Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
Oocyte-specific Ahr deletion disrupts folliculogenesis and female fertility in mice.
Chen P, Ruan J, Xue F … +9 more , Dai X, Tang C, Chen M, Xiao N, Cai Z, Yang C, He C, Wang W, Zuo Z
Mol Cell Endocrinol · 2025 Nov · PMID 40945597 · Publisher ↗
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates various biological processes, including xenobiotic metabolism, immune response, and reproduction. Although previous studies ha...
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates various biological processes, including xenobiotic metabolism, immune response, and reproduction. Although previous studies have shown that AHR plays a role in ovarian follicle development, the precise role of oocyte-expressed AHR in female reproduction remains unclear. In this study, oocyte-specific Ahr knockout (cKO) mice generated by crossing the Ahr (Ahr) and Gdf9-cre transgenic mouse strains were used to answer this open question. The cKO female mice exhibited a disrupted estrous cyclicity and subfertility. Histological analyses demonstrated that oocyte AHR loss reduces the number of primary follicles while increasing the number of secondary follicles and corpus lutea in mouse ovary. Hormonal analysis revealed decreased serum estradiol and follicle-stimulating hormone, indicating a disruption of the hypothalamic-pituitary-gonadal axis in cKO mice. TUNEL and Western blotting results demonstrate that deletion of oocyte AHR also results in increased apoptosis in ovarian granulosa cells (GCs), downregulated expression of Gdf9 and Bmp15 in oocytes, and disrupted bidirectional oocyte-GC communication. In conclusion, our findings reveal that the aryl hydrocarbon receptor plays a role beyond sensing environmental chemicals and endogenous compounds and underscore a critical role of oocyte-expressed Ahr in maintain follicle development, ovarian function, and female reproductive health.
Developmental programming: Differing impact of prenatal testosterone and prenatal bisphenol-A -treatment on hepatic methylome in female sheep.
Dou J, Thangaraj SV, Zhou Y … +2 more , Padmanabhan V, Bakulski K
Mol Cell Endocrinol · 2025 Nov · PMID 40914344 · Full text
Steroid hormones are integral to pregnancy and fetal development, regulating processes such as metabolism, inflammation, and immune responses. Excessive prenatal steroid exposure, through lifestyle choices or environment...
Steroid hormones are integral to pregnancy and fetal development, regulating processes such as metabolism, inflammation, and immune responses. Excessive prenatal steroid exposure, through lifestyle choices or environmental chemicals, can lead to metabolic dysfunctions in offspring. The research focuses on how exposure to testosterone (T) and bisphenol A (BPA) affects the liver's DNA methylome, a key component of the epigenome influencing long-term health. Using Suffolk sheep, the study involved two cohorts: one exposed to prenatal-T and the other to prenatal-BPA. Whole genome bisulfite sequencing was employed to map DNA methylation across over 22 million CpG sites. Regions with p-value<10 and a magnitude of difference of at least 5 % methylation between groups were considered differentially methylated. Results demonstrated substantial differential methylation in the liver tissues due to both treatments, with prenatal-T causing unique epigenetic modifications distinct from those induced by prenatal-BPA. Specifically, prenatal-T treatment resulted in 53 differentially methylated regions (DMRs), of which 31 were located in gene regions, including exons. Prenatal-BPA exposure led to 32 DMRs, with 22 associated with gene regions. These modifications were associated with genes governing lipid and glucose metabolism, potentially underlying the observed metabolic disruptions such as insulin resistance and dyslipidemia. Pathway analysis revealed that genes differentially methylated due to prenatal-T were involved in cellular organization, while those affected by prenatal-BPA were enriched in signal regulation pathways. The findings underscore how prenatal exposure to steroid excess and steroid-mimics influence epigenetic landscapes, contributing to metabolic disease programming.
RNA binding protein SERBP1 is indispensable for oocyte development and maturation in mice.
Wang L, OuYang S, Li B … +1 more , Kong N
Mol Cell Endocrinol · 2025 Sep · PMID 40902969 · Publisher ↗
RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression and RNA processing during mammalian oocyte development. SERPINE1 mRNA-binding protein 1 (SERBP1), a conserved RNA-binding protei...
RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression and RNA processing during mammalian oocyte development. SERPINE1 mRNA-binding protein 1 (SERBP1), a conserved RNA-binding protein (RBP), exhibits prominent expression in the female reproductive system and throughout oogenesis. Conditional deletion of Serbp1 using oocyte-specific Zp3/Gdf9-Cre drivers resulted in arrested oocyte growth, female infertility, and failure of blastocyst formation from two-cell embryos. Phenotypic analysis revealed spindle assembly defects, impaired asymmetric division, and compromised meiotic competence in oocytes. Notably, Serbp1 ablation also induced granulosa cell apoptosis and elevated Erk1/2 phosphorylation levels, indicating dysregulation of somatic microenvironment. Furthermore, conditional knockout mice exhibited prolonged diestrus cycles. Collectively, these findings demonstrate that SERBP1 coordinates essential RNA-regulatory functions for oocyte developmental competence through both cell-autonomous mechanisms and somatic-germline crosstalk.
The N-terminal region of HASPIN regulates phosphorylation of AURKA and meiotic progression in spermatocytes.
Li H, Xu Y, Jiang X … +13 more , Ren J, Wang Y, Zhang X, Gao M, Zhang L, Wang Y, Li Z, Wang S, Wang T, Wang M, Situ C, Guo X, Zhu H
Mol Cell Endocrinol · 2025 Nov · PMID 40885374 · Publisher ↗
Protein phosphorylation is an important post-translational modification that plays a critical regulatory role in meiosis. HASPIN, a kinase highly conserved from yeast to mammals, is required for male fertility. In this s...
Protein phosphorylation is an important post-translational modification that plays a critical regulatory role in meiosis. HASPIN, a kinase highly conserved from yeast to mammals, is required for male fertility. In this study, we found that the intrinsically disordered N-terminal domain of HASPIN is also required for this function. Mice with deletion of N-terminal amino acids (aa) 1-243 of HASPIN exhibited reduced testicular size, sperm count, and fertility. Using immunoprecipitation-mass spectrometry and phosphoproteomics analysis, we found that HASPIN could interact with AURKA and regulate its phosphorylation at T279 via its N-terminus. Taken together, our results suggest that the N-terminus of HASPIN regulates AURKA kinase activity to affect male fertility.
α-Linolenic acid rich-chia seed improves glucose tolerance, modulates gluconeogenic pathway and hepatic insulin signaling in an experimental model of metabolic syndrome.
Vega Joubert MB, Oliva ME, Ingaramo P … +1 more , D'Alessandro ME
Mol Cell Endocrinol · 2025 Nov · PMID 40846265 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is recognized as the hepatic manifestation of Metabolic Syndrome. The aim of this work was to evaluate the effects of chia seed, rich in α-linolenic acid,...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is recognized as the hepatic manifestation of Metabolic Syndrome. The aim of this work was to evaluate the effects of chia seed, rich in α-linolenic acid, on glucose tolerance, enzyme activities and transcription factors involved in gluconeogenesis, and key molecules in insulin signaling in sucrose-rich diet (SRD) fed rats. Male Wistar rats were fed a reference diet (RD) for 6 months or a SRD for 3 months. Then, the latter group was randomly divided into two subgroups. One subgroup continued receiving SRD for up to 6 months and the other was fed with a SRD where chia seed was incorporated as a source of dietary fat for the next 3 months (SRD + CHIA). The results showed that chia seed improved glucose tolerance, reversed the increase in PEPCK, FBPase, and Glucose-6-Pase, and reduced the Glucose-6-Pase/GK ratio. Additionally, chia seed improved tAMPK and pAMPK protein levels, while maintaining GLUT-2 protein levels similar to those in the RD group. Under insulin stimulation, p-AKT protein levels were higher in the SRD + CHIA group than in the unstimulated group. IRS-1 and PGC-1α protein expression levels were similar among the three experimental groups. Liver FOXO-1 mRNA expression was decreased in the SRD + CHIA group. Finally, chia seed increased the n-3/n-6 ratio in hepatic membrane phospholipids. The present study demonstrated that chia seed modulate multiple mechanisms that enhance glucose metabolism and insulin signaling in SRD fed rats. These effects are mediated, at least in part, by the enrichment of n-3 PUFAs in liver tissue.
Transcriptomic modifications in maternal pancreatic islets during the period around weaning in mice.
Burgos-Gamez X, Morales-Castillo P, Hernández-Vázquez A … +3 more , Pastén-Hidalgo K, García-Vázquez F, Fernandez-Mejia C
Mol Cell Endocrinol · 2025 Nov · PMID 40812554 · Publisher ↗
Identifying the mechanisms and molecular factors that enhance beta-cell mass is crucial for developing strategies to combat diabetes, as beta-cell mass declines with disease progression. Recent research has indicated an...
