initials: S
authors.lastname: Mutlu
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: El-Tayeb
authors.affiliation: Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, 04318 Leipzig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Kranz
authors.affiliation: Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, 04318 Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, 04318 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Lidell
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Betz
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Enerbäck
authors.affiliation: Department for Molecular Cardiology, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schrader
authors.affiliation: Medicity Research Laboratory, University of Turku, 20520 Turku, Finland.
authors.forename: Gennady G
authors.initials: GG
authors.lastname: Yegutkin
authors.affiliation: 1] Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn, Germany [2] Pharma Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany [2] Pharma Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D017667:Adipocytes / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004032:Diet; D006801:Humans; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D010627:Phenethylamines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine