Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome
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ABSTRACT:
PROVIDER: PRJNA996902 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25367318_1.fastq.gz | Fastqsanger.gz | |||
| SRR25367318_2.fastq.gz | Fastqsanger.gz | |||
| SRR25367319_1.fastq.gz | Fastqsanger.gz | |||
| SRR25367319_2.fastq.gz | Fastqsanger.gz | |||
| SRR25367320_1.fastq.gz | Fastqsanger.gz |
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Project description:Obesity has emerged as a common disease worldwide. Risks of developing other metabolic diseases, such as Type 2 diabetes are also higher in obese population. However, current treatment options are limited. Here we discovered a new approach for mitigating obesity and metabolic disorders by targeting intestinal nuclear receptor corepressor (NCoR). In mice with diet-induced obesity, NCoR deficiency in intestinal epithelial cells (IECs) improved obesity, insulin resistance, and glucose intolerance, corrected atherogenic dyslipidemia, and reduced hepatic steatosis. These effects were mediated through regulation of energy expenditure, energy harvest, and gut hormone secretion. Mechanistically, NCoR deficiency in IECs stimulated peroxisome proliferator-activated receptor α (PPARα) signaling pathway-mediated succinate production and thermogenesis. Intestinal cholesterol excretion was induced by derepression of intestinal liver X receptor (LXR), and triglyceride and fatty acid absorption in the upper intestine was reduced by disrupted bile acid synthesis and altered bile acid composition. In the distal intestine, increased fatty acid uptake stimulated glucagon-like peptide-1 (GLP-1) secretion and improved glycemic control.
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Project description:Heme is the endogenous ligand for the constitutively repressive REV-ERB nuclear receptors, REV-ERBα (NR1D1) and REV-ERBβ (NR1D2), but how heme regulates REV-ERB activity remains unclear. While cellular studies indicate heme is required for the REV-ERBs to bind the corepressor NCoR and repress transcription, fluorescence-based biochemical assays and crystal structures suggest that heme displaces NCoR. Here, we found that heme artifactually influences detection of NCoR interaction in fluorescence-based assays. Using fluorescence-independent methods, including isothermal titration calorimetry, NMR spectroscopy, and XL-MS, we determined that heme remodels the thermodynamic profile of NCoR binding to REV-ERBβ ligand-binding domain (LBD) and directly increases LBD binding affinity for an NCoR interaction motif. We further report two crystal structures of REV-ERBβ LBD cobound to heme and NCoR peptides, which reveal the heme-dependent NCoR binding mode. By resolving previous contradictory biochemical, structural, and cellular studies, our findings should facilitate renewed progress toward understanding heme-dependent REV-ERB activity.
2021-02-24 | PXD021761 | Pride
Project description:Macrophages are primary immune cells involved in obesity-triggered chronic low-grade inflammation in adipose tissues. Prostaglandin (PG) E2, mainly generated from macrophages, can regulate adipose tissue remodeling. Here, we observed that PGE2 receptor subtype 3 (EP3) was remarkably downregulated in adipose tissue macrophages from high-fat diet (HFD)-fed mice and patients with obesity. Notably, macrophage-specific deletion of EP3 exacerbated HFD-induced obesity in mice, whereas EP3α isoform overexpression in macrophages alleviated obesity phenotype in HFD-fed mice. EP3 deficiency suppressed anti-adipogenic secreted protein acidic and rich in cysteine (SPARC) secretion in macrophages. SPARC deletion in macrophages abrogated the protection of EP3α-overexpression against HFD-induced obesity in mice. Mechanistically, EP3 activation promoted SPARC expression by suppressing DNA methylation in macrophages through the PKA/Sp1/Dnmt1/3a signaling cascade. EP3 agonist treatment ameliorates HFD-induced obesity in mice. Thus, EP3 inhibits adipogenesis through promoting macrophage releasing SPARC and may serve as a therapeutic target for managing diet-induced obesity.
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Project description:The NCOR/SMRT corepressor complex is a fundamental coregulator of these mechanisms. However, the individual roles and the relative importance of the two major subunits NCOR and SMRT remain poorly understood. Here, we assessed the genome-wide roles of NCOR and SMRT in mouse macrophages by integrative analysis of cistrome, epigenome, and transcriptome. Although both corepressors exhibit genome-wide cooccupancy, their depletion revealed that SMRT primarily represses inflammation-related genes, whereas NCOR primarily represses metabolism-related genes. NCOR also activates inflammatory genes, some characteristic of tumor-associated macrophages. Corepressor depletion selectively alters chromatin accessibility, acetylation at enhancers, and the interplay with transcription factors. Both corepressors influence each other at chromatin, with SMRT superior to NCOR.
2025-09-24 | GSE291538 | GEO
Project description:The thyroid hormone receptor (TR) has been proposed to regulate target genes in the absence of triiodothyronine (T3), through the recruitment of the corepressors, NCoR and SMRT. NCoR and SMRT may thus play a key role in both hypothyroidism and resistance to thyroid hormone, though this has never been tested in vivo. To accomplish this we developed mice that express in the liver a NCoR protein (L-NCoR∆ID) that cannot interact with the TR. L-NCoR∆ID mice develop normally, however when made hypothyroid the repression of many positively regulated T3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by the unliganded TR. Remarkably, in the euthyroid state, expression of many T3-targets are also upregulated in L-NCoR∆ID mice, demonstrating that NCoR also determines the magnitude of the response to T3 in euthyroid animals. While positive T3 targets were upregulated in L-NCoR∆ID mice in the hypo and euthyroid state there was less effect seen on negatively regulated T3 target genes. Thus, NCoR is a specific regulator of T3-action in vivo and mediates the activity of the unliganded TR. Furthermore, NCoR may play a key role in determining the differences in individual responses to similar levels of circulating T3. Keywords: NCoR, thyroid hormone signaling, mouse liver, DNA Microarray To better assess the role of NCoR in positive and negative regulation we performed micorarray analysis of gene expression in the livers of euthyroid and hypothyroid control and L-NCoR∆ID mice.
2008-12-03 | E-GEOD-10001 | biostudies-arrayexpress
Project description:The thyroid hormone receptor (TR) has been proposed to regulate target genes in the absence of triiodothyronine (T3), through the recruitment of the corepressors, NCoR and SMRT. NCoR and SMRT may thus play a key role in both hypothyroidism and resistance to thyroid hormone, though this has never been tested in vivo. To accomplish this we developed mice that express in the liver a NCoR protein (L-NCoR∆ID) that cannot interact with the TR. L-NCoR∆ID mice develop normally, however when made hypothyroid the repression of many positively regulated T3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by the unliganded TR. Remarkably, in the euthyroid state, expression of many T3-targets are also upregulated in L-NCoR∆ID mice, demonstrating that NCoR also determines the magnitude of the response to T3 in euthyroid animals. While positive T3 targets were upregulated in L-NCoR∆ID mice in the hypo and euthyroid state there was less effect seen on negatively regulated T3 target genes. Thus, NCoR is a specific regulator of T3-action in vivo and mediates the activity of the unliganded TR. Furthermore, NCoR may play a key role in determining the differences in individual responses to similar levels of circulating T3. Keywords: NCoR, thyroid hormone signaling, mouse liver, DNA Microarray
2008-12-04 | GSE10001 | GEO
Project description:Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors have been tested in treating metabolic disorders both in preclinical and clinic studies, the tissue-specific role of SCD1 in modulating obesity-associated metabolic disorders remains unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, a SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 (MT1) in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.
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