title: Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.
abstract: Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.|Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Bâtiment H, Lausanne, Switzerland.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Weger
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.|Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Meltem
authors.initials: M
authors.lastname: Weger
authors.affiliation: Institute for Organic Chemistry, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.|Institute for Biological Interfaces 4 -Magnetic Resonance, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.
authors.forename: Benjamin
authors.identifier: http://orcid.org/0000-0003-2927-3152
authors.initials: B
authors.lastname: Görling
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schink
authors.affiliation: Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Bâtiment H, Lausanne, Switzerland.|Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Gobet
authors.affiliation: Plateforme Biopuces et séquençage, IGBMC, 1 rue Laurent Fries, Parc d'Innovation, Illkirch, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Keime
authors.affiliation: Centre for Organismal Studies (COS), University of Heidelberg, Heidelberg, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Poschet
authors.affiliation: Plateforme Biopuces et séquençage, IGBMC, 1 rue Laurent Fries, Parc d'Innovation, Illkirch, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jost
authors.affiliation: Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Nils
authors.identifier: http://orcid.org/0000-0002-3402-4727
authors.initials: N
authors.lastname: Krone
authors.affiliation: Centre for Organismal Studies (COS), University of Heidelberg, Heidelberg, Germany.
authors.forename: Rüdiger
authors.identifier: http://orcid.org/0000-0002-6238-4818
authors.initials: R
authors.lastname: Hell
authors.affiliation: Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Bâtiment H, Lausanne, Switzerland.|Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Frédéric
authors.identifier: http://orcid.org/0000-0002-9279-9707
authors.initials: F
authors.lastname: Gachon
authors.affiliation: Institute for Organic Chemistry, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.|Institute for Biological Interfaces 4 -Magnetic Resonance, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.
authors.forename: Burkhard
authors.identifier: http://orcid.org/0000-0001-9580-6397
authors.initials: B
authors.lastname: Luy
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dickmeis
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000096:biosynthesis* / Q000235:genetics; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D019343:Citric Acid / Q000378:metabolism; D024721:E-Box Elements / Q000235:genetics*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006728:Hormones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics; D014508:Urea / Q000378:metabolism; D015027:Zebrafish
chemical_list: D005938:Glucocorticoids; D006728:Hormones; D019343:Citric Acid; D014508:Urea; D056926:CLOCK Proteins