1. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity
- Author
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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., and Cypess, Aaron M.
- Subjects
United States. National Institute of Diabetes and Digestive and Kidney Diseases ,Obesity -- Care and treatment ,Mirabegron -- Physiological aspects ,Glucose -- Physiological aspects ,Blood glucose tests -- Physiological aspects ,Glucose metabolism -- Physiological aspects ,Bile acids -- Physiological aspects ,Adipose tissue -- Physiological aspects ,Insulin -- Physiological aspects ,Blood cholesterol -- Physiological aspects ,Metabolites -- Physiological aspects ,Glucose tolerance test -- Physiological aspects ,Diabetes therapy -- Physiological aspects ,Body weight -- Physiological aspects ,Cholesterol ,Hormones ,Biological markers ,Positron emission tomography ,Diseases ,Kidney diseases ,Research funding ,Urinary incontinence ,Health care industry - Abstract
BACKGROUND. Mirabegron is a [beta]3-adrenergic receptor ([beta]3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that [beta]3-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 [+ or -] 1.1 years of age, BMI of 25.4 [+ or -] 1.2 kg/[m.sup.2]) 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 [[sup.18]F]-2-fluoro -D-2-deoxy-D-glucose ([sup.18]F-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 [beta]3-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)., Introduction The rising rates of obesity are a global health epidemic. In the US alone, by 2030 it is predicted that 86% of adults will be overweight or obese (1). [...]
- Published
- 2020
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