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.
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Project description:Hypothalamus of diet-induced obese (DIO) mice treated with celastrol or DMSO
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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).
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Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) mesenchymal stem cells (MSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS MSCs were differentiated into bone in the presence or absence of sodium salicylate. Total RNA was extracted and global gene expression was analyzed.
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