The effects of the ₁-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis

Aim: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a beta(3)-adrenergic receptor (beta(3)-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a beta(1)-AR antagonist could suppress these unwanted effects and increase the stimulation of the beta(3)-AR and beta(2)-AR in BAT. Methods: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the beta(1)-AR antagonist bisoprolol (10 mg). Dynamic [C-11]-acetate and 2-deoxy-2-[F-18]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron +/- bisoprolol. Results: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 +/- 0.46 vs. 1.79 +/- 0.91 min(-1), p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [F-18]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 +/- 10 vs. 16 +/- 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate. Conclusion: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.