Impaired glucocorticoid receptor expression in liver disrupts feeding-induced gene expression, glucose uptake, and glycogen storage

The transition from a fasted to a fed state is associated with extensive transcriptional remodeling in hepatocytes facilitated by hormonal- and nutritional-regulated transcription factors. Here, we use a liver-specific glucocorticoid receptor (GR) knockout (L-GRKO) model to investigate the temporal hepatic expression of GR target genes in response to feeding. Interestingly, in addition to the well-described fasting-regulated genes, we identify a subset of hepatic feeding-induced genes that requires GR for full expression. This includes Gck, which is important for hepatic glucose uptake, utilization, and storage. We show that insulin and glucocorticoids cooperatively regulate hepatic Gck expression in a direct GR-dependent manner by a 4.6 kb upstream GR binding site operating as a Gck enhancer. L-GRKO blunts preprandial and early postprandial Gck expression, which ultimately affects early postprandial hepatic glucose uptake, phosphorylation, and glycogen storage. Thus, GR is positively involved in feeding-induced gene expression and important for postprandial glucose metabolism in the liver. [Display omitted] •GR controls the expression of a subset of hepatic feeding-induced genes•Hepatic glucokinase (Gck) gene expression is positively regulated by GR•GR disruption leads to reduced preprandial RNAPII recruitment to the Gck promoter•Liver-specific GRKO impairs hepatic glucose uptake, phosphorylation, and utilization Præstholm et al. show that the glucocorticoid receptor (GR) controls a subset of temporally expressed genes in the liver. This includes many feeding-induced genes, such as Gck, encoding the glucokinase, a key enzyme in glucose metabolism. Acute GR disruption ultimately leads to reduced hepatic glucose uptake and storage.