TY - JOUR AU - O’Mara, Alana E. AU - Johnson, James W. AU - Linderman, Joyce D. AU - Brychta, Robert J. AU - McGehee, Suzanne AU - Fletcher, Laura A. AU - Fink, Yael A. AU - Kapuria, Devika AU - Cassimatis, Thomas M. AU - Kelsey, Nathan AU - Cero, Cheryl AU - Sater, Zahraa Abdul AU - Piccinini, Francesca AU - Baskin, Alison S. AU - Leitner, Brooks P. AU - Cai, Hongyi AU - Millo, Corina M. AU - Dieckmann, William AU - Walter, Mary AU - Javitt, Norman B. AU - Rotman, Yaron AU - Walter, Peter J. AU - Ader, Marilyn AU - Bergman, Richard N. AU - Herscovitch, Peter AU - Chen, Kong Y. AU - Cypess, Aaron M. T1 - Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity PY - 2020/05/01/ AB - BACKGROUND Mirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODS We treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTS Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSION These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATION Clinicaltrials.gov NCT03049462.FUNDING This work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014). JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI131126 VL - 130 IS - 5 UR - https://doi.org/10.1172/JCI131126 SP - 2209 EP - 2219 PB - The American Society for Clinical Investigation ER -