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Although therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR- γ ) agonists rosiglitazone and pioglitazone against Cushing's disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR- γ  agonist, MEKT1, on  Pomc  expression/ACTH secretion using murine corticotroph-derived AtT20 cells and compared its effects with those of rosiglitazone and pioglitazone. AtT20 cells were treated with either 1 nM~10  μ M MEKT1, rosiglitazone, or pioglitazone for 24 hours. Thereafter, their effects on proopiomelanocortin gene  (Pomc)  mRNA expression were studied by qPCR and the  Pomc  promoter (−703/+58) activity was demonstrated by luciferase assay.  Pomc  mRNA expression and promoter activity were significantly inhibited by MEKT1 at 10  μ M compared to rosiglitazone and pioglitazone. SiRNA-mediated PPAR- γ  knockdown significantly abrogated MEKT1-mediated  Pomc  mRNA suppression. ACTH secretion from AtT20 cells was also significantly inhibited by MEKT1. Deletion/point mutant analyses of  Pomc  promoter indicated that the MEKT1-mediated suppression was mediated via NurRE, TpitRE, and NBRE at −404/−383, −316/−309, and −69/−63, respectively. Moreover, MEKT1 significantly suppressed  Nur77 ,  Nurr1 , and  Tpit  mRNA expression. MEKT1 also was demonstrated to inhibit the protein-DNA interaction of Nur77/Nurr1-NurRE, Tpit-TpitRE, and Nur77-NBRE by ChIP assay. Taken together, it is suggested that MEKT1 could be a novel therapeutic medication for Cushing's disease.

Inhibitory Effects of a Novel PPAR-γAgonist MEKT1 onPomcExpression/ACTH Secretion in AtT20 Cells