Leptin secreted from testicular microenvironment modulates hedgehog signaling to augment the endogenous function of Leydig cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA806937 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18016544_1.fastq.gz | Fastqsanger.gz | |||
| SRR18016544_2.fastq.gz | Fastqsanger.gz | |||
| SRR18016545_1.fastq.gz | Fastqsanger.gz | |||
| SRR18016545_2.fastq.gz | Fastqsanger.gz | |||
| SRR18016546_1.fastq.gz | Fastqsanger.gz |
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Project description:Although testosterone deficiency (TD) may be present in 1 out of 5 men 40 years or older, the factors responsible for TD remain largely unknown. Leydig stem cells (LSCs) differentiate into adult Leydig cells (ALC) and produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. However, recent studies have suggested that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells (PMC), plays an instrumental role in LSC differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). It was hypothesized that TME releases paracrine factors to modulate LSC differentiation. For this purpose, cells (Sertoli, PMCs, LSCs and ALCs) were extracted from men undergoing testis biopsies for sperm retrieval and were evaluated for the paracrine factors in the presence or absence of TME (Sertoli and PMC). The results demonstrated that TME secretes leptin which induces LSC differentiation and increases T production. Leptin’s effects on LSC differentiation and T production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, leptin acts on LSCs upstream of DHH; leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effects on leptin levels. Taken together, these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD.
2022-02-17 | GSE196702 | GEO
Project description:Although testosterone deficiency (TD) may be present in one out of five men 40 years or older, the factors responsible for TD remain largely unknown. Leydig stem cells (LSCs) differentiate into adult Leydig cells (ALC) and produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. However, recent studies have suggested that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells (PMC), plays an instrumental role in LSC differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). It was hypothesized that the TME releases paracrine factors to modulate LSC differentiation. For this purpose, cells (Sertoli, PMCs, LSCs, and ALCs) were extracted from men undergoing testis biopsies for sperm retrieval and were evaluated for the paracrine factors in the presence or absence of the TME (Sertoli and PMC). The results demonstrated that TME secretes leptin, which induces LSC differentiation and increases testosterone production. Leptin's effects on LSC differentiation and testosterone production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, leptin binds to the leptin receptor on LSCs and induces DHH signaling to modulate LSC differentiation. Leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effect on leptin levels. Taken together, these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD.
| S-EPMC8897450 | biostudies-literature
Project description:Ad4BP/SF-1 is a transcription factor regulating gene expression related to steroidogenesis and energy metabolism. Previous studies have indicated that Ad4BP/SF-1 regulates fetal Leydig cell differentiation from progenitor cells. However, the underlying regulatory mechanisms remain unclear. Here, we reveal that Ad4BP/SF-1 directly regulates energy metabolisms in differentiated fetal Leydig cells through transcriptional upregulation.
2025-03-24 | GSE292012 | GEO
Project description:Fetal Leydig cells are essential for masculinization through androgen production during fetal development. Previous studies have indicated that Desert Hedgehog regulates differentiation from progenitor cells. Our previous research showed a significant upregulation of energy metabolism-related genes during fetal Leydig cell differentiation. However, the underlying regulatory mechanisms remain unresolved. Here, we reveal that Desert Hedgehog rapidly activates energy metabolisms in testicular interstitial cells (W-EGFP cells) containing fetal Leydig progenitor cells without activating gene expression.
2025-03-24 | GSE292010 | GEO
Project description:Testicular aging commonly leads to testosterone deficiency and impaired spermatogenesis, yet the underlying mechanisms remain elusive. Here, a comprehensive analysis of senescence landscapes in mice testes during aging revealed that the Leydig cells (LCs) are particularly vulnerable to aging processes. Single-cell RNA sequencing identified the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme of ketogenesis, decreased significantly in LCs from aged mice. Additionally, the concentrations of ketone bodies β-hydroxybutyric acid (BHB) and acetoacetic acid (AcAc) in the young testes were substantially higher than that in serum, but significantly diminished in aged testes. Silencing of Hmgcs2 in young LCs resulted in decreased ketone body production, which in turn drove LCs senescence and accelerated testicular aging. Mechanistically, BHB acted as an endogenous inhibitor of histone deacetylase 1 to upregulate the expression of Foxo3a by promoting histone acetylation, thereby mitigating LCs senescence and promoting testosterone production. Consistently, enhanced ketogenesis by genetic manipulation or oral BHB supplementation alleviated LCs senescence and ameliorated testicular aging in aged mice. These findings highlight defective ketogenesis as a pivotal factor in testicular aging, suggesting novel therapeutic avenues for addressing age-related testicular dysfunction.
