Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity

Thorsten Gnad; Gemma Navarro; Minna Lahesmaa; Laia Reverte-Salisa; Francesca Copperi; Arnau Cordomi; Jennifer Naumann; Aileen Hochhäuser; Saskia Haufs-Brusberg; Daniela Wenzel; Frank Suhr; Naja Zenius Jespersen; Camilla Scheele; Volodymyr Tsvilovskyy; Christian Brinkmann; Joern Rittweger; Christian Dani; Mathias Kranz; Winnie Deuther-Conrad; Holger K Eltzschig; Tarja Niemi; Markku Taittonen; Peter Brust; Pirjo Nuutila; Leonardo Pardo; Bernd K Fleischmann; Matthias Blüher; Rafael Franco; Wilhelm Bloch; Kirsi A Virtanen; Alexander Pfeifer

doi:10.1016/j.cmet.2020.06.006

Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity

Cell Metab. 2020 Jul 7;32(1):56-70.e7. doi: 10.1016/j.cmet.2020.06.006. Epub 2020 Jun 25.

Authors

Thorsten Gnad¹, Gemma Navarro², Minna Lahesmaa³, Laia Reverte-Salisa¹, Francesca Copperi¹, Arnau Cordomi⁴, Jennifer Naumann¹, Aileen Hochhäuser¹, Saskia Haufs-Brusberg¹, Daniela Wenzel⁵, Frank Suhr⁶, Naja Zenius Jespersen⁷, Camilla Scheele⁸, Volodymyr Tsvilovskyy⁹, Christian Brinkmann¹⁰, Joern Rittweger¹¹, Christian Dani¹², Mathias Kranz¹³, Winnie Deuther-Conrad¹³, Holger K Eltzschig¹⁴, Tarja Niemi¹⁵, Markku Taittonen¹⁶, Peter Brust¹³, Pirjo Nuutila³, Leonardo Pardo⁴, Bernd K Fleischmann¹⁷, Matthias Blüher¹⁸, Rafael Franco², Wilhelm Bloch¹⁹, Kirsi A Virtanen²⁰, Alexander Pfeifer²¹

Affiliations

¹ Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany.
² Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, Madrid, Spain.
³ Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland.
⁴ Laboratory of Computational Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain.
⁵ Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, 53105 Bonn, Germany; Department of Systems Physiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany.
⁶ Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany; Exercise Physiology Research Group, Biomedical Sciences Group, KU Leuven, Leuven, Belgium.
⁷ Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁸ Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹ Institute of Pharmacology, Ruprecht-Karls University, Heidelberg, Germany.
¹⁰ Department of Preventive and Rehabilitative Sport Medicine, German Sport University Cologne, Cologne, Germany.
¹¹ Department of Muscle and Bone Metabolism, German Aerospace Center (DLR), Institute of Aerospace Medicine, Cologne, Germany.
¹² Université Côte d'Azur, CNRS, Inserm, iBV, Faculté de Médecine, 06107 Nice Cedex 2, France.
¹³ Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Leipzig, Germany.
¹⁴ Department of Anesthesiology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
¹⁵ Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland.
¹⁶ Department of Anesthesiology, Turku University Hospital, Turku, Finland.
¹⁷ Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
¹⁸ Department of Medicine, University of Leipzig, Leipzig, Germany.
¹⁹ Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany.
²⁰ Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland; Institute of Public Health and Clinical Nutrition, University of Eastern Finland (UEF), Kuopio, Finland.
²¹ Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany. Electronic address: [email protected].

Abstract

The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas pharmacological A2B activation counteracted these processes. Adipose tissue-specific ablation of A2B exacerbated age-related processes and reduced BAT EE, whereas A2B stimulation ameliorated obesity. In humans, A2B expression correlated with EE in SKM, BAT activity, and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment increased EE from human adipocytes, myocytes, and muscle explants. Mechanistically, A2B forms heterodimers required for adenosine signaling. Overall, adenosine/A2B signaling links muscle and BAT and has both anti-aging and anti-obesity potential.

Keywords: GPCR; adenosine; adenosine receptor A2B; aging; brown adipose tissue; browning; energy metabolism; muscle; obesity; sarcopenia.

Publication types

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

MeSH terms

Adolescent
Adult
Aging / metabolism*
Animals
Cells, Cultured
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Middle Aged
Obesity / metabolism*
Receptor, Adenosine A2B / deficiency
Receptor, Adenosine A2B / metabolism*
Signal Transduction
Young Adult

Substances

Receptor, Adenosine A2B

Abstract

Publication types

MeSH terms

Substances

Grants and funding