Myeloid specific ASXL2 deletion limits diet induced obesity by regulating energy expenditure
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA602939 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10959600.fastq.gz | Fastqsanger.gz | |||
| SRR10959601.fastq.gz | Fastqsanger.gz | |||
| SRR10959602.fastq.gz | Fastqsanger.gz | |||
| SRR10959603.fastq.gz | Fastqsanger.gz | |||
| SRR10959604.fastq.gz | Fastqsanger.gz |
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Project description:We previously reported that global deletion of the Enhancer of Trithorax and Polycomb (ETP) gene, Asxl2, attenuates osteoclast differentiation and also completely protects mice from HFD-induced weight gain. To determine role of this gene specifically in myeloid compartment, ASXL2flox mice were bred with LysM cre (Asxl2LysM). Bone marrow-derived macrophages (BMM) were cultured for 2 days with or without Rank-ligand (RANKL). We characterized the transcriptomic profiles of BMMs and osteoclast by performing unbiased RNA-sequencing. The expression profiles of both macrophages and osteoclast was significantly distinct between two genotypes. In particular, Enrichr analysis of differentially expressed genes (DEG) reveals substantial downregulation of those associated with extracellular matrix (ECM) organization, collagen formation, cytokine-cytokine interaction and inflammatory response including genes encoding TNFα, MMPs and CXCLs, in Asxl2LysM BMMs. In contrast, cell cycle and mitosis related genes are upregulated. The fact that most of the dominant downregulated genes are also implicated in modulating adipose tissue inflammation and fibrosis, supports the concept that genetic deletion of ASXL2, in myeloid cells, may modify obesity.
2021-01-23 | GSE144180 | GEO
Project description:We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells' inflammatory phenotype may impact obesity and its complications.
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Project description:Exercise benefits M2 macrophage polarization, energy homeostasis and protects against obesity partially through exercise-induced circulating factors. Here, by unbiased quantitative proteomics on serum samples from sedentary and exercised mice, we identify parvalbumin as a circulating factor suppressed by exercise. Parvalbumin functions as a non-competitive CSF1R antagonist to inhibit M2 macrophage activation and energy expenditure in adipose tissue. More importantly, serum concentrations of parvalbumin positively correlate with obesity in mouse and human, while treating mice with a recombinant parvalbumin blocker prevents its interaction with CSF1R and promotes M2 macrophage polarization and ameliorates diet-induced obesity. Thus, although further studies are required to assess the significance of parvalbumin in mediating the effects of exercise, our results implicate parvalbumin as a potential therapeutic strategy against obesity.
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Project description:Prader-Willi syndrome (PWS), a genetic cause of childhood obesity, is characterized by intellectual disabilities and sleep abnormalities. PWS-causing deletions include a neuronal long, non-coding RNA (lncRNA) processed into small nucleolar RNAs and a spliced lncRNA,116HG. We show that 116HG forms a subnuclear RNA cloud that co-purifies with the transcriptional activator RBBP5 and active metabolic genes, remains tethered to the site of its transcription and increases in size in postnatal neurons. Snord116del mice lacking 116HG exhibited increased energy expenditure corresponding to dysregulation of diurnally expressed Mtor and circadian genes Clock, Cry1, and Per2. Genomic and metabolic analyses demonstrate altered diurnal energy regulation in the Snord116del mouse cortex and link the loss of 116HG to the energy imbalance observed in PWS. Examination of lncRNA binding sites by ChIRP-seq using an oligo-based purification method from WT and Snord116del (+/-) mouse brain with specific and nonspecific control oligos. Transcript abundance levels by RNA-seq analysis of 3 adult WT and 2 adult Snord116del (+/-) mouse brain cortices at Zt+6 and 2 adult WT and 2 adult Snord116del (+/-) mouse brain cortices at Zt+16.
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2022-05-31 | PXD032153 | Pride
Project description:Objectives: Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue. Methods: We firstly investigated the role of mitoxantrone, an Mcu inhibitor, in the regulation of glucose and lipid metabolism in mouse adipocytes (3T3-L1 cells). Secondly, C57BL/6J mice were used as a research model to investigate the effects of Mcu inhibitors on fat accumulation and glucose metabolism in mice on a high-fat diet (HFD), and by using CRISPR/Cas9 technology, adipose tissue-specific Mcu knockdown mice (Mcu fl/+ AKO) and Mcu knockout of mice (Mcu fl/fl AKO) were obtained, to further investigate the direct effects of Mcu on fat deposition, glucose tolerance and insulin sensitivity in mice on a high-fat diet. Results: we found the Mcu inhibitor reduced adipocytes lipid accumulation and adipose tissues mass in mice fed an HFD. Both Mcu fl/+ AKO mice and Mcu fl/fl AKO mice were resistant to HFD-induced obesity, compared to control mice. Mice with Mcu fl/fl AKO showed improved glucose tolerance and insulin sensitivity as well as reduced hepatic lipid accumulation. Mechanistically, inhibition of Mcu promoted mitochondrial biogenesis and adipocyte browning, increase energy expenditure and alleviates diet-induced obesity. Conclusion: Our study demonstrates a link between adipocyte lipid accumulation and mCa2+ levels, suggesting that adipose-specific Mcu deficiency alleviates HFD-induced obesity and ameliorates metabolic disorders such as insulin resistance and hepatic steatosis. These effects may be achieved by increasing mitochondrial biosynthesis, promoting white fat browning and enhancing energy metabolism.
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Project description:Prader-Willi syndrome (PWS), a genetic cause of childhood obesity, is characterized by intellectual disabilities and sleep abnormalities. PWS-causing deletions include a neuronal long, non-coding RNA (lncRNA) processed into small nucleolar RNAs and a spliced lncRNA,116HG. We show that 116HG forms a subnuclear RNA cloud that co-purifies with the transcriptional activator RBBP5 and active metabolic genes, remains tethered to the site of its transcription and increases in size in postnatal neurons. Snord116del mice lacking 116HG exhibited increased energy expenditure corresponding to dysregulation of diurnally expressed Mtor and circadian genes Clock, Cry1, and Per2. Genomic and metabolic analyses demonstrate altered diurnal energy regulation in the Snord116del mouse cortex and link the loss of 116HG to the energy imbalance observed in PWS.
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