Glucocorticoid-stimulated senescence phenotype in differentiated bone marrow adipocytes treated with PPARgamma inhibitor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA847251 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19589071.fastq.gz | Fastqsanger.gz | |||
| SRR19589072.fastq.gz | Fastqsanger.gz | |||
| SRR19589073.fastq.gz | Fastqsanger.gz | |||
| SRR19589074.fastq.gz | Fastqsanger.gz | |||
| SRR19589075.fastq.gz | Fastqsanger.gz |
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Project description:Glucocorticoids, powerful anti-inflammatory and immunosuppressive agents, can decrease bone mass and quality and increase bone marrow adiposity. Here, we show that a small number of bone marrow adipocytes (BMAds) in mice undergo rapid cellular senescence in response to glucocorticoid treatment. The senescent BMAds acquire a senescence-associated secretory phenotype (SASP), which reinforces and spreads senescence in the bone/bone marrow microenvironment in a paracrine manner. Mechanistically, glucocorticoid treatment increases the synthesis of oxylipins such as 15d-PGJ2 in BMAds to positively regulate the activity of PPARγ, which stimulates the expression of key cellular senescence effector genes. PPARγ activation, in turn, promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Inhibition of the initial BMAd senescence by deleting p16INK4a from adipocytes or pharmacological suppression of the SASP efficiently interrupts the secondary spread of senescent cells and alleviates glucocorticoid-induced bone deficits. We identify senescent BMAds as initial mediators for glucocorticoid-induced bone deterioration and reveal a lipid metabolism circuit that robustly triggers the senescence of BMAds.
2023-06-09 | GSE205732 | GEO
Project description:In order to identify the molecular mechanisms of PPARgamma phosphorylation at Set273, we generated cell-lines of PPARgamma KO MEFs expressing wtPPARgamma or S273APPARgamma. In addition, because our data showed that PPARgamma ligand drugs such as rosiglitazone and MRL24 blocked this phopshorylation, we treated cells with these drugs, then prepared RNA samples to look at the gene profiling. PPARgamma KO MEFs were introduced by wtPPARgamma or S273APPARgamma. Cells were differentiated for 6 days. Then, wtPPARgamma-introduced KO MEFs were treated with either 1 uM rosiglitazone or 1uM MRL24 for 24h. Cells were harvested and we purified total RNA samples.
2010-06-08 | E-GEOD-22033 | biostudies-arrayexpress
Project description:Energy-storing white adipocytes maintain their identity by suppressing the gene program defining energy-burning thermogenic brown/beige adipocytes. Here, we reveal that the protein-protein interaction between the transcriptional co-regulator ZFP423 and brown/beige cell determination factor, EBF2, is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423-EBF2 protein interaction through CRISPR-Cas9 gene editing triggers widespread “browning” of WAT in adult mice. Mechanistically, adipocyte Zfp423 deficiency induces an EBF2 NuRD-to-BAF co-regulator switch and a shift in PPARgamma occupancy to thermogenic genes. This shift in PPARgamma occupancy increases the anti-diabetic efficacy of the PPARgamma agonist rosiglitazone in obesity while diminishing the unwanted weight-gaining effect of the drug. These data indicate that ZFP423 controls EBF2 co-activator recruitment and PPARgamma occupancy to determine the thermogenic plasticity of adipocytes and raise the concept of targeting transcriptional brakes in adipocyte gene expression as a therapeutic strategy to induce thermogenic adipocyte biogenesis in obesity.
2022-05-01 | GSE175654 | GEO
Project description:Energy-storing white adipocytes maintain their identity by suppressing the gene program defining energy-burning thermogenic brown/beige adipocytes. Here, we reveal that the protein-protein interaction between the transcriptional co-regulator ZFP423 and brown/beige cell determination factor, EBF2, is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423-EBF2 protein interaction through CRISPR-Cas9 gene editing triggers widespread “browning” of WAT in adult mice. Mechanistically, adipocyte Zfp423 deficiency induces an EBF2 NuRD-to-BAF co-regulator switch and a shift in PPARgamma occupancy to thermogenic genes. This shift in PPARgamma occupancy increases the anti-diabetic efficacy of the PPARgamma agonist rosiglitazone in obesity while diminishing the unwanted weight-gaining effect of the drug. These data indicate that ZFP423 controls EBF2 co-activator recruitment and PPARgamma occupancy to determine the thermogenic plasticity of adipocytes and raise the concept of targeting transcriptional brakes in adipocyte gene expression as a therapeutic strategy to induce thermogenic adipocyte biogenesis in obesity.
