Adriamycin inhibits adipogenesis through the modulation of PPARγ and restoration of adriamycin-mediated inhibition of adipogenesis by PPARγ over-expression

Abstract

Adriamycin is an anti-cancer drug, effective against a wide range of cancers. However, its clinical application is limited by its cardiotoxicity. A number of reports suggest that adriamycin induces bodyweight loss also. The aim of this study was to investigate the effect of adriamycin on adipogenesis as bodyweight chancges can be directly correlated with adipocytes. Fat accumulation in 3T3-L1 pre-adipocytes, as a result of adipogenesis was detected using oil red O staining. We performed western immunoblot for the expression of adipocyte differentiation related genes to analyze the molecular mechanism of adriamycin-mediated inhibition of adipogenesis. Over-expression of target gene was done by using recombinant adenoviruses. Adriamycin inhibited adipogenesis in a dose-dependent manner. It was observed that adriamycin down-regulated the expression of PPARγ. Moreover, up-stream elements of PPARγ were also found to be down-regulated by adriamycin. Adriamycin might prevent bodyweight gain through inbibition of adipogenesis by the down-regulation of PPARγ and its up-stream transcriptional regulators like C/EBPβ and KLF4. To reverse the adriamycin-mediated inhibition of adipogenesis, PPARγ was over-expressed by adenoviral mediated gene delivery. Over-expression of PPARγ partially restored adipogenesis. Moreover, the early regulators of adipogenesis were also found to be restored after the over-expression of PPARγ. Adriamycin down-regulates the expression of PPARγ which leads to prevention of bodyweight gain through inhibition of adipogenesis. Activation of PPARγ by either adenoviral mediated gene delivery or by using PPARγ agonist may be useful in controlling the bodyweight loss.