Novel anti-adipogenic activity of anti-malarial amodiaquine through suppression of PPAR gamma activity

Abstract

Amodiaquine (AQ) was developed as a selective drug against Plasmodium falciparum malaria infection and has received increasing attention as a therapeutic agent for the treatment of rheumatoid arthritis, Parkinson's disease, and cancer due to its anti-inflammatory, anti-proliferative, and autophagic-lysosomal blockade properties. As autophagy activation is involved in promoting adipogenic differentiation, we examined whether anti-autophagic AQ affected adipocyte differentiation of 3T3-L1 pre-adipocytes. AQ dose-dependently and significantly suppressed adipocyte differentiation in conjunction with decreases in lipid droplet formation and expression of adipogenic markers including adiponectin, adipocyte fatty acid-binding protein 2 (aP2), resistin, and leptin. Although peroxisome proliferator-activated receptor gamma (PPAR gamma) decreases by inhibition of autophagy, AQ treatment did not induce PPAR gamma degradation despite the suppression of autophagolysosomal degradation. Instead, AQ suppressed the PPAR gamma activity to transcriptionally activate the aP2 gene transcription through the selective prevention of nuclear localization of PPAR gamma. These results demonstrated the novel anti-adipogenic activity of AQ and identified its underlying mechanism that AQ suppressed adipogenic gene expression and lipid formation by inhibiting nuclear localization of PPAR gamma in an autophagy-independent manner. AQ is recommended as a safe and effective anti-obesity drug for controlling overweight and obesity.