Abstract
Treatment of subjects who are obese/insulin resistant with the β3AR agonist mirabegron resulted in increased beige adipose tissue, without a change in brown adipose tissue (BAT), along with an improvement in glucose tolerance, HbA1c, and an increase in type 1 fibers in skeletal muscle. Pioglitazone has been demonstrated to increase beiging, and it has been demonstrated that combination of a thiazolidinedione with a β3AR agonist further increased beige adipocyte markers in vitro. The goal of this study was to determine whether combination therapy with pioglitazone and mirabegron would further increase beiging, BAT volume or activity, or skeletal muscle fiber type switching, and improve glucose homeostasis more than each drug separately. We randomized obese and insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination treatment groups. Adipose and muscle tissue biopsies and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mitochondrial bioenergetics were determined in purified mitochondria from adipose tissue. Although mirabegron and pioglitazone treatment significantly induced SC WAT beiging separately, the combination of the two drugs resulted in less beiging than mirabegron treatment alone, and did not increase mitochondrial uncoupling. Furthermore, neither pioglitazone nor combination therapy increased BAT or fiber-type switching to type 1 fibers. Although each drug improved glucose homeostasis, the effect of the combination was not significantly additive. Analysis of mRNA expression revealed that pioglitazone or combination treatment induced the expression of p107, which promotes white versus brown adipose gene expression, suggesting a mechanism for inhibition of mirabegron-induced beiging by pioglitazone. These results suggest that pioglitazone inhibits mirabegron-induced beiging and does not augment other beneficial effects of mirabegron treatment. Disclosure P.A. Kern: None. H. Memetimin: None. B. Zhu: None. A.L. Confides: None. Z. Johnson: None. H.J. Vekaria: None. P. Westgate: None. P.G. Sullivan: None. E.E. Dupont-Versteegden: None. B. Finlin: None. Funding National Institutes of Health (DK112282)
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