Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glucocorticoid Activation of Anti-Inflammatory Macrophages in Coordination with STAT6 Protects Against Insulin Resistance

ABSTRACT: Deletion of the GC receptor (GR) in macrophages in mice, aggravates obesity-related insulin resistance, by reducing anti-inflammatory macrophages, and enhancing adipose tissue inflammation. Consequently, the reduction of anti-inflammatory macrophages leads to exaggerated adipose tissue lipolysis and severe hepatic steatosis. Mechanistically, macrophages deficient for GR show a diminished response to IL-4 driven anti-inflammatory polarization, due to disruption of an epigenetic crosstalk between GC and IL-4 signaling involving synergistic loading of GR and STAT6. Our results demonstrate that GR plays an important role in macrophage polarization during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity

ORGANISM(S): Mus musculus

PROVIDER: GSE200371 | GEO | 2022/09/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice.

Project description:Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell–like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization. 15 samples; 2 genotypes and 2 time points

2012-03-22 | E-GEOD-36669 | biostudies-arrayexpress

Brd4 modulates diet-induced obesity via PPARγ-dependent Gdf3 expression in adipose tissue macrophages

Project description:Macrophage-mediated inflammatory response has been implicated in the pathogenesis of obesity and insulin resistance. Brd4 has emerged as a key regulator in the innate immune response. However, the role of Brd4 in obesity-associated inflammation and insulin resistance remains uncharacterized. Here, we demonstrated that myeloid-lineage specific Brd4 knockout (Brd4-CKO) mice were protected from high-fat-diet (HFD)-induced obesity with less fat accumulation, higher energy expenditure, and increased lipolysis in adipose tissue. Brd4-CKO mice also displayed reduced local and systemic inflammation with improved insulin sensitivity upon HFD. RNA-sequencing of adipose tissue macrophages (ATMs) from HFD-fed wide-type and Brd4-CKO mice revealed that expression of antilipolytic factor Gdf3 was significantly decreased in ATMs of Brd4-CKO mice. We also found that Brd4 bound to the promoter and enhancers of Gdf3 to facilitate PPARγ-dependent Gdf3 expression in macrophages. Furthermore, Brd4-mediated expression of Gdf3 acted as a paracrine signal targeting adipocytes to suppress the expression of lipases and the associated lipolysis in cultured cells and mice. Controlling the expression of Gdf3 in ATMs could be one of the mechanisms by which Brd4 modulates lipid metabolism and diet-induced obesity. This study suggests that Brd4 could be a potential therapeutic target for obesity and insulin resistance.

2021-03-24 | GSE169475 | GEO

IL-37 protects against obesity-induced inflammation and insulin resistance

Project description:Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here, we report that IL-37, a newly-described antiinflammatory member of the IL-1 family, affects obesity-induced inflammation and insulin resistance. IL-37 transgenic mice (IL-37tg) did not develop an obese phenotype in response to a high-fat diet (HFD). Unlike WT mice, IL-37tg mice exhibited reduced numbers of adipose tissue macrophages and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. A short-term HFD intervention revealed that the IL-37-mediated improvement in glucose tolerance is independent of bodyweight. IL-37tg mice manifested a beneficial metabolic profile with higher circulating levels of the anti-inflammatory adipokine adiponectin. In vitro treatment of differentiating adipocytes with recombinant IL-37 reduced adipogenesis. The beneficial effects of recombinant IL-37 involved activation of AMPK signaling. In humans, steady-state IL-37 adipose tissue mRNA levels were positively correlated with insulin sensitivity, lower adipose tissue levels of leptin and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes. Gene arrays were performed on epidydimal white adipose tissue samples from wild type and human IL37-overexpressing transgenic mice fed a high fat diet for 16 weeks.

2015-05-18 | E-GEOD-58952 | biostudies-arrayexpress

Divergent transcriptional activation by glucocorticoids in mouse and human macrophages is the result of gain and loss of enhancers

Project description:Macrophages are amongst the major targets of glucocorticoids (GC) as therapeutic anti-inflammatory agents. Here we show that GC treatment of mouse and human macrophages initiates a cascade of induced gene expression including many anti-inflammatory genes. Inducible binding of the glucocorticoid receptor (GR) was detected at candidate enhancers in the vicinity of induced genes in both species and this was strongly associated with canonical GR binding motifs. However, the sets of inducible genes, the candidate enhancers, and the GR motifs within them, were highly-divergent between the two species. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-12-17 | E-GEOD-61881 | biostudies-arrayexpress

Expression response of human monocyte derived macrophages to dexamethasone over a 24h time series

Project description:Macrophages are amongst the major targets of glucocorticoids (GC) as therapeutic anti-inflammatory agents. Here we show that GC treatment of mouse and human macrophages initiates a cascade of induced gene expression including many anti-inflammatory genes. Inducible binding of the glucocorticoid receptor (GR) was detected at candidate enhancers in the vicinity of induced genes in both species and this was strongly associated with canonical GR binding motifs. However, the sets of inducible genes, the candidate enhancers, and the GR motifs within them, were highly-divergent between the two species.. The data cast further doubt upon the predictive value of mouse models of inflammatory disease. Four biological replicates of a 6 point 24h time series transcriptional response of human monocyte derived macrophages to dexamethasone 100nM.

