2. Academic Validation
  3. Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

  • Cell Metab. 2020 Aug 4;32(2):287-300.e7. doi: 10.1016/j.cmet.2020.07.005.
Denis P Blondin 1,  Soren Nielsen 2,  Eline N Kuipers 3,  Mai C Severinsen 2,  Verena H Jensen 2,  Stéphanie Miard 4,  Naja Z Jespersen 2,  Sander Kooijman 3,  Mariëtte R Boon 3,  Mélanie Fortin 5,  Serge Phoenix 6,  Frédérique Frisch 5,  Brigitte Guérin 7,  Éric E Turcotte 7,  François Haman 8,  Denis Richard 4,  Frédéric Picard 4,  Patrick C N Rensen 3,  Camilla Scheele 9,  André C Carpentier 10
Affiliations

Affiliations

  • 1 Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Department of Physiology-Pharmacology, Université de Sherbrooke, Sherbrooke, QC, Canada.
  • 2 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Righospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
  • 3 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.
  • 4 Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada.
  • 5 Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
  • 6 Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Department of Nuclear Medicine and Radiobiology, Centre d'Imagerie Moléculaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.
  • 7 Department of Nuclear Medicine and Radiobiology, Centre d'Imagerie Moléculaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.
  • 8 Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada.
  • 9 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Righospitalet, University Hospital of Copenhagen, Copenhagen, Denmark. Electronic address: [email protected].
  • 10 Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada. Electronic address: [email protected].
PMID: 32755608 DOI: 10.1016/j.cmet.2020.07.005
Abstract

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β3-adrenergic receptor (β3-AR), the Adrenergic Receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β3-AR. Oral administration of the β3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β1-AR and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the β2-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β2-AR signaling in humans (ClinicalTrials.govNCT02811289).

Keywords

brown adipocyte; brown adipose tissue; cold-induced thermogenesis; energy metabolism; mirabegron; positron emission tomography; β(2)-adrenergic receptor.

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