Adiponectin receptor agonist, AdipoRon, restores hepatic clock gene expression in PCOS-associated NAFLD

Persistent lower levels of adiponectin are associated with hyperandrogenism, predisposing PCOS women to NAFLD. This study elucidated the therapeutic potential of a small molecule adiponectin receptor agonist-AdipoRon, utilizing an in-vivo PCOS rat model mimicking the manifestation of PCOS along with hepatosteatosis. Our study demonstrated that Adiporon reduced lipid accumulation in PCOS-associated NAFLD by alleviating insulin resistance & lipogenesis. AdipoRon also reversed hyperandrogenism and adiponectin deficiency in PCOS animals. In addition, AdipoRon was found to restore altered PCOS-induced hepatic circadian gene expression (Bmal1, Clock, Per3, Cry2, Reverba, and Rora). Interestingly, at the epigenetic level, global transcription activation marks, i.e., H3K4me3, H3K9/14ac, and H3K36me2, were upregulated in disease conditions. Furthermore, our ChIP data confirmed that circadian genes Bmal1, Reverba, And Rora are epigenetically regulated. ChIP assay data showed an increased H3K36 dimethylation at the Bmal1 and Rora promoter, whereas a significant decrease was observed at the Reverbα promoter in PCOS-associated NAFLD. AdipoRon ameliorated these PCOS-induced epigenetic alterations, modulating the hepatic circadian gene expression. We present the preliminary evidence illustrating the epigenetic modulation of AdipoRon, thereby regulating hepatic circadian gene expression. This study provides insights regarding the therapeutic potential of AdipoRon in PCOS-associated NAFLD, which can be of profound clinical significance.