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Insulin signaling and reduced glucocorticoid receptor activity attenuate post-prandial gene expression in liver

ABSTRACT: Insulin signaling and reduced glucocorticoid receptor activity attenuate post-prandial gene expression in liver

PROVIDER: PRJNA490094 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7813120.fastq.gz	Fastqsanger.gz
	SRR7813130.fastq.gz	Fastqsanger.gz
	SRR7813140.fastq.gz	Fastqsanger.gz
	SRR7813150.fastq.gz	Fastqsanger.gz
	SRR7813160.fastq.gz	Fastqsanger.gz

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Insulin signaling and reduced glucocorticoid receptor activity attenuate post-prandial gene expression in liver

Project description:C57BL/6J mice were subjected to night restricted feeding (ZT12-ZT24) and livers were isolated immediate before (ZT10) and after feeding (ZT14). Combined RNA-seq, DNase-seq and H3K27Ac ChIP-seq identified hundreds of genes and enhancers regulated by acute feeding. Importantly, this feeding regulated transcriptional program follows similar rhythmic expression patterns as the intrinsic circadian transcriptional programs. ChIP-seq showed that feeding repressed enhancers were occupied by both GR and FOXO1 and occupancy of these factors were suppressed by feeding correlating with increased insulin levels and reduced corticosterone levels. Interestingly, despite considerable genome-wide overlap between GR and FOXO1, injection of dexamethasone (dex) or insulin receptor antagonist (S961) immediately before feeding, demonstrated that the glucocorticoid and insulin receptor pathways control distinct transcriptional programs. And strikingly, only combined dex and S961 treatment reversed feeding induced changes to most of the hepatic transcriptome. These corticosteroid and insulin regulated transcriptional programs are dysregulated in diet-induced obese animals.

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

Project description: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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Project description:Glucocorticoids play a key role in metabolic adaptation during stress, such as fasting and starvation. Excess and/or chronic glucocorticoid exposure, however, cause metabolic disorders that include insulin resistance dyslipidemia and hepatic steatosis. We previously showed that chronic glucocorticoid treatment elevates hepatic production of ceramides and sphingosine-1-phosphate (S1P). Ceramides are converted to sphingosine that is further converted to S1P. We showed that ceramide-initiated signaling in turn inhibits insulin signaling and increases lipogenic program in hepatocytes. However, the role of S1P, a signaling molecule that modulates physiological responses through membrane S1P receptors (S1PRs), in glucocorticoid actions is unclear. Here we found that inhibiting S1PR2 activity, but not S1PR1 and S1PR3, resulted in improved glucocorticoid-induced insulin resistance. Similarly, reducing hepatic S1PR2 expression showed similar results. Interestingly, reducing S1PR2 expression did not affect the ability of glucocorticoids to modify insulin signaling. Instead, glucocorticoids enhanced gluconeogenesis was reduced. Moreover, glucocorticoid-induced dyslipidemia and fatty liver was also compromised in mice with reduced hepatic S1PR2 expression. Indeed, RNA sequencing analysis showed that lipogenic, gluconeogenic and glycolytic genes are significantly lower in glucocorticoid-treated hepatic S1PR2 knockdown mice than those of glucocorticoid-treated hepatic scramble small hairpin RNA (shRNA) expressing mice (Control). Overall, our studies highlight the importance role of S1PR2 signaling in the mediating glucocorticoid regulation on gluconeogenesis and hepatic lipid homeostasis.

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