Insulin signaling and reduced glucocorticoid receptor activity attenuate post-prandial gene expression in liver

C57BL/6J mice were subjected to night restricted feeding (ZT12-ZT24) and livers were isolated immediate before (ZT10) and after feeding (ZT14). Combined RNA-seq, DNase-seq and H3K27Ac ChIP-seq identified hundreds of genes and enhancers regulated by acute feeding. Importantly, this feeding regulated transcriptional program follows similar rhythmic expression patterns as the intrinsic circadian transcriptional programs. ChIP-seq showed that feeding repressed enhancers were occupied by both GR and FOXO1 and occupancy of these factors were suppressed by feeding correlating with increased insulin levels and reduced corticosterone levels. Interestingly, despite considerable genome-wide overlap between GR and FOXO1, injection of dexamethasone (dex) or insulin receptor antagonist (S961) immediately before feeding, demonstrated that the glucocorticoid and insulin receptor pathways control distinct transcriptional programs. And strikingly, only combined dex and S961 treatment reversed feeding induced changes to most of the hepatic transcriptome. These corticosteroid and insulin regulated transcriptional programs are dysregulated in diet-induced obese animals. Hepatic mRNA expression, DNase accessibility and H3K27 acetylation profiles were obtained from mice fed during the night and fasted during the day. Livers were isolated at ZT10, ZT14-fed and ZT14-unfed. In addition, hepatic pre-prandial or post-prandial mRNA expression profiles were obtained from mice with liver specific disruption of Irs1 and Irs2 or mice with liver specific disruption of Nr3c1. Moreover, pre -and post-prandial hepatic mRNA expression, GR occupancy and H3K27 acetylation profiles were obtained from mice injected pre-prandial with dexamethasone and pre -and post-prandial mRNA expression profiles were obtained from mice injected pre-prandial with S961. Lastly, pre -and postprandial mRNA expression profiles were obtained from diet-induced obese mice and lean controls.