Beneficial metabolic effects of mirabegron in vitro and in high-fat diet-induced obese mice

Mirabegron, a β3-adrenergic receptor agonist, has been shown to stimulate activity of brown fat and increase resting metabolic rate in humans. However, it is unknown if mirabegron can reduce body weight and improve metabolic health. We investigated the anti-obesity effects of mirabegron using both in vitro and in vivo models. Mouse brown preadipocytes and 3T3-L1 cells were treated with different concentrations of mirabegron (0.03-3 µg/ml), and expression of brown fat-related genes was measured by quantitative real-time PCR. Furthermore, male C57BL/6J mice were fed a high-fat diet for 10 weeks, and mirabegron (2 mg/kg body weight) or a vehicle control was delivered to interscapular brown adipose tissue (iBAT) using ALZET® osmotic pumps from week 7 to 10. Metabolic parameters and tissues were analyzed. In both mouse brown preadipocytes and 3T3-L1 cells, mirabegron stimulated uncoupling protein 1 (UCP1) expression. In animal studies, mirabegron-treated mice had lower body weight and adiposity. Lipid droplets in iBAT of mirabegron-treated mice were fewer and smaller in size compared to those from vehicle-treated mice. Haemotoxylin and Eosin staining and immunohistochemistry indicated that mirabegron increased the abundance of beige cells in inguinal white adipose tissue (iWAT). Compared to vehicle-treated mice, mirabegron-treated mice had higher gene expression of UCP1 (14-fold) and cell death-inducing DNA fragmentation factor alpha-like effector A (4-fold) in iWAT. Furthermore, mirabegron-treated mice had improved glucose tolerance and insulin sensitivity. Taken together, mirabegron enhances UCP1 expression and promotes browning of iWAT which are accompanied by improved glucose tolerance and insulin sensitivity and prevention from high-fat diet-induced obesity.