SMRT regulates metabolic homeostasis and adipose tissue macrophage phenotypes in tandem
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA531031 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8857560.fastq.gz | Fastqsanger.gz | |||
| SRR8857570.fastq.gz | Fastqsanger.gz | |||
| SRR8857551.fastq.gz | Fastqsanger.gz | |||
| SRR8857561.fastq.gz | Fastqsanger.gz | |||
| SRR8857571.fastq.gz | Fastqsanger.gz |
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Project description:The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor that regulates the transcriptional activity of many transcription factors critical for metabolic processes. While the importance of SMRT’s role in the adipocyte has been well-established, prior mouse models have yielded contradictory phenotypes, limiting our understanding of its in vivo function in the context of homeostatic maintenance. Multiple models suggest that SMRT deficiency leads to increased adiposity, though the effects of SMRT loss on glucose tolerance and insulin sensitivity have been variable. We therefore generated an adipocyte-specific SMRT knockout (adSMRT-/-) mouse to more clearly define SMRT’s metabolic contributions. In doing so, we found that SMRT deletion in the adipocyte does not, in fact, lead to obesity, despite increased food consumption in knockouts – even when mice are challenged with a high-fat diet. This suggests that prior adiposity phenotypes described in generalized models were due to effects beyond the adipocyte. However, an adipocyte-specific SMRT deficiency still led to dramatic effects on systemic glucose tolerance and adipocyte insulin sensitivity, impairing both. This metabolically deleterious effect was coupled with a surprising immune phenotype, wherein most genes differentially expressed in the adipose tissue of adSMRT-/- mice were upregulated in pro-inflammatory pathways. Flow cytometry and conditioned media experiments demonstrated that secreted factors from knockout adipose tissue strongly informed resident macrophages to develop a pro-inflammatory, MMe (metabolically activated) phenotype. Taken together, these studies suggest a novel role for SMRT as an integrator of metabolic and inflammatory signals to effectively maintain physiological homeostasis.
2019-07-05 | GSE129369 | GEO
Project description:ChIP-seq of mouse embryonic fibroblast-adipose like cell line 3T3-L1 to identify binding sites of NCoR1 and SMRT following induction of differentiation, and RNA Pol-II after SMRT knock down
2012-04-23 | E-MTAB-1031 | biostudies-arrayexpress
Project description:Adipose Energy Homeostasis is the important guarantee to maintain the body's energy balance. Recently, it is reported that, in the adipose cell, Kisspeptins play important role in cell proliferation, differentiation, lipid metabolism and some adipocytokine secretion, so Kisspeptins maybe the novel targets of adipose energy homeostasis regulation. Adipose tissue is the core organs that regulates adipose energy homeostasis. Our early studies observed that there is organizational difference that exercise regulated adipose energy homeostasis, and the response of the Kisspeptins to exercise is closely related to the energy state of the body, so we speculated that Kisspeptins play some important role in the exercise regulated adipose energy homeostasis. Based on the cell experiments to clarify the role of Kisspeptins in regulating adipose energy homeostasis, the role of Kisspeptins in the regulation of adipose energy homeostasis were determined in the adipose tissue of conditioned Kiss1 gene knockout mice of CRISPR/Cas9, then we use the single cell transcriptome sequencing, untargeted proteome and targeted metabolome techniques to further explore and elucidate the possible pathways and mechanisms of Kisspeptins mediated adipose energy homeostasis regulated by exercise.
2024-04-22 | PXD051630 |
Project description:Objective: Nuclear receptor action is mediated in part by the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT; also known as NCOR2). NCOR1 and SMRT regulate metabolic pathways that govern body mass, insulin sensitivity and energy expenditure and represent an understudied area in the realm of metabolic health and disease. Previously, we found that NCOR1 and SMRT are essential for maintaining metabolic homeostasis and their knockout (KO) leads to rapid weight loss and hypoglycemia, which is not survivable. Because of a potential defect in glucose absorption, we sought to determine the role of NCOR1 and SMRT specifically in intestinal epithelial cells (IECs). Methods: We used a post-natal strategy to disrupt NCOR1 and SMRT throughout IECs in adult mice. These mice were characterized metabolically by assessing body weight, glucose levels and subjecting the mice to metabolic phenotyping, body composition analysis and glucose tolerance testing. IECs were isolated from the jejunum of the small intestine and profiled by bulk RNA sequencing. Results: We found that the post-natal KO of NCOR1 and SMRT from IECs leads to rapid weight loss and hypoglycemia with a significant reduction in survival. This was accompanied by alterations in glucose metabolism and activation of fatty acid oxidation in IECs. Metabolic phenotyping confirmed a reduction in body mass driven by a loss of body fat without any difference in food intake. This appeared to be driven by a reduction of key intestinal carbohydrate transporters, including SGLT1, GLUT2 and GLUT5. Conclusions: Intestinal NCOR1 and SMRT act in tandem to regulate glucose levels and body weight. This in part may be mediated by regulation of intestinal carbohydrate transporters.
