Physiological Responses to Daily Use of Beta-Three Adrenergic Receptor Agonist, Mirabegron

Background: Brown Adipose Tissue (BAT) in adult humans has become increasingly recognized to contribute to energy consumption and modulate metabolism. To date, BAT stimulation has predominately relied on cold exposure. However, long-term cold exposure is impractical as a treatment option for obesity and diabetes. Thus, we investigated if a chronic pharmacotherapeutic approach could stimulate BAT and contribute to metabolic health.

Methods: In an ongoing study, 6 healthy female volunteers received 4 weeks of daily mirabegron (Myrbetriq, Astellas Pharma) 100 mg, a β3 adrenergic receptor (AR) agonist. Acute responses were determined by comparing effects before and then five hours after dosing. Chronic changes were assessed after 4 weeks of treatment. The primary endpoint was the change in BAT metabolic activity measured by ¹⁸F-FDG PET/CT. Secondary endpoints included resting energy expenditure (REE), insulin and glucose sensitivity, liver steatosis, and cardiovascular stimulation.

Results: Acute effects of mirabegron included consistent increases in rate pressure product (RPP), REE, and serum non-esterified fatty acids (NEFA) (p<0.05, p=0.06, p<.05). After 4 weeks, there was a wide range of changes in BAT volume (41 ± 223 mL, p=0.86). Body weight was unchanged (0.3 ± 0.62 kg). Several physiological responses after chronic treatment were blunted, including smaller mirabegron-induced increases in RPP, NEFA, and REE. Yet, there were significant increases in sleeping EE (72 ± 23 kcal/d, p=0.03), insulin sensitivity (1.5 ± .6 (mU/L*min, p=0.05), and liver steatosis (30 ± 10 dB/m, p = 0.04) after 4 weeks.

Conclusions: Acute treatment with mirabegron in women successfully activates BAT thermogenesis. Preliminary data show chronic treatment resulted in a blunting of several responses, consistent with physiological attenuation of β-AR signaling. The increases in sleeping EE and improved insulin sensitivity suggest chronic mirabegron treatment may help alleviate metabolic disease.