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Clinical MedicineIn-Press PreviewClinical trialsMetabolism Open Access | 10.1172/jci.insight.143650

Pioglitazone does not synergize with mirabegron to increase beige fat or further improve glucose metabolism

Brian S. Finlin,1 Hasiyet Memetimin,1 Beibei Zhu,1 Amy L. Confides,2 Hemendra J. Vekaria,3 Riham H. El Khouli,4 Zachary R. Johnson,1 Philip M. Westgate,5 Jianzhong Chen,6 Andrew J. Morris,6 Patrick G. Sullivan,3 Esther E. Dupont-Versteegden,2 and Philip A. Kern1

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Finlin, B. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Memetimin, H. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Zhu, B. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Confides, A. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Vekaria, H. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by El Khouli, R. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Johnson, Z. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Westgate, P. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Chen, J. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Morris, A. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Sullivan, P. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Dupont-Versteegden, E. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Kentucky, Lexington, United States of America

2Department of Physical Therapy, University of Kentucky, Lexington, United States of America

3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States of America

4Department of Radiology, University of Kentucky, Lexington, United States of America

5College of Public Health, University of Kentucky, Lexington, United States of America

6Division of Cardiovascular Medicine and Lexington Veterans Affairs Medical , University of Kentucky, Lexington, United States of America

Find articles by Kern, P. in: JCI | PubMed | Google Scholar |

Published February 11, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.143650.
Copyright © 2021, Finlin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 11, 2021 - Version history
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Abstract

BACKGROUND. Beige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3AR agonist mirabegron induced beige adipose tissue in obese insulin resistant subjects, and this was accompanied by improved glucose metabolism. Here, we evaluated whether pioglitazone treatment, or the combination pioglitazone and mirabegron treatment, was more effective at inducing beige adipose or BAT than mirabegron treatment alone. Both drugs were used at FDA-approved dosages.

METHODS. We measured BAT by PET CT scans, beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs.

RESULTS. Treatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments were evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The three treatments also had different effects on muscle fiber type switching and capillary density.

CONCLUSION. The addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese, insulin-resistant research participants.

TRIAL REGISTRATION. Clinicaltrials.gov NCT02919176.

FUNDING. NIH: DK112282, P20GM103527, and CTSA grant UL1TR001998.

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