Novel anti-adipogenic activity of anti-malarial amodiaquine through suppression of PPARc activity

Amodiaquine (AQ) was developed as a selectivedrug against Plasmodium falciparum malaria infection andhas received increasing attention as a therapeutic agent forthe treatment of rheumatoid arthritis, Parkinson’s disease,and cancer due to its anti-inflammatory, anti-proliferative,and autophagic–lysosomal blockade properties. As autophagyactivation is involved in promoting adipogenic differentiation,we examined whether anti-autophagic AQaffected adipocyte differentiation of 3T3-L1 pre-adipocytes. AQ dose-dependently and significantly suppressedadipocyte differentiation in conjunction with decreases inlipid droplet formation and expression of adipogenicmarkers including adiponectin, adipocyte fatty acid-bindingprotein 2 (aP2), resistin, and leptin. Although peroxisomeproliferator-activated receptor c (PPARc) decreasesby inhibition of autophagy, AQ treatment did not inducePPARc degradation despite the suppression ofautophagolysosomal degradation. Instead, AQ suppressedthe PPARc activity to transcriptionally activate the aP2gene transcription through the selective prevention ofnuclear localization of PPARc. These results demonstratedthe novel anti-adipogenic activity of AQ and identified itsunderlying mechanism that AQ suppressed adipogenicgene expression and lipid formation by inhibiting nuclearlocalization of PPARc in an autophagy-independent manner. AQ is recommended as a safe and effective anti-obesitydrug for controlling overweight and obesity. KCI Citation Count: 7