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. 2020 Aug 4;32(2):287-300.e7.
doi: 10.1016/j.cmet.2020.07.005.

Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

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
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Free article

Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Denis P Blondin et al. Cell Metab. .
Free article

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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Conflict of interest statement

Declaration of Interests A.C.C. received funding from Eli Lilly, HLS Therapeutics, Janssen Inc., Novartis Pharmaceuticals Canada Inc., and Novo Nordisk Canada Inc. as a consultant. None of these commercial relationships are relevant to the present study. The remaining authors have declared that no conflict of interest exists related to the content of this manuscript.

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