The sperm quality in DIO male mice is linked to the NF-κB signaling and Ppp2ca expression in the hypothalamus
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ABSTRACT:
PROVIDER: PRJNA1198956 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31735325_1.fastq.gz | Fastqsanger.gz | |||
| SRR31735325_2.fastq.gz | Fastqsanger.gz | |||
| SRR31735326_1.fastq.gz | Fastqsanger.gz | |||
| SRR31735326_2.fastq.gz | Fastqsanger.gz | |||
| SRR31735327_1.fastq.gz | Fastqsanger.gz |
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Project description:Emerging studies have reported a significant correlation between obesity and a decline in sperm quality among males, however, the underlying mechanism remains elusive. In this study, we observed that male mice with diet-induced obesity (DIO) exhibited functional alteration in the hypothalamic-pituitary-gonadal (HPG) axis, as evidenced by disruption of luteinizing hormone (LH) pulse release. This alteration was attributed to the activation of nuclear factor kappa B subunit (NF-κB) signaling in the hypothalamus, which subsequently led to a decline in sperm quality. The application of RNA-seq analysis in the hypothalamic arcuate nucleus (ARC) of DIO male mice has revealed a signaling network implicating protein phosphatase 2 catalytic subunit alpha (Ppp2ca), which is involved in the disruption of LH pulse secretion. Activation of NF-κB signaling increased expression, which decreased the Kiss1 expression through inhibition of Akt kinase (AKT) and cAMP responsive element binding protein 1 (CREB1) activities. Overexpression of the Ppp2ca gene in the hypothalamic ARC resulted in disrupted LH pulse secretion patterns and reduced sperm quality. Collectively, our findings provide novel insights into the molecular mechanisms underlying the decline in sperm quality observed in male DIO mice.
2025-03-05 | GSE284408 | GEO
Project description:Since leptin signaling in the hypothalamus is critical to regulate food intake and body weight, we investigated how celastrol alters the hypothalamic transcriptome of DIO mice. By doing this analysis, genes with potential relevance for celastrol-mediated leptin sensitization could be identified.
2018-12-27 | GSE124353 | GEO
Project description:Hypothalamus of diet-induced obese (DIO) mice treated with celastrol or DMSO
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Project description:Ppp2ca is a subunit of PP2A complex, which plays critical roles in variaty of tumors and autoimmune diseases. Deletion of Ppp2ca in mice led to hematopoietic disorders, showing increased myeloid differentiation and decreased lymphoid differentiation. Metabolic analysis indicated that Ppp2ca deficiency resulted in aerobic glycolysis in hematopoietic stem cells (HSCs), with elevated levels of lactate. Genetic deletion of LDHA or blocking of lactate metabolism was found to be able to rescue the phenotypic abnormal caused by Ppp2ca insufficiency. Therefore, this study proposed that LDHA could be served as a novel target for the treatment of Ppp2ca related diseases.
2025-11-11 | GSE248148 | GEO
Project description:Ppp2ca is a subunit of PP2A complex. In addition to functioning through its phosphatase activity, PPP2CA has been demonstrated to form a complex with the INTEGRATOR in the promoter of genes and regulate downstream gene expression at the transcriptional level. We found that Ppp2ca deficiency resulted in a global increased transcripiton of genes, with most significantly changed genes enriched in metabolic pathways.
2025-11-11 | GSE248147 | GEO
Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).
2015-06-18 | E-GEOD-68317 | biostudies-arrayexpress
Project description:Ppp2ca is a subunit of PP2A complex, which plays critical roles in a variaty of tumors. Compared with control, ppp2ca deficient hematopoietic stem cells (HSCs) showed increased myeloid differentiation and decreased lymphoid differentiation. We further found that Ppp2ca deficiency led to global increased acetylation of H3K27 in HSCs. Consistent with these, the acetylation levels of H3K27 in the promoters of myeloid genes were found elevated. Thus, PPP2CA might affect hematopoietic differentiation through epigenetic regulation.
2025-11-11 | GSE248146 | GEO
Project description:Protein phosphatase 2A (PP2A) is an essential Ser/Thr phosphatase that regulates a plethora of cellular processes. PP2A operates as a holoenzyme complex, comprising one each of the scaffolding (A), regulatory (B) and catalytic (C) subunits. PPP2CA is the principal catalytic subunit of the PP2A holoenzyme complex. Although previous studies have reported many substrates of specific PP2A holoenzyme complexes, the full scope of PP2A substrates in cells remains to be defined. To address this, we generated HEK293 cells in which PPP2CA was homozygously knocked in with a dTAG, allowing for efficient and selective degradation of dTAG-PPP2CA with proteolysis-targeting chimeras (PROTACs) targeting the dTAG. By employing an unbiased global phospho-proteomic analysis, we identified 6,280 phospho-peptides corresponding to 2,204 proteins that showed a significant increase in abundance upon dTAG-PPP2CA degradation, implicating them as potential PPP2CA substrates. Among these, some were established PP2A substrates, while most were novel. Bioinformatic analyses revealed the involvement of the identified potential PPP2CA substrates in many cellular processes, including spliceosome function, the cell cycle, RNA transport and ubiquitin-mediated proteolysis. We show that a pSP/pTP motif is a predominant target for PPP2CA. We confirmed some of our phosphoproteomic data with immunoblotting, by utilising commercially available phospho-specific antibodies. We provide an in-depth atlas of potential PPP2CA substrates and establish targeted degradation as a robust tool to unveil phosphatase substrates in cells.
2024-03-18 | PXD045779 | Pride
Project description:To further identify the mostly influenced signal pathways under Kdm6 inhibitor treatment, the microarray analysis was performed to screen the gene expression profile in the hypothalamus of DIO mice. The DIO mice were administrated with vehicle or 30 mg/kg GSK-J4 i.p. for 4 days. Totally, 205 genes were up regulated over 2 fold and 845 genes were down regulated over 2 fold.
2021-05-01 | GSE115113 | GEO
Project description:The hypothalamus is the brain region that regulates systemic body metabolism and multiple functions in other brain regions. In adult mice, the hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with the dysregulation of body metabolism and physiology that occurs during aging, the NSC population in the hypothalamus declines with age. Here, we introduce a novel protocol that yields scalable and storable hypothalamus-specific NSCs (htNSCs) from hypothalamus-like organoids derived from human pluripotent stem cells (hPSCs). Implanting htNSCs into the medio-basal hypothalami of aged mice conspicuously ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function and produced corresponding histologic changes in various body tissues. Single transcriptome and immunohistochemical analyses of the grafted hypothalamic tissues showed that the anti-aging effects were attained by correcting glial NF-κB, TNFα, and NLRP3 inflammasome pathways. Collectively, our findings support the potential of anti- or healthy aging therapies that target htNSCs and hypothalamic inflammation.
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