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

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

doi:10.1172/JCI134892

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

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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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.

Original language	English
Pages (from-to)	2319-2331
Number of pages	13
Journal	Journal of Clinical Investigation
Volume	130
Issue number	5
DOIs	https://doi.org/10.1172/JCI134892
State	Published - May 1 2020

Bibliographical note

Funding Information:
We wish to thank the staff of the University of Kentucky Clinical Research Unit for assistance with this study and Dorothy Ross for coordinating the recruitment of the participants. We acknowl- edge Charlotte Peterson for providing the primary myoblasts and Rachel Davidowitz for her help with the graphical abstract. This study was funded by NIH grants DK112282, P30GM127211, and DK 71349 and by CTSA, NIH grant UL1TR001998.

Funding Information:
FUNDING. NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.

Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.

ASJC Scopus subject areas

Medicine (all)

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10.1172/JCI134892

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Finlin, B. S., Memetimin, H., Zhu, B., Confides, A. L., Vekaria, H. J., El Khouli, R. H., Johnson, Z. R., Westgate, P. M., Chen, J., Morris, A. J., Sullivan, P. G., Dupont-Versteegden, E. E., & Kern, P. A. (2020). The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. Journal of Clinical Investigation, 130(5), 2319-2331. https://doi.org/10.1172/JCI134892

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title = "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.",

author = "Finlin, {Brian S.} and Hasiyet Memetimin and Beibei Zhu and Confides, {Amy L.} and Vekaria, {Hemendra J.} and {El Khouli}, {Riham H.} and Johnson, {Zachary R.} and Westgate, {Philip M.} and Jianzhong Chen and Morris, {Andrew J.} and Sullivan, {Patrick G.} and Dupont-Versteegden, {Esther E.} and Kern, {Philip A.}",

note = "Funding Information: We wish to thank the staff of the University of Kentucky Clinical Research Unit for assistance with this study and Dorothy Ross for coordinating the recruitment of the participants. We acknowl- edge Charlotte Peterson for providing the primary myoblasts and Rachel Davidowitz for her help with the graphical abstract. This study was funded by NIH grants DK112282, P30GM127211, and DK 71349 and by CTSA, NIH grant UL1TR001998. Funding Information: FUNDING. NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998. Publisher Copyright: Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

year = "2020",

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doi = "10.1172/JCI134892",

language = "English",

volume = "130",

pages = "2319--2331",

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Finlin, BS, Memetimin, H, Zhu, B, Confides, AL, Vekaria, HJ, El Khouli, RH, Johnson, ZR, Westgate, PM, Chen, J, Morris, AJ, Sullivan, PG , Dupont-Versteegden, EE & Kern, PA 2020, 'The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans', Journal of Clinical Investigation, vol. 130, no. 5, pp. 2319-2331. https://doi.org/10.1172/JCI134892

TY - JOUR

T1 - The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans

AU - Finlin, Brian S.

AU - Memetimin, Hasiyet

AU - Zhu, Beibei

AU - Confides, Amy L.

AU - Vekaria, Hemendra J.

AU - El Khouli, Riham H.

AU - Johnson, Zachary R.

AU - Westgate, Philip M.

AU - Chen, Jianzhong

AU - Morris, Andrew J.

AU - Sullivan, Patrick G.

AU - Dupont-Versteegden, Esther E.

AU - Kern, Philip A.

N1 - Funding Information: We wish to thank the staff of the University of Kentucky Clinical Research Unit for assistance with this study and Dorothy Ross for coordinating the recruitment of the participants. We acknowl- edge Charlotte Peterson for providing the primary myoblasts and Rachel Davidowitz for her help with the graphical abstract. This study was funded by NIH grants DK112282, P30GM127211, and DK 71349 and by CTSA, NIH grant UL1TR001998. Funding Information: FUNDING. NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998. Publisher Copyright: Copyright: © 2020, American Society for Clinical Investigation.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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.

AB - 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.

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

Abstract

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