BACKGROUND. Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3 adrenergic receptors (β3-AR), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3AR 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 β3AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemistry and gene expression profiling were performed from 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. Clinical effects of mirabegron treatment included improved oral glucose tolerance (P<0.01), reduced hemoglobin A1c (P=0.01), and improved insulin sensitivity (P=0.03) and β-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 demonstrated the most improvement in β-cell function. In skeletal muscle, mirabegron reduced triglycerides, increased expression of 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 significantly improves glucose tolerance in obese, insulin resistant humans. Since β-cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β-cell function. TRIAL REGISTRATION. Clinicaltrials.gov NCT02919176.FUNDING. NIH (DK112282, P30GM127211, DK 71349, and CTSA grant UL1TR001998).
Brian S. Finlin, Hasiyet Memetimin, Beibei Zhu, Amy L. Confides, Hemendra J. Vekaria, Riham H. El Khouli, Zachary R. Johnson, Philip M. Westgate, Jianzhong Chen, Andrew J. Morris, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern