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

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

Author information

1
Institute for Diabetes and Obesity (IDO), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), Ingolstaedter Landstr. 1, 85764 Neuherberg (Munich), Germany; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), Ingolstaedter Landstr. 1, 85764 Neuherberg (Munich), Germany.
2
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried (Munich), Germany.
3
Institute of Computational Biology (ICB), HMGU, Ingolstaedter Landstr. 1, 85764 Neuherberg (Munich), Germany.
4
Institute of Computational Biology (ICB), HMGU, Ingolstaedter Landstr. 1, 85764 Neuherberg (Munich), Germany; Department of Informatics, Boltzmannstr. 3, 85748 Garching, Technische Universitaet Muenchen (TUM), Munich, Germany.
5
Institute of Computational Biology (ICB), HMGU, Ingolstaedter Landstr. 1, 85764 Neuherberg (Munich), Germany; School of Life Sciences Weihenstephan, Maximus-von-Imhof-Forum 3, 85354 Freising, Technische Universitaet Muenchen (TUM), Munich, Germany.
6
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
7
Institute for Diabetes and Obesity (IDO), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), Ingolstaedter Landstr. 1, 85764 Neuherberg (Munich), Germany; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), Ingolstaedter Landstr. 1, 85764 Neuherberg (Munich), Germany; Metabolic Programming, School of Life Sciences Weihenstephan, Gregor Mendel Str. 2, 85354 Freising, Technische Universitaet Muenchen (TUM), Munich, Germany. Electronic address: henriette.uhlenhaut@helmholtz-muenchen.de.

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 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

PMID:
31706703
DOI:
10.1016/j.molcel.2019.10.007
[Indexed for MEDLINE]

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