Identifying the mechanisms and molecular factors that enhance beta-cell mass is crucial for developing strategies to combat diabetes, as beta-cell mass declines with disease progression. Recent research has indicated an increase in beta-cell proliferation and a significant islet expansion around the weaning period in mice. This study aims to identify transcripts associated with changes in the islets around weaning-a physiological stage previously unexplored in islets. A ribonucleic acid (RNA) sequencing analysis of the transcriptome was performed at four key time points: the end of lactation, when beta-cell proliferation increases; the day of weaning, when the hormonal and metabolic environment transitions from lactation to the non-lactating stage; the third day post-weaning, when islet area peaks, as observed in our prior studies; and in age-matched female control mice. The results revealed dynamic transcriptomic changes. The messenger ribonucleic acid (mRNA) expression levels of genes regulated by prolactin, including its receptor, signaling inhibitor Cish, tryptophan hydroxylase, and osteoprotegerin, increased during lactation and subsequently declined. Plasma prolactin concentrations rose during lactation, but plasma osteoprotegerin levels remained stable across groups. Notably, no changes were observed in known prolactin-regulated cyclins that positively influence the cell cycle, such as Ccna2, Ccnb1, and Ccnb2. However, a decrease in the expression of Cdkn1a, a negative regulator of the cell cycle, was noted. Surprisingly, microscopy analysis indicated increased apoptosis markers in islet peripheral cells that were negative for insulin immunostaining. This study is the first to identify transcriptomic and cellular changes around weaning, offering new insights into islet mass plasticity.
4T1 breast cancer cells exposed to extracellular vesicles from MDA-MB-231 cells stimulated with Bisphenol A increase the growth of mammary tumors and metastasis in female Balb/cJ mice.
Torres-Alamilla P, Castillo-Sanchez R, Cortes-Reynosa P … +3 more , Sanchez-Juarez M, Gomez R, Salazar EP
Mol Cell Endocrinol · 2025 Oct · PMID 40782997 · Publisher ↗
Breast cancer is the most prevalent neoplasia in women worldwide. Triple negative breast cancer (TNBC) is a subtype characterized by the absence of estrogen receptor, progesterone receptor and HER2 expression. Bisphenol...
Breast cancer is the most prevalent neoplasia in women worldwide. Triple negative breast cancer (TNBC) is a subtype characterized by the absence of estrogen receptor, progesterone receptor and HER2 expression. Bisphenol A (BPA) is a chemical used in the synthesis of polycarbonate plastics and epoxy resins and its intake is related with breast cancer progression. Extracellular vesicles (EVs) are vesicles released by cells that mediate intercellular communication. However, the role of BPA in the release of EVs mediating cancer progression in TNBC remains to be studied. We hypothesize that EVs from BPA-stimulated TNBC cells promote metastasis-related processes, tumor growth and enhanced metastasis in a breast cancer mouse model. This study aims to evaluate the functional role of EVs from BPA-stimulated TNBC cells in metastasis-related processes and breast cancer progression using "in vitro" 4T1 cells models and an "in vivo" breast cancer mouse model. Findings demonstrate that exposition of TNBC 4T1 cells to EVs from TNBC MDA-MB-231 cells stimulated with 1 μM BPA for 24 h (BPA-EVs) significantly increases migration, invasion and MMP-9 secretion, compared to 4T1 cells exposed to EVs from non-stimulated MDA-MB-231 cells (Ctrl-EVs). Furthermore, Balb/cJ mice inoculated in mammary fat pad with 4T1 cells exposed to BPA-EVs show mammary tumors with more weight and volume, and more metastatic nodules in lung and liver than Balb/cJ mice inoculated with 4T1 cells exposed to Ctrl-EVs. In conclusion, BPA-EVs represent a significant mediator of TNBC progression, which defining the EVs as a novel element through which BPA promotes breast cancer progression.
Deciphering the allosteric control of androgen receptor DNA binding by its disordered N-terminal domain.
Heling LWHJ, van der Veen J, Rofe A … +9 more , West E, Jiménez-Panizo A, Alegre-Martí A, Sheikhhassani V, Ng J, Schmidt T, Estébanez-Perpiñá E, McEwan IJ, Mashaghi A
Mol Cell Endocrinol · 2025 Oct · PMID 40782996 · Publisher ↗
The androgen receptor (AR) plays a pivotal role in male physiological development and is implicated in the pathogenesis of various diseases, including prostate cancer. Its N-terminal domain (NTD), characterized by intrin...
