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.gov NCT02811289).

刺激人类棕色脂肪组织 (BAT) 产热已成为改善代谢健康的有吸引力的目标。针对 β _{3 -}肾上腺素能受体 (β ₃ -AR) 的药理学刺激，该肾上腺素能受体被认为介导 BAT 产热，在人类临床试验中历来表现不佳。在这里我们报告说，与啮齿动物相比，人类 BAT 产热不是由 β ₃ -AR的刺激介导的。当以最大允许剂量摄入时，β ₃ -AR 激动剂米拉贝隆的口服给药仅引起 BAT 产热增加。这导致与 β ₁ -AR 和 β _{2 的}脱靶结合-AR，从而分别增加心血管反应和白色脂肪组织脂肪分解。ADRB2在人类棕色脂肪细胞中与UCP1共表达。人棕色脂肪细胞中β ₂ -AR 的药理学刺激和抑制以及ADRB1、ADRB2或ADRB3 的敲低都证实了 BAT 脂肪分解和产热是通过人类中的β ₂ -AR 信号传导发生的(ClinicalTrials.gov NCT02811289)。