Human BAT Thermogenesis is Stimulated by the β <sub>2</sub>-Adrenergic Receptor

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 the β3-AR but rather driven primarily through the β2-AR. Oral administration of the β3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. Such a dose led to off-target binding to the β1-AR and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. In vitro pharmacological stimulation as well as pharmacological and genetic inhibition of the β2-AR in human primary brown adipocytes all confirmed that this β-AR subtype is essential to simulate BAT lipolysis and thermogenesis in humans (ClinicalTrials.gov NCT02811289).