Cistromic Reprogramming of the Diurnal Glucocorticoid Hormone Response by High-Fat Diet

Mol Cell. 2019 Nov 21;76(4):531-545.e5. doi: 10.1016/j.molcel.2019.10.007. Epub 2019 Nov 6.


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 of oscillatory gene expression and postprandial GR binding 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.

Keywords: PPARα; STAT5; circadian clock; cistromes; glucocorticoid receptor; glucose and lipid metabolism; high-fat diet; hormones; mouse liver.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Chromatin / metabolism*
  • Circadian Clocks* / genetics
  • Circadian Rhythm* / genetics
  • Diet, High-Fat*
  • Dietary Fats / administration & dosage
  • Dietary Fats / blood
  • Dietary Fats / metabolism*
  • Disease Models, Animal
  • Energy Metabolism* / genetics
  • Fasting / metabolism
  • Gene Expression Regulation
  • Glucocorticoids / metabolism
  • Gluconeogenesis
  • Ligands
  • Liver / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / blood
  • Obesity / genetics
  • Obesity / metabolism*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Postprandial Period
  • Receptors, Glucocorticoid / deficiency
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Secretory Pathway
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • Triglycerides / blood


  • Blood Glucose
  • Chromatin
  • Dietary Fats
  • Glucocorticoids
  • Ligands
  • PPAR alpha
  • Ppara protein, mouse
  • Receptors, Glucocorticoid
  • STAT5 Transcription Factor
  • Stat5a protein, mouse
  • Stat5b protein, mouse
  • Triglycerides