Systemic LSD1 inhibition prevents aberrant remodeling of metabolism in obesity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA867384 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20964745.fastq.gz | Fastqsanger.gz | |||
| SRR20964746.fastq.gz | Fastqsanger.gz | |||
| SRR20964747.fastq.gz | Fastqsanger.gz | |||
| SRR20964748.fastq.gz | Fastqsanger.gz | |||
| SRR20964749.fastq.gz | Fastqsanger.gz |
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Project description:The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates non-alcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting LSD1 has a context-dependent role in promoting maladaptive changes in obesity. Analysis of insulin target tissues identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD.
2022-10-17 | GSE210761 | GEO
Project description:Heterochromatin is a specialized form of chromatin that restricts access to DNA and inhibits genetic processes, including transcription and recombination. In Neurospora crassa, constitutive heterochromatin is characterized by trimethylation of lysine 9 on histone H3, hypoacetylation of histones, and DNA methylation. Here we explore whether the conserved histone demethylase, lysine-specific demethylase 1 (LSD1), regulates heterochromatin in Neurospora, and if so, how. Though LSD1 is implicated in heterochromatin regulation, its function is inconsistent across different systems; orthologs of LSD1 have been shown to either promote or antagonize heterochromatin expansion by removing H3K4me or H3K9me respectively. We identify three members of the Neurospora LSD complex (LSDC): LSD1, PHF1, and BDP-1, and strains deficient for any exhibit variable spreading of heterochromatin and establishment of new heterochromatin domains dispersed across the genome. Heterochromatin establishment outside of canonical domains in Neurospora share the unusual characteristic of DNA methylation-dependent H3K9me3; typically, H3K9me3 establishment is independent of DNA methylation. Consistent with this, the hyper-H3K9me3 phenotype of LSD1 knock-out strains is dependent on the presence of DNA methylation, as well as HCHC-mediated histone deacetylation, suggesting spreading is dependent on some feedback mechanism. Altogether, our results suggest LSD1 works in opposition to HCHC to maintain proper heterochromatin boundaries.
2021-07-21 | PXD017300 | Pride
Project description:Obesity is associated with insulin resistance, an important risk factor of type 2 diabetes, atherogenic dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. It has been postulated that accumulation of visceral adipose tissue (VAT) causes obesity-induced insulin resistance. The major purpose of this study was to test hypothesis that prophylactic VAT removal prevents the development of obesity-induced multi-organ (liver, skeletal muscle, adipose tissue) insulin resistance, dyslipidemia, and NAFLD. Accordingly, we surgically removed epididymal VAT from adult C57BL/6J mice and then evaluated in vivo and cellular metabolic pathways involved in glucose and lipid metabolism following feeding of chronic high-fat diet (HFD). We found that VAT removal prevented HFD-induced insulin resistance and markedly increased AKT-mediated insulin signaling in subcutaneous adipose tissue (SAT), liver, and skeletal muscle. VAT removal improved plasma lipid profiling and prevented obesity-induced NAFLD. In addition, VAT removal significantly increased circulating level of adiponectin, a key insulin-sensitizing adipokine, whereas it decreased interleukin-6, a pro-inflammatory adipokine. Data obtained from RNA-sequencing suggest that VAT removal prevents obesity-induced oxidative stress and inflammation in liver and SAT respectively. These findings demonstrate the causative role of VAT in the development of obesity and related systemic metabolic complications, such as insulin resistance, dyslipidemia, and NAFLD.
2021-04-01 | GSE157798 | GEO
Project description:Heterochromatin is a specialized form of chromatin that restricts access to DNA and inhibits genetic processes, including transcription and recombination. In Neurospora crassa, constitutive heterochromatin is characterized by trimethylation of lysine 9 on histone H3, hypoacetylation of histones, and DNA methylation. We explored whether the conserved histone demethylase, lysine-specific demethylase 1 (LSD1), regulates heterochromatin in Neurospora, and if so, how. Though LSD1 is implicated in heterochromatin regulation, its function is inconsistent across different systems; orthologs of LSD1 have been shown to either promote or antagonize heterochromatin expansion by removing H3K4me or H3K9me respectively. We identify three members of the Neurospora LSD complex (LSDC): LSD1, PHF1, and BDP-1. Strains deficient for any of these proteins exhibit variable spreading of heterochromatin and establishment of new heterochromatin domains throughout the genome. Although establishment of H3K9me3 is typically independent of DNA methylation in Neurospora, instances of DNA methylation-dependent H3K9me3 have been found outside regions of canonical heterochromatin. Consistent with this, the hyper-H3K9me3 phenotype of Δlsd1 strains is dependent on the presence of DNA methylation, as well as HCHC-mediated histone deacetylation, suggesting that spreading is dependent on some feedback mechanism. Altogether, our results suggest LSD1 works in opposition to HCHC to maintain proper heterochromatin boundaries.
