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.
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Project description:Glucagon (GCG) analogues are gaining attention as promising components in incretin-based therapeutics for obesity and metabolic dysfunction-associated steatohepatitis. However, the biology of chronic glucagon treatment, in particular, the molecular underpinnings of GCG-induced energy expenditure and lipid metabolism, remain poorly defined. We utilized a long-acting GCG analogue (LA-GCG) in conjunction with hepatic and adipose glucagon receptor knockout mouse models. Through an integrative approach that combined metabolic, biochemical and omics techniques, we investigated the molecular mechanisms underlying GCG-induced energy expenditure and metabolic benefits. We demonstrate that the LA-GCG enhances energy expenditure in diet-induced obese mice with an essential role of hepatic, but not adipose, GCGR signaling. Intriguingly, the enhancement in energy expenditure is observed only in obese but not in lean mice. The preferential efficacy is plausibly found in a prolonged activation of cAMP/PKA signaling through PDE4B/4D downregulation by LA-GCG. Conversely, the cAMP/PKA signaling is promptly attenuated by the PDE4B/4D activity in lean mice. Interestingly, unlike the EE phenotype, the lipid-clearing capacity of LA-GCG is independent of the PDE4/cAMP/PKA axis. These findings provide the molecular basis for GCG-induced energy expenditure and metabolic benefits and suggest the phenotypic segregation of cAMP/PKA-dependent and independent effects.
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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:Background & Aims: Glucagon (GCG) analogues are gaining attention as promising components in incretin-based therapeutics for obesity and metabolic dysfunction-associated steatohepatitis. However, the biology of chronic glucagon treatment, in particular, the molecular underpinnings of GCG-induced energy expenditure and lipid metabolism, remain poorly defined. Methods: We utilized a long-acting GCG analogue (LA-GCG) in conjunction with hepatic and adipose glucagon receptor knockout mouse models. Through an integrative approach that combined metabolic, biochemical and omics techniques, we investigated the molecular mechanisms underlying GCG-induced energy expenditure and metabolic benefits. Results: We demonstrate that the LA-GCG enhances energy expenditure in diet-induced obese mice with an essential role of hepatic, but not adipose, GCGR signaling. Intriguingly, the enhancement in energy expenditure is observed only in obese but not in lean mice. The preferential efficacy is plausibly found in a prolonged activation of cAMP/PKA signaling through PDE4B/4D downregulation by LA-GCG. Conversely, the cAMP/PKA signaling is promptly attenuated by the PDE4B/4D activity in lean mice. Interestingly, unlike the EE phenotype, the lipid-clearing capacity of LA-GCG is independent of the PDE4/cAMP/PKA axis. Conclusions: These findings provide the molecular basis for GCG-induced energy expenditure and metabolic benefits and suggest the phenotypic segregation of cAMP/PKA-dependent and independent effects.
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