2024-08-12 | GSE268594 | GEO
Project description:Skeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning
2023-10-24 | PXD046337 |
Project description:Exercise training improves whole body glucose homeostasis through effects largely attributed to adaptations in skeletal muscle; however, training also affects other tissues including adipose tissue. To determine if exercise-induced adaptations to adipose tissue contribute to training-induced improvements in glucose homeostasis, subcutaneous white adipose tissue (scWAT) from trained or sedentary donor mice was transplanted into the visceral cavity of sedentary recipients. Remarkably, nine days post-transplantation, mice receiving trained scWAT had improved glucose tolerance and enhanced insulin sensitivity compared to mice transplanted with sedentary scWAT or sham-treated mice. Mice transplanted with trained scWAT had increased insulin-stimulated glucose uptake in tibialis anterior and soleus muscles and brown adipose tissue, suggesting that the transplanted scWAT exerted endocrine effects. Furthermore, the deleterious effects of high-fat feeding on glucose tolerance and insulin sensitivity were completely reversed if high-fat fed recipient mice were transplanted with trained scWAT. In additional experiments, voluntary exercise training by wheel running for only 11 days resulted in profound changes in scWAT including increased expression of ∼1550 genes involved in numerous cellular functions, including metabolism. Exercise training causes adaptations to scWAT that elicit metabolic improvements in other tissues, demonstrating a previously unrecognized role for adipose tissue in the beneficial effects of exercise on systemic glucose homeostasis. Microarray analysis of scWAT obtained from a cohort of mice that were housed in wheel cages for 11 days compared to sedentary control mice.
2015-04-22 | E-GEOD-68161 | biostudies-arrayexpress
Project description:In utero environment is crucial to ensure normal development of the fetus and to program metabolic health throughout the life. Beside macronutrients, the role of micronutrients, including vitamin D, begins to be explore. The aim of this study was to decipher the impact of maternal vitamin D deficiency (VDD), in normal and high-fat (HF) diet context, on adipose tissue metabolism and energy homeostasis in offspring, considering sex-specific responses. Body weight, energy expenditure, and spontaneous activity was differential impacted in juvenile male and female offspring born from VDD mice. In adulthood, a HF diet combined with maternal VDD disrupted glucose homeostasis and adiposity in male offspring but not in females. Such phenotypes were associated to different transcriptomic profiles in adipose tissue, which could be related to differential modulation of plasma 17b-estradiol concentrations. Thus, maternal VDD sex-dependently modulated metabolic fate of the offspring, especially when associated with HF diet in adulthood.
2022-06-22 | GSE206372 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE27001: Inhibition of Bcl6-SMRT/NCoR interactions by an inhibitory peptide affects inflammatory pathways GSE27033: Genome-wide location analysis of SMRT and NCoR in wild-type and Bcl6 knockout macrophages Refer to individual Series
2012-03-29 | E-GEOD-27060 | biostudies-arrayexpress
Project description:The nuclear receptor corepressor 1 (NCoR1) and the silencing mediator of retinoic acid and thyroid hormone (SMRT) are critical coregulators of nuclear receptors, including the thyroid hormone receptor and they mediate transcriptional repression via histone deacetylation. Although they are highly homologous and have similar receptor interacting domains, they have different roles in different tissues. Recently, de novo genetic variants in nuclear corepressors were found in pediatric patients with neurodevelopmental disorders. Thus, we generated novel mouse models to understand the role of NCOR1 and SMRT in the central nervous system. We used the mice with conditional NCoR1 or SMRT (NCoR1lox/lox or SMRTlox/lox) alleles in combination with the mice that express Cre recombinase in a neuronal specific fashion (Snap25-IRES2-cre). First, we performed behavioral tests to assess for any behavioral phenotypes. We found hypoactivity, social deficits, and mild anxiety in neuronal specific deletion of NCoR1 or SMRT KO mice. In addition, NCoR1 KO mice displayed higher learning abilities in a pairwise visual discrimination task. Next, we performed RNA-sequencing analysis with cells from the amygdala taken at postnatal day 21 to investigate gene expression mediated by NCoR1 and SMRT. We found that 449 genes were upregulated by SMRT deletion, whereas only 8 genes were upregulated by NCoR1 deletion. Overall, our data demonstrate that NCoR1 and SMRT have separate functions in the central nervous system.
2026-06-14 | GSE293505 | GEO
Project description:NCoR and SMRT are two paralogous vertebrate proteins that function as corepressors with unliganded nuclear receptors. Although C. elegans has a large number of nuclear receptors, orthologues of the corepressors NCoR and SMRT have not unambiguously been identified in Drosophila or C. elegans. Here, we identify GEI-8 as the closest homologue of NCoR and SMRT in C. elegans and demonstrate that GEI-8 is expressed as at least two isoforms throughout development in multiple tissues, including neurons, muscle and intestinal cells. We demonstrate that a homozygous deletion within the gei-8 coding region, which is predicted to encode a truncated protein lacking the predicted NR domain, results in severe mutant phenotypes with developmental defects, slow movement and growth, arrested gonadogenesis and defects in cholinergic neurotransmission. Whole genome expression analysis by microarrays identified sets of de-regulated genes consistent with both the observed mutant phenotypes and a role of GEI-8 in regulating transcription. Interestingly, the upregulated transcripts included a predicted mitochondrial sulfide:quinine reductase encoded by Y9C9A.16. This locus also contains non-coding, 21-U RNAs of the piRNA. Inhibition of the expression of the region coding for 21-U RNAs leads to irregular gonadogenesis in the homozygous gei-8 mutants, but not in an otherwise wild-type background, suggesting that GEI-8 may function in concert with the 21-U RNAs to regulate gonadogenesis. Our results confirm that GEI-8 is the orthologue of the vertebrate NCoR/SMRT corepressors and demonstrate important roles for this putative transcriptional corepressor in development and neuronal function. Comparison of Mutant vs. WT control with three replications per treatment group
2013-08-11 | E-GEOD-40127 | biostudies-arrayexpress