| S-EPMC7544195 | biostudies-literature
Project description:Obesity is often associated with a low-grade systemic inflammation state that contributes to the development of insulin resistance and atherosclerotic complications. This is usually coupled with increased macrophage infiltration in the adipose tissue and a defect in adipocyte differentiation that results in accumulation of hypertrophic fat cells characterized by a deregulated pattern of adipokine expression. Here we show that knockdown of histone demethylase lsd1 in 3T3-L1 preadipocytes results in defective adipogenesis and derepression of an inflammatory program in these cells. The dataset consists of four sample groups: [1] 3T3-L1 preadipocytes (passage 19) transfected with a control scrambled siRNA at 24h after transfection (siC.24h), [2] 3T3-L1 preadipocytes (p.19) transfected with a siRNA directed against LSD1 at 24h after transfection (siLsd1.24h), [3] 3T3-L1 preadipocytes (p.21) transfected with a control scrambled siRNA at 48h after transfection (siC.48h), and [4] 3T3-L1 preadipocytes (p.21) transfected with a siRNA directed against LSD1 at 48h after transfection (siLsd1.48h). The 24h sample groups (siC.24h and siLsd1.24h) consist of two biological replicate samples; the 48h sample groups (siC.48h and siLsd1.48h) consist of three biological replicate samples. Each sample was hybridized to a separate array, for a total of ten arrays.
2013-12-31 | E-GEOD-25423 | biostudies-arrayexpress
Project description:Obesity is often associated with a low-grade systemic inflammation state that contributes to the development of insulin resistance and atherosclerotic complications. This is usually coupled with increased macrophage infiltration in the adipose tissue and a defect in adipocyte differentiation that results in accumulation of hypertrophic fat cells characterized by a deregulated pattern of adipokine expression. Here we show that knockdown of histone demethylase lsd1 in 3T3-L1 preadipocytes results in defective adipogenesis and derepression of an inflammatory program in these cells.
2013-12-31 | GSE25423 | GEO
Project description:Analysis of the effect of using a fruit and vegetable juice concentrate to reduce systemic inflammation in obesity. The hypothesis tested whether the presence of polyphenols in the fruit and vegetable juice concentrate could reduce the expression of systemic inflammatory genes in the blood of Obese patients with high levels of plasma CRP (≥3.0). Results provide evidence that systemic inflammatory genes/ and or pathways may be modulated by the fruit and vegetable juice concentrate.
2016-09-29 | GSE87454 | GEO
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Project description:CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity
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Project description:Lysine specific demethylase 1 (LSD1), which demethylates mono- and di- methylated histone H3-Lys4 as part of a complex including CoREST and histone deacetylases (HDAC), is essential for embryonic development in the mouse beyond e6.5 days. Here, we demonstrate that LSD1 expression and therefore function, is restricted to the epiblast of the post- implantation embryo. Conditional deletion of LSD1 in mouse embryonic stem (ES) cells, in vitro counterpart of the epiblast, revealed a reduction in CoREST protein, a subsequent decrease in associated HDAC activity and a global increase in Histone H3 Lys56 acetylation. Despite this biochemical perturbation, LSD1 deleted ES cells proliferate normally and retain stem cell characteristics. Loss of LSD1 causes the aberrant expression of 588 genes, including a number of transcription factors with roles in tissue development such as brachyury, Hoxb7, Hoxd8 and RARγ. Brachyury, a key-regulator of mesodermal differentiation, is a direct target gene of LSD1 and is over-expressed in e6.5 day Lsd1 genetrap embryos. Thus, LSD1 is required for the appropriate expression of key developmental regulators, via the stabilization of the LSD1/CoREST/HDAC complex, during early embryonic development. RNA samples from Lsd1Lox/Δ3 and Lsd1Δ3/Δ3 cells were compared, three biological replicates were performed.
2010-12-06 | E-GEOD-21131 | biostudies-arrayexpress