Systems pharmacology of adiposity reveals inhibition of EP300 as a common therapeutic mechanism of caloric restriction and resveratrol in obesity. Danio rerio

Both caloric restriction (CR) and resveratrol (RSV) have beneficial effects on obesity. However, the biochemical pathways that mediate the beneficial effects of CR and RSV can be highly interconnected and have not been fully elucidated. To reveal the common therapeutic mechanism of CR and RSV, we performed comparative transcriptome analysis of adipose tissues from diet-induced obese (DIO) zebrafish and obese human. We identified 9 and 7 genes whose expressions were regulated in common by CR and RSV in DIO zebrafish and obese human, respectively. Although the gene lists were not overlapped except for one gene, the gene ontologies enriched in the gene lists were highly overlapped, including adipocyte differentiation, lipid storage and lipid metabolism. Bioinformatic analysis of cis-regulatory sequence of these genes revealed that their transcriptional regulators were also well overlapped, including EP300, HDAC2, CEBPB, CEBPD, FOXA1 and FOXA2. We also identified 15 and 46 genes dysregulated in adipose tissue of DIO zebrafish and obese human, respectively. The bioinformatics analysis identified EP300, HDAC2, and CEBPB as common transcriptional regulators for these genes. EP300 is a histone and lysyl acetyltransferase that modulate the function of histone and various proteins including CEBPB, CEBPD, FOXA1 and FOXA2. We were able to demonstrate that the adiposity in larval zebrafish were significantly reduced by C646, an inhibitor of EP300 that antagonizes acetyl-CoA. The reduction of adiposity by C646 was not significantly different to those by RSV or co-treatment of C646 and RSV. These results suggest that inhibition of EP300 may be a common therapeutic mechanism between CR and RSV in adipose tissue of obese individuals. Overall design: Gene expression regulated by resveratrol in visceral adipose tissue from diet-induced obese zebrafish (OF+RSV) was measured. Gene expression in visceral adipose tissue from diet-induced obese zebrafish not treated with resveratrol (OF) and from control zebrafish were also measured. Three independent experiments were performed for each group.