2025-03-27 | GSE287203 | GEO
Project description:Spermatogonial stem cells are quiescent, undergo self-renewal or differentiating divisions, thereby forming the cellular basis of spermatogenesis. This cellular development is orchestrated by follicle-stimulating hormone (FSH), through the production of Sertoli cell-derived factors, and by Leydig cell-released androgens. Here, we investigate the transcriptional events induced by Fsh in a steroid-independent manner on the restart of zebrafish (Danio rerio) spermatogenesis ex vivo, using testis from adult males where type A spermatogonia were enriched by estrogen treatment in vivo. Under these conditions, RNA sequencing preferentially detected differentially expressed genes in somatic/Sertoli cells. Fsh-stimulated spermatogonial proliferation was accompanied by modulating several signaling systems (i.e. Tgf-β, Hedgehog, Wnt and Notch pathways). In silico protein-protein interaction analysis indicated a role for Hedgehog family members potentially integrating signals from different pathways during fish spermatogenesis. Moreover, Fsh had a marked impact on metabolic genes, such as lactate and fatty acid metabolism, or on Sertoli cell barrier components. Fish Leydig cells express the Fsh receptor and one of the most robust Fsh-responsive genes was insulin-like 3 (insl3), a Leydig cell-derived growth factor. Follow-up work showed that recombinant zebrafish Insl3 mediated pro-differentiation effects of Fsh on spermatogonia in an androgen-independent manner. Our experimental approach allowed focusing on testicular somatic genes in zebrafish and showed that the activity of signaling systems known to be relevant in stem cell systems was modulated by Fsh, providing promising leads for future work, as exemplified by the studies on Insl3.
2016-09-13 | GSE84436 | GEO
Project description:Evidence that persistent environmental pollutants may target the male reproductive system is increasing. The male reproductive system is regulated by secretion of testosterone by testicular Leydig cells, and perturbation of Leydig cells function may have ultimate consequences. 3-methylsulfonyl-DDE (3-MeSO2-DDE) is a potent adrenal toxicants formed from the persistent insecticide DDT. Although studies have revealed endocrine disruptive effect of 3-MeSO2-DDE, the underlying mechanisms at cellular level in steroidogenic Leydig cells remains to be established. The current study addresses the effect of 3-MeSO2-DDE viability, hormone production and proteome response of primary neonatal porcine Leydig cells. The AlamarBlue™ assay was used to evaluate cell viability. Solid phase radioimmunoassay was used to measure concentration of hormones produced by both unstimulated and luteinizing hormone (LH)-stimulated Leydig cells following 48 h exposure. Protein samples from Leydig cells exposed to a non-cytotoxic concentration of 3-MeSO2-DDE (10µM) were subjected to nano-LC-MS/MS and analyzed on a Q Exactive mass spectrometer and quantified using label-free quantitative algorithm. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) were carried out for functional annotation and identification of protein interaction networks. 3-MeSO2-DDE regulated Leydig cell steroidogenesis differentially depending on cell culture condition. Whereas its effect on testosterone secretion at basal condition was stimulatory, the effect on LH-stimulated cells was inhibitory. From triplicate experiments, a total of 7540 proteins were identified in which the abundance of 87 proteins in unstimulated Leydig cells and 146 proteins in LH-stimulated Leydig cells were found to be significantly regulated in response to 3-MeSO2-DDE exposure. These proteins not only are the first reported in relation to 3-MeSO2-DDE exposure, but also display small number of proteins shared between culture conditions, suggesting the action of 3-MeSO2-DDE on several targeted pathways, including mitochondrial dysfunction, oxidative phosphorylation, EIF2-signaling, and glutathion-mediated detoxification. Further identification and characterization of these proteins and pathways may build our understanding to the molecular basis of 3-MeSO2-DDE induced endocrine disruption in Leydig cells.
2016-01-05 | PXD003165 | Pride
Project description:To determine whole target genes of Ad4BP/SF-1, ChIP-seq was performed. Soluble chromatin was prepared from mouse Leydig cells treated or non-treated with cAMP. As a result, 5,721 and 4,025 ChIP-peaks were identified in Leydig and cAMP-treated Leydig cells, respectively.
2018-02-01 | GSE106955 | GEO