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

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.