PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA AND RECEPTOR-GAMMA ARE ACTIVATED BY INDOMETHACIN AND OTHER NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) and cyc looxygenase inhibitor that is frequently used as a research tool to st udy the process of adipocyte differentiation. Treatment of various pre adipocyte cell lines with micromolar concentrations of indomethacin in the presence of insulin promotes their terminal differentiation. Howe ver, the molecular basis for the adipogenic actions of indomethacin ha d remained unclear. In this report, we show that indomethacin binds an d activates peroxisome proliferator-activated receptor gamma (PPAR gam ma), a ligand-activated transcription factor known to play a pivotal r ole in adipogenesis. The concentration of indomethacin required to act ivate PPAR gamma is in good agreement with that required to induce the differentiation of C3H10T1/2 cells to adipocytes. We demonstrate that several other NSAIDs, including fenoprofen, ibuprofen, and flufenamic acid, are also PPAR gamma ligands and induce adipocyte differentiatio n of C3H10T1/2 cells. Finally, we show that the same NSAIDs that activ ate PPAR gamma are also efficacious activators of PPAR alpha, a liver- enriched PPAR subtype that plays a key role in peroxisome proliferatio n. Interestingly, several NSAIDs have been reported to induce peroxiso mal activity in hepatocytes both in vitro and in vivo. Our findings de fine a novel group of PPAR gamma ligands and provide a molecular basis for the biological effects of these drugs on adipogenesis and peroxis ome activity.