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

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

doi:10.1172/jci.insight.143650

Abstract

BACKGROUNDBeige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages.METHODSWe measured BAT by PET CT scans, measured 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.RESULTSTreatment 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 was 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 3 treatments also had different effects on muscle fiber type switching and capillary density.CONCLUSIONThe addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese insulin-resistant research participants.TRIAL REGISTRATIONClinicalTrials.gov NCT02919176.FUNDINGNIH DK112282 and P20GM103527 and Clinical and Translational Science Awards grant UL1TR001998.

Highlights

White adipose tissue (WAT) functions to store and release lipid and serves as an endocrine gland, secreting adipokines such as adiponectin and leptin to promote metabolic homeostasis [1]
We evaluated the bioenergetics profile of mitochondria purified from SC WAT as previously described [16] but did not find changes in free fatty acid–induced uncoupled respiration caused by pioglitazone or combination treatment
Despite the fact that both drugs, when used alone, stimulated beiging, the results of this study and our previously published observations indicate that the addition of pioglitazone to mirabegron treatment resulted in less beiging of adipose than by mirabegron treatment alone

Summary

Introduction

White adipose tissue (WAT) functions to store and release lipid and serves as an endocrine gland, secreting adipokines such as adiponectin and leptin to promote metabolic homeostasis [1]. In contrast to WAT, brown adipose tissue (BAT) consumes glucose and lipids to generate heat by uncoupled respiration mediated by uncoupling protein 1 (UCP1) [6], leading to improved glucose and lipid homeostasis. Our recent studies in humans found that mirabegron increased beiging, and this was accompanied by improved glucose homeostasis [15, 16]. Beige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. We evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone.

Methods

Results

Conclusion