2022-05-01 | GSE175653 | GEO
Project description:The nuclear receptor Peroxisome Proliferator Activated Receptor gamma (PPARgamma) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that macrophage respiration is enhanced by rosiglitazone, an activating PPARgamma ligand, in a PPARgamma dependent manner. Moreover, PPARgamma is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARgamma dramatically affects the oxidation of glutamine. Both glutamine and PPARgamma have been implicated in alternative activation (AA) of macrophages and PPARgamma was required for IL4-dependent gene expression and stimulation of macrophage respiration. Remarkably, depletion of PPARgamma phenocopied the effects of glutamine depletion on transcription. Thus, PPARgamma supports alternative activation by facilitating glutamine metabolism. Yet PPARgamma expression is itself markedly increased by IL4. Thus, PPARgamma functions at the center of a feed forward loop that is central to AA of macrophages.
2018-09-06 | GSE111102 | GEO
Project description:The nuclear receptor Peroxisome Proliferator Activated Receptor gamma (PPARgamma) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that macrophage respiration is enhanced by rosiglitazone, an activating PPARgamma ligand, in a PPARgamma dependent manner. Moreover, PPARgamma is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARgamma dramatically affects the oxidation of glutamine. Both glutamine and PPARgamma have been implicated in alternative activation (AA) of macrophages and PPARgamma was required for IL4-dependent gene expression and stimulation of macrophage respiration. Remarkably, depletion of PPARgamma phenocopied the effects of glutamine depletion on transcription. Thus, PPARgamma supports alternative activation by facilitating glutamine metabolism. Yet PPARgamma expression is itself markedly increased by IL4. Thus, PPARgamma functions at the center of a feed forward loop that is central to AA of macrophages.
2018-09-06 | GSE111104 | GEO
Project description:The nuclear receptor Peroxisome Proliferator Activated Receptor gamma (PPARgamma) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that macrophage respiration is enhanced by rosiglitazone, an activating PPARgamma ligand, in a PPARgamma dependent manner. Moreover, PPARgamma is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARgamma dramatically affects the oxidation of glutamine. Both glutamine and PPARgamma have been implicated in alternative activation (AA) of macrophages and PPARgamma was required for IL4-dependent gene expression and stimulation of macrophage respiration. Remarkably, depletion of PPARgamma phenocopied the effects of glutamine depletion on transcription. Thus, PPARgamma supports alternative activation by facilitating glutamine metabolism. Yet PPARgamma expression is itself markedly increased by IL4. Thus, PPARgamma functions at the center of a feed forward loop that is central to AA of macrophages.
2018-09-06 | GSE111103 | GEO
Project description:Single cell sequencing of de-differentiated dermal adipocytes
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Project description:Adipose tissue in the mammary gland undergoes dramatic remodeling during reproduction. Adipocytes are replaced by mammary alveolar structures during pregnancy and lactation, then reappear upon weaning. Here, we reveal that adipocytes in the mammary gland de-differentiate into Pdgfrα+ preadipocyte- and fibroblast-like cells during pregnancy, and remain de-differentiated during lactation. Upon weaning, de-differentiated fibroblasts proliferate and re-differentiate into adipocytes. In order to determine the molecular signature of these de-differentiated adipocytes in the mammary gland, we compared these cells with classical adipocytes. Using the AdipoChaser-mT/mG system, we pre-labeled mature adipocytes with GFP expression to characterize the features of these de-differentiated adipocytes (Figure 4A), and then purified CD31-/CD45-/PDGFRα+/Tomato+ and CD31-/CD45-/PDGFRα+/GFP+ cells from the stromal vascular fraction (SVF) of lactating mammary gland at the peak of lactation through FACS. Gene expression analyses showed that the CD31-/CD45-/PDGFRα+/Tomato+ cells were indeed enriched with Tomato expression, while the CD31-/CD45-/PDGFRα+/GFP+ cells were enriched with GFP expression (Figure 4C). We then collected CD31-/CD45-/PDGFRα+/GFP+ cells as single cells for subsequent single cell RNA-sequencing analysis (Figure 4D-G, Supplemental. Figure S1A-G). After the flow sorting and single cell RNA amplification, 26 CD31-/CD45-/PDGFRα+/GFP+ cells passed the quality control, and these cells were used for single-cell RNA-sequencing analysis. Due to technical difficulties in sorting single mature white adipocyte through flow cytometry, adipocytes differentiated from the immortalized murine-derived brown pre-adipocyte cell line were used as mature adipocyte control (Pradhan et al., 2017). Additionally, we also included population RNA-seq experiments, i.e. three mature white adipocyte samples, two GFP+, and six GFP- ones.
2018-06-17 | E-MTAB-6818 | biostudies-arrayexpress
Project description:We compared transcriptomes of terminally differentiated mouse 3T3-L1 adipocytes [Series GSE14004] and human adipocytes to identify cell-specific differences. Gene expression and high content analysis (HCA) data identified the androgen receptor (AR) as both expressed and functional, exclusively during early human adipocyte differentiation. We used HCA to determine mechanisms of AR regulation and activity in human adipocytes. We found that AR is regulated in a feed-forward fashion by glucocorticoids. Total RNA isolated from human subcutaneous preadipocytes differentiated for up to 14 days.
2012-07-12 | E-GEOD-39342 | biostudies-arrayexpress