Novel PPARγ partial agonists with weak activity and no cytotoxicity; identified by a simple PPARγ ligand screening system

Peroxisome proliferator-activated receptors (PPARs) are the transcriptional factor that regulate glucose and lipid homeostasis and widely well-known as molecular targets for improvement of metabolic disorder. Because major transcriptional activity of PPARs depends on their proper ligands, the studies for PPAR ligands have been continuously developed. We previously reported the simple enzyme-linked immunosorbent assay (ELISA) systems to screen PPAR ligands and a chemical library including flavonoid derivatives have applied to these systems. In this study, we introduce two compounds (KU16476 and KU28843) identified as PPAR gamma partial agonists by a screening ELISA for PPAR gamma ligand. KU16476 and KU28843 significantly increased binding between PPAR gamma and SRC-1 in a simple ELISA system. Co-activator recruiting-induced abilities of two compounds were less than that of indomethacin, a well-known PPAR gamma agonist. To determine whether these compounds would be PPAR gamma partial agonists, each candidate with indomethacin were applied to a simple ELISA based on binding between PPAR gamma and SRC-1. Cotreatment with indomethacin significantly increased binding between PPAR gamma and SRC-1 than treatment of indomethacin or candidate alone. Two compounds had no considerable cytotoxicities, induced partial adipogenesis, and accumulated lipid droplets in 3T3-L1 fibroblast. Also, these two compounds enhanced expression of PPAR gamma-mediated genes such as aP2 and UCP-2. By docking study, we confirmed that two compounds bound well to the active site of PPAR gamma with hydrophobic interactions. We suggest that two compounds identified by a simple ELISA system can be PPAR gamma partial agonists. These PPAR gamma partial agonists and these studies to find out novel PPAR gamma agonists may contribute to drug development against metabolic disorders.