Open AccessInsulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver
Author(s) -
Adrija Kalviša,
Majken Siersbæk,
Stine M. Præstholm,
Line Julie Lindorf Christensen,
Ronni Nielsen,
Oliver Stöhr,
Sabine Vettorazzi,
Jan Tuckermann,
Morris F. White,
Susanne Mandrup,
Lars Grøntved
Publication year - 2018
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.2006249
Subject(s) - biology , foxo1 , endocrinology , postprandial , medicine , insulin receptor , enhancer , glucocorticoid receptor , circadian rhythm , transcriptome , insulin , glucocorticoid , transcription factor , insulin resistance , gene expression , gene , genetics
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.