Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity

• Published in: The Journal of clinical investigation 2020-05, Vol.130 (5), p.2209-2219
• Main Authors: O'Mara, Alana E, Johnson, James W, Linderman, Joyce D, Brychta, Robert J, McGehee, Suzanne, Fletcher, Laura A, Fink, Yael A, Kapuria, Devika, Cassimatis, Thomas M, Kelsey, Nathan, Cero, Cheryl, Sater, Zahraa Abdul, Piccinini, Francesca, Baskin, Alison S, Leitner, Brooks P, Cai, Hongyi, Millo, Corina M, Dieckmann, William, Walter, Mary, Javitt, Norman B, Rotman, Yaron, Walter, Peter J, Ader, Marilyn, Bergman, Richard N, Herscovitch, Peter, Chen, Kong Y, Cypess, Aaron M
• Format: Article
• Language: English
• Subjects: Acetanilides - administration & dosage; Acetanilides - adverse effects; Adipocytes; Adiponectin; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - diagnostic imaging; Adipose Tissue, Brown - metabolism; Adolescent; Adrenergic receptors; Adult; Agonists; Antidiabetics; Apolipoprotein A-I - blood; Bile acids; Biological markers; Biomarkers - blood; Biomedical research; Blood cholesterol; Blood glucose tests; Body weight; Care and treatment; Cholesterol; Cholesterol, HDL - blood; Clinical Medicine; Diabetes mellitus; Diabetes therapy; Diseases; Drug dosages; Energy expenditure; Fatty acids; Female; Gene expression; Glucose; Glucose metabolism; Glucose tolerance; Glucose tolerance test; High density lipoprotein; Hormones; Humans; Insulin; Insulin Resistance; Insulin secretion; Intravenous administration; Kidney diseases; Lipolysis; Metabolic disorders; Metabolites; Mirabegron; Obesity; Physiological aspects; Plasma levels; Positron emission tomography; Positron Emission Tomography Computed Tomography; Research funding; Sensitivity analysis; Thermogenesis; Thiazoles - administration & dosage; Thiazoles - adverse effects; Urinary Bladder, Overactive - blood; Urinary Bladder, Overactive - diagnostic imaging; Urinary Bladder, Overactive - drug therapy; Urinary incontinence; Weight control
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/jci131126

BACKGROUNDMirabegron 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.METHODSWe 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.RESULTSChronic 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.CONCLUSIONThese 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 REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).