Abstract
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.
Highlights
The liver plays an essential role in maintaining metabolic homeostasis during the daily changes in fasting and feeding
Hepatic temporal gene expression regulated by the glucocorticoid receptor (GR) Mice subjected to night-restricted feeding (NRF) show increased insulin levels in the early postprandial phase and peak levels of serum corticosterone near the fast-feeding transition at zeitgeber 12 (ZT12) (Figure 1A), described previously for ad libitumfed mice (Ahren, 2000; Harris et al, 1994; Le Minh et al, 2001; Weinert et al, 1994)
This observation, together with the reported cooperativity between glucocorticoid- and insulin-regulated signaling pathways (Kalvisa et al, 2018), led us to hypothesize a functional role of GR for induced gene expression in the prandial phase
Summary
The liver plays an essential role in maintaining metabolic homeostasis during the daily changes in fasting and feeding. Mice housed under 12-h light/dark conditions and fed ad libitum have circadian-circulating glucocorticoid levels peaking at the light-dark transition at zeitgeber 12 (ZT12) when mice enter the active/feeding phase (Le Minh et al, 2001; Weinert et al, 1994, 2005). Restricting their access to food in the night causes no change in total food intake or locomotor activity (Acosta-Rodrıguez et al, 2017) but enhances existing rhythms in gene expression (Greenwell et al, 2019)
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