Targeting adrenergic receptors to activate brown fat without cardiovascular effects

Background: We previously revealed that oral administration of the β3-adrenergic receptor (AR) agonist mirabegron only elicited small increases in brown adipose tissue (BAT) thermogenesis when ingested at the maximal allowable dose (200 mg). This led to off-target binding of the β1- and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. We hypothesize that a balanced activation between β1- and β3-AR is key to stimulating metabolic benefits without cardiovascular side effects. Method: We performed a randomized crossover trial in 8 lean men over two study days. The intervention consisted of oral administration of mirabegron (200 mg) with or without the cardio selective β1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT scans were performed sequentially starting at 210 min after oral administration of mirabegron ± bisoprolol. Results: Compared to baselines measures, mirabegron alone or with bisoprolol increased energy expenditure (EE) by 27% (+18.2±6.7 kcal/h) and 11% (7.4±8.1 kcal/h), respectively. However, EE was significantly lower when mirabegron was co-ingested with bisoprolol (P=0.0402) Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.631±0.267 vs 1.695±1.097 min-1 from the [11C]-acetate, P=0.0421), but was not different from mirabegron with bisoprolol (1.273±0.651 min-1). Metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron combined with bisoprolol (24±10 vs 16±8 nmol/g/min, P=0.0284). Mirabegron also increased systolic blood pressure (+5±5 vs -6±10 mmHg, P=0.0252) and heart rate (6±7 vs -5±6 beats·min-1, P=0.0081) relative to baseline levels, which was prevented with bisoprolol. The glycerolipid-fatty acid cycling was not different between mirabegron without or with bisoprolol treatment (total cycling: 118.1±346.9 vs 168.5±439.5 μmol·min-1, P=0.8023). Conclusion: The administration of a β1-AR antagonist decreases the adverse cardiovascular effects of mirabegron. However, at the provided dose, it also restricts the stimulating effects of mirabegron on the thermogenesis. Public foundation grants This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.