The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans
Brian S. Finlin, … , Esther E. Dupont-Versteegden, Philip A. Kern
Brian S. Finlin, … , Esther E. Dupont-Versteegden, Philip A. Kern
Published January 21, 2020
Citation Information: J Clin Invest. 2020;130(5):2319-2331. https://doi.org/10.1172/JCI134892.
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Clinical Research and Public Health Metabolism

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

Abstract

BACKGROUND Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-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 β3-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 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 showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (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 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 Clinical and Translational science Awards (CTSA) grant UL1TR001998.

Authors

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

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Figure 7

Mirabegron treatment reduces state 4 respiration but does not increase uncoupled respiration in purified mitochondria isolated from SC WAT.

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Mirabegron treatment reduces state 4 respiration but does not increase u...
Mitochondria were purified and the bioenergetics analyzed using an Oxytherm before and after mirabegron treatment as described in Methods. This involved the sequential addition of adenosine diphosphate (ADP), oligomycin (Oligo), FFA (60 μM linoleic acid), fatty acid–free BSA, and trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP) (10 μm). (A and B) OCRs before and after treatment are shown. (C) The difference between oligomycin and BSA was calculated before and after treatment. Data indicate the mean ± SEM (n = 12). *P = 0.05, by Wilcoxon matched-pairs, signed-rank test.