Beta2-adrenergic stimulation by fenoterol increases energy expenditure without activating human brown adipose tissue.

Brown adipose tissue (BAT) can increase whole-body energy expenditure (EE) and is associated with metabolic health, making it a promising pharmacologic target. In rodents, BAT activation by norepinephrine is mainly mediated by beta3-adrenergic receptor (AR) stimulation. However, recent evidence suggests that, in humans, the beta2-AR may be more important for the activation of BAT than the beta3-AR. We investigated in 12 healthy volunteers whether the specific beta2-AR agonist fenoterol activates human BAT comparable to the natural stimulus, cold exposure. Both interventions robustly increased EE, but only cold exposure activated BAT as assessed by FDG uptake. RNA sequencing (RNA-seq) analysis of human BAT revealed that the expression of beta3-AR, but not of beta2-AR, correlates with the expression of UCP1, the hallmark of thermogenic brown adipocytes. Our data indicate that the beta2-AR is not the main activating receptor of human BAT and suggest that beta2-AR agonism increases EE in tissues other than BAT.