Abstract
The glucocorticoid receptor (GR) is a potent metabolic regulator and a major drug target. While GR is known to play integral roles in circadian biology, its rhythmic genomic actions have never been characterized. Here we mapped GR's chromatin occupancy in mouse livers throughout the day and night cycle. We show how GR partitions metabolic processes by time-dependent target gene regulation and controls circulating glucose and triglycerides differentially during feeding and fasting. Highlighting the dominant role GR plays in synchronizing circadian amplitudes, we find that the majority of oscillating genes are bound by and depend on GR. This rhythmic pattern is altered by high-fat diet in a ligand-independent manner. We find that the remodeling ofoscillatory gene expression and postprandial GRbinding results from a concomitant increase of STAT5 co-occupancy in obese mice. Altogether, our findings highlight GR's fundamental role in the rhythmic orchestration of hepatic metabolism.
Highlights
Circadian rhythms drive the physiological adaptation to daily phases of resting/fasting and activity/feeding (Eckel-Mahan and Sassone-Corsi, 2013; Panda, 2016)
We show how glucocorticoid receptor (GR) partitions metabolic processes by time-dependent target gene regulation and controls circulating glucose and triglycerides differentially during feeding and fasting
Highlighting the dominant role GR plays in synchronizing circadian amplitudes, we find that the majority of oscillating genes are bound by and depend on GR
Summary
Circadian rhythms drive the physiological adaptation to daily phases of resting/fasting and activity/feeding (Eckel-Mahan and Sassone-Corsi, 2013; Panda, 2016). The circadian clock consists of a 24-h feedback loop in which the activators CLOCK and BMAL1 (ARNTL) induce their own repressors, CRY1/2 and PER1/2/3. Glucocorticoids (GCs) are steroid hormones secreted with a prominent circadian rhythm. GCs peak at the onset of the feeding phase, occurring in the early night in rodents and the early morning in humans (Spiga et al, 2014). It has been shown that GCs can synchronize daily rhythmicity in peripheral tissues and that treating cells and mice with GCs induces circadian gene expression and corresponding oscillations (Balsalobre et al, 2000; Oishi et al, 2005; Reddy et al, 2007)
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