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Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

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  1. Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men

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  2. Proteomics-Based Comparative Mapping of the Secretomes of Human Brown and White Adipocytes Reveals EPDR1 as a Novel Batokine

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Vis graf over relationer

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β 3-adrenergic receptor (β 3-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 β 3-AR. Oral administration of the β 3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β 1-AR and β 2-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 β 2-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β 2-AR signaling in humans (ClinicalTrials.gov NCT02811289). Blondin et al. reveal that therapeutic doses of the β 3-AR agonist mirabegron do not stimulate human BAT. Biopsies from participants show that the lack of effect may be explained by the absence of β 3-AR and primary expression of β 2-AR. In human brown adipocytes, β 2-AR agonism increases respiration, whereas pharmacological and genetic inhibition of β 2-AR decrease respiration.

OriginalsprogEngelsk
TidsskriftCell Metabolism
Vol/bind32
Udgave nummer2
Sider (fra-til)287-300.e7
ISSN1550-4131
DOI
StatusUdgivet - 4 aug. 2020

Bibliografisk note

Copyright © 2020 Elsevier Inc. All rights reserved.

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