期刊
CELL METABOLISM
卷 32, 期 2, 页码 287-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2020.07.005
关键词
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资金
- Canadian Institutes of Health Research (CIHR) [299962, PJT 159758, PJT 148550]
- Dutch Diabetes Research Foundation Fellowship [2015.81.1808]
- CIHR postdoctoral fellowship
- Canada Research Chair in Molecular Imaging of Diabetes
- Fonds de Recherche du Quebec -Sante
- Danish Diabetes Academy - Novo Nordisk Foundation [PD007-18]
- Novo Nordisk Foundation [NNF18CC0034900]
- TrygFonden [101390, 20045]
- Danish National Research Foundation [DNRF55]
- DD2, the Danish Center for Strategic Research in Type 2 Diabetes (Danish Council for Strategic Research) [09-067009, 09-075724]
- Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation
- Netherlands CardioVascular Research Initiative: Dutch Federation of University Medical Centers
- Netherlands CardioVascular Research Initiative: Netherlands Organization for Health Research and Development
- Netherlands CardioVascular Research Initiative: Royal Netherlands Academy of Sciences
- Netherlands Heart Foundation [2009T038]
Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the beta(3)-adrenergic receptor (beta(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 beta(3)-AR. Oral administration of the beta(3)-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to beta(1)-AR and beta(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 beta(2)-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through beta(2)-AR signaling in humans (ClinicalTrials.gov NCT02811289).
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