2015-12-17 | E-GEOD-61880 | biostudies-arrayexpress

Gene expression of BAT from GRBATKO mice exposed to cold

Project description:GRBATKO_BAT_COLDEXPOSURE Aberrant activity of the glucocorticoid (GC)/glucocorticoid receptor (GR) endocrine system has been linked to obesity-related metabolic dysfunction. Traditionally, the GC/GR axis has been believed to play a crucial role in adipose tissue formation and function in both, white (WAT) and brown adipose tissue (BAT). While recent studies have challenged this notion for WAT, the contribution of GC/GR signaling to BAT-dependent energy homeostasis remained unknown. Here, we have generated and characterized a BAT-specific GR knockout mouse (GRBATKO), for the first time allowing to genetically interrogate the metabolic impact of BAT GR. The HPA axis in GRBATKO mice was intact, as was the ability of mice to adapt to cold. BAT GR was dispensable for the adaptation to fasting-feeding cycles and the development of diet-induced obesity. In obesity, glucose and lipid metabolism, insulin sensitivity, and food intake remained unchanged, aligning with the absence of changes in thermogenic gene expression. Together, we demonstrate that the GR in UCP1-positive BAT adipocytes plays a negligible role in systemic metabolism and BAT function, thereby opposing a long-standing paradigm in the field.

2019-08-26 | GSE135544 | GEO

Expression data from a 24h time series of dexamethasone treatment for mouse bone marrow derived macrophages

Project description:Macrophages are amongst the major targets of glucocorticoids (GC) as therapeutic anti-inflammatory agents. Here we show that GC treatment of mouse and human macrophages initiates a cascade of induced gene expression including many anti-inflammatory genes. Inducible binding of the glucocorticoid receptor (GR) was detected at candidate enhancers in the vicinity of induced genes in both species and this was strongly associated with canonical GR binding motifs. However, the sets of inducible genes, the candidate enhancers, and the GR motifs within them, were highly-divergent between the two species. 3 biological replicates of a 6 point time series for the transcriptional response to dexamethasone 100nM

2015-12-17 | E-GEOD-61879 | biostudies-arrayexpress

Genome wide binding of glucocorticoid receptor in dexamethasone treated human monocyte derived macrophages

Project description:Macrophages are amongst the major targets of glucocorticoids (GC) as therapeutic anti-inflammatory agents. Here we show that GC treatment of mouse and human macrophages initiates a cascade of induced gene expression including many anti-inflammatory genes. Inducible binding of the glucocorticoid receptor (GR) was detected at candidate enhancers in the vicinity of induced genes in both species and this was strongly associated with canonical GR binding motifs. However, the sets of inducible genes, the candidate enhancers, and the GR motifs within them, were highly-divergent between the two species.. The data cast further doubt upon the predictive value of mouse models of inflammatory disease. human monocyte derived macrophages were treated with dexamethasone for 2h, fixed and ChIP performed. Material from 4 volunteers was pooled for the IP.

2015-12-17 | E-GEOD-61878 | biostudies-arrayexpress

Genome wide binding of glucocorticoid receptor in dexamethasone treated mouse bone marrow derived macrophages

Project description:Macrophages are amongst the major targets of glucocorticoids (GC) as therapeutic anti-inflammatory agents. Here we show that GC treatment of mouse and human macrophages initiates a cascade of induced gene expression including many anti-inflammatory genes. Inducible binding of the glucocorticoid receptor (GR) was detected at candidate enhancers in the vicinity of induced genes in both species and this was strongly associated with canonical GR binding motifs. However, the sets of inducible genes, the candidate enhancers, and the GR motifs within them, were highly-divergent between the two species. Mouse bone marrow derived macrophages were generated from two male 10 week old C57BL/6 mice, treated with dexamethsone 100nM or vehicle and glucocorticoid receptor bound DNA extracted by chromatin immunoprecipitation

2015-12-17 | E-GEOD-61877 | biostudies-arrayexpress

Adipose METTL14-elicited N6-methyladenosine promotes obesity, insulin resistance, and NAFLD by suppressing β adrenergic signaling and lipolysis

Project description:Obesity is associated with impaired β-adrenergic receptor (Adrb1-3) signaling and lipolysis, leading to aberrant white adipose tissue (WAT) growth. WAT research has been centered on transcriptional and posttranslational regulations, but posttranscriptional regulation and mRNA modifications are poorly understood. Here, we unveil a METTL14/N6-methyladenosine (m6A) paradigm guiding β-adrenergic signaling and lipolysis. METTL14 complex installs m6A on RNA, regulating mRNA fate and translation. We found that feeding and insulin increased adipose Mettl14 and m6A levels. Adipose Mettl14 and m6A were upregulated in high fat diet (HFD)-induced obesity. Ablation of adipose Mettl14 decreased Adrb2, Adrb3, Atgl (encoding lipase), and Cig-58 (Atgl activator) transcript m6A contents while increasing their translation and protein levels, thereby enhancing adipose β-adrenergic signaling and lipolysis. Consequently, adipocyte-specific Mettl14 knockout mice were resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and NAFLD. These results unravel a METTL14/m6A-based epitranscriptomic mechanism governing β-adrenergic signaling, lipolysis, and adipose growth in health and disease.

2023-06-04 | GSE233782 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data