The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans

BACKGROUND. Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains beta 3-adrenergic receptors (beta 3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the beta 3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis. METHODS. Before and after beta 3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle. RESULTS. The clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and beta cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in beta cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPAR. coactivator 1 alpha (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001). CONCLUSION. Mirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since beta cells and skeletal muscle do not express beta 3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves beta cell function.