The effects of the β1‐adrenergic receptor antagonist bisoprolol administration on mirabegron‐stimulated human brown adipose tissue thermogenesis

Abstract

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 β 3‐adrenergic receptor (β 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 β 1‐AR antagonist could suppress these unwanted effects and increase the stimulation of the β 3‐AR and β 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 β 1‐AR antagonist bisoprolol (10 mg). Dynamic [11 C]‐acetate and 2‐deoxy‐2‐[18 F]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 [18 F]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.