Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver

Adrija Kalvisa, Majken S. Siersbæk, Stine M. Præstholm, Line J.L. Christensen, Ronni Nielsen, Oliver Stohr, Sabine Vettorazzi, Jan Tuckermann, Morris White, Susanne Mandrup, Lars Grøntved

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Abstract

Hepatic circadian gene transcription is tightly coupled to feeding behavior, which has a profound impact on metabolic disorders associated with diet-induced obesity. Here, we describe a genomics approach to uncover mechanisms controlling hepatic postprandial gene expression. Combined transcriptomic and cistromic analysis identified hundreds of circadian-regulated genes and enhancers controlled by feeding. Postprandial suppression of enhancer activity was associated with reduced glucocorticoid receptor (GR) and Forkhead box O1 (FOXO1) occupancy of chromatin correlating with reduced serum corticosterone levels and increased serum insulin levels. Despite substantial co-occupancy of feeding-regulated enhancers by GR and FOXO1, selective disruption of corticosteroid and/or insulin signaling resulted in dysregulation of specific postprandial regulated gene programs. In combination, these signaling pathways operate a major part of the genes suppressed by feeding. Importantly, the feeding response was disrupted in diet-induced obese animals, which was associated with dysregulation of several corticosteroid- and insulin-regulated genes, providing mechanistic insights to dysregulated circadian gene transcription associated with obesity.

Original languageEnglish
Article numbere2006249
JournalPLOS Biology
Volume16
Issue number12
Pages (from-to)1-32
ISSN1544-9173
DOIs
Publication statusPublished - 10. Dec 2018

Fingerprint

Glucocorticoid Receptors
Gene expression
Liver
insulin
Genes
Insulin
gene expression
liver
genes
adrenal cortex hormones
Transcription
Nutrition
Adrenal Cortex Hormones
obesity
transcription (genetics)
Diet
metabolic diseases
corticosterone
Corticosterone
Serum

Cite this

Kalvisa, Adrija ; Siersbæk, Majken S. ; Præstholm, Stine M. ; Christensen, Line J.L. ; Nielsen, Ronni ; Stohr, Oliver ; Vettorazzi, Sabine ; Tuckermann, Jan ; White, Morris ; Mandrup, Susanne ; Grøntved, Lars. / Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver. In: PLOS Biology. 2018 ; Vol. 16, No. 12. pp. 1-32.
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abstract = "Hepatic circadian gene transcription is tightly coupled to feeding behavior, which has a profound impact on metabolic disorders associated with diet-induced obesity. Here, we describe a genomics approach to uncover mechanisms controlling hepatic postprandial gene expression. Combined transcriptomic and cistromic analysis identified hundreds of circadian-regulated genes and enhancers controlled by feeding. Postprandial suppression of enhancer activity was associated with reduced glucocorticoid receptor (GR) and Forkhead box O1 (FOXO1) occupancy of chromatin correlating with reduced serum corticosterone levels and increased serum insulin levels. Despite substantial co-occupancy of feeding-regulated enhancers by GR and FOXO1, selective disruption of corticosteroid and/or insulin signaling resulted in dysregulation of specific postprandial regulated gene programs. In combination, these signaling pathways operate a major part of the genes suppressed by feeding. Importantly, the feeding response was disrupted in diet-induced obese animals, which was associated with dysregulation of several corticosteroid- and insulin-regulated genes, providing mechanistic insights to dysregulated circadian gene transcription associated with obesity.",
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Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver. / Kalvisa, Adrija; Siersbæk, Majken S.; Præstholm, Stine M.; Christensen, Line J.L.; Nielsen, Ronni; Stohr, Oliver; Vettorazzi, Sabine; Tuckermann, Jan; White, Morris; Mandrup, Susanne; Grøntved, Lars.

In: PLOS Biology, Vol. 16, No. 12, e2006249, 10.12.2018, p. 1-32.

Research output: Contribution to journalJournal articleResearchpeer-review

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AU - Kalvisa, Adrija

AU - Siersbæk, Majken S.

AU - Præstholm, Stine M.

AU - Christensen, Line J.L.

AU - Nielsen, Ronni

AU - Stohr, Oliver

AU - Vettorazzi, Sabine

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AU - White, Morris

AU - Mandrup, Susanne

AU - Grøntved, Lars

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AB - Hepatic circadian gene transcription is tightly coupled to feeding behavior, which has a profound impact on metabolic disorders associated with diet-induced obesity. Here, we describe a genomics approach to uncover mechanisms controlling hepatic postprandial gene expression. Combined transcriptomic and cistromic analysis identified hundreds of circadian-regulated genes and enhancers controlled by feeding. Postprandial suppression of enhancer activity was associated with reduced glucocorticoid receptor (GR) and Forkhead box O1 (FOXO1) occupancy of chromatin correlating with reduced serum corticosterone levels and increased serum insulin levels. Despite substantial co-occupancy of feeding-regulated enhancers by GR and FOXO1, selective disruption of corticosteroid and/or insulin signaling resulted in dysregulation of specific postprandial regulated gene programs. In combination, these signaling pathways operate a major part of the genes suppressed by feeding. Importantly, the feeding response was disrupted in diet-induced obese animals, which was associated with dysregulation of several corticosteroid- and insulin-regulated genes, providing mechanistic insights to dysregulated circadian gene transcription associated with obesity.

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