The androgen receptor (AR) plays a pivotal role in male physiological development and is implicated in the pathogenesis of various diseases, including prostate cancer. Its N-terminal domain (NTD), characterized by intrinsic disorder, is essential for transcriptional activation. Despite its importance, the precise mechanisms by which the NTD regulates AR's DNA-binding activity remain incompletely understood. This research elucidates the allosteric control mediated by specific NTD subregions-the N-terminal region (NR) and the C-terminal region (CR)-over the DNA binding properties of a truncated AR construct comprising the DNA-binding and ligand-binding domains (ΔNTD-AR). Microscale Thermophoresis (MST) and single-molecule fluorescence imaging were employed to investigate these interactions. This study demonstrates that the NTD subregions exert differential modulatory effects on the kinetics and affinity of ΔNTD-AR binding to DNA. MST analyses indicated that CR reduces ΔNTD-AR DNA binding affinity concentration-dependently, whereas NR did not significantly alter affinity. Single-molecule investigations revealed NR accelerates dissociation, while CR markedly diminishes binding frequency and accelerates dissociation. Combined NR and CR exerted complex effects, synergistically reducing affinity at high concentrations and altering kinetics distinctively compared to individual subregions. Collectively, these results delineate distinct functional roles for the NR and CR subregions in allosterically modulating AR-DNA interactions. This detailed understanding of intrinsic AR regulation offers mechanistic insights into receptor function and highlights potential allosteric sites for therapeutic intervention.
Adipose tissue-specific Yap knockout exacerbates diet-induced obesity through suppression of lipolysis.
Xiao H, Jiang P, Xia F … +7 more , Wu D, Huang H, Tu S, Luo H, Wu Y, Duan Q, Zhu L
Mol Cell Endocrinol · 2025 Nov · PMID 40780686 · Publisher ↗
BACKGROUND AND AIMS: YAP regulates various cellular processes, including cell contact inhibition, mechanotransduction, cell differentiation and proliferation, apoptosis, and cancer progression. Although YAP suppresses ad...
BACKGROUND AND AIMS: YAP regulates various cellular processes, including cell contact inhibition, mechanotransduction, cell differentiation and proliferation, apoptosis, and cancer progression. Although YAP suppresses adipogenesis in vitro, its role in obesity has not yet been completely elucidated. METHODS AND RESULTS: In this study, we generated an adipose tissue-specific Yap knockout mouse model (YapaKO), and found that male, but not female, YapaKO mice showed an enhanced high-fat diet-induced obesity phenotype compared to control mice. Mechanistically, this effect is potentially due to suppressed lipolytic activity, which results from the decreased expression of triglyceride lipolytic enzymes, including ATGL and HSL. The inhibition of lipolytic activity led to reduced levels of circulating free fatty acids during fasting, making male mice unable to maintain core body temperature after cold exposure and showing impaired exercise capability in the fasted state. This study reveals a novel role of YAP in controlling lipolysis. CONCLUSION: YAP is a physiological regulator of lipolysis in the adipose tissue. YAP activation in adipose tissue may facilitate lipolysis and reduce obesity.
MeCP2 attenuates inflammation and regulates T cell phenotype via SFRP4 suppression in preeclampsia.
Peng M, Nie Y, Luo Y … +12 more , Nkoua GDM, Zhang S, Liu H, Zhang W, Xiao S, Zhou Y, Lai W, Deng Y, Yu L, Liu J, Zhou X, Ding Y
Mol Cell Endocrinol · 2025 Nov · PMID 40780685 · Publisher ↗
Preeclampsia (PE) is a major pregnancy complication characterized by an aberrant immune response. Methyl CpG binding protein 2 (MeCP2) is a potential regulator of secreted frizzled-related protein 4 (SFRP4), and both MeC...
Preeclampsia (PE) is a major pregnancy complication characterized by an aberrant immune response. Methyl CpG binding protein 2 (MeCP2) is a potential regulator of secreted frizzled-related protein 4 (SFRP4), and both MeCP2 and SFRP4 are implicated in immune homeostasis. This study investigated the regulatory role of MeCP2/SFRP4 in immune cells in PE. A rat model of PE induced by reduced uterine perfusion pressure (RUPP) and an in vitro model using lipopolysaccharide (LPS)-stimulated HTR-8/SVneo cells were established. A co-culture system of LPS-challenged HTR-8/SVneo cells and T cells was also employed. MeCP2 expression was reduced and inversely correlated with SFRP4 levels in PE. MeCP2 overexpression suppressed Th1/Th17 differentiation while promoting Th2/Treg phenotypes, along with modulation of associated immune cytokines. It also enhanced colony formation, proliferation, migration, and invasion, while reducing apoptosis following co-culture. SFRP4 supplementation reversed the effects of MeCP2 overexpression on T cell proliferation and cytokine release. Collectively, these findings suggest that MeCP2 regulates T cell phenotype and inflammatory responses by inhibiting SFRP4, providing potential avenues for immunotherapeutic intervention in PE.
The role of IGFBP7 in the immune regulation of PCOS-like symptoms based on spleen transcriptome and TCR β CDR3 repertoire analysis.
Chen L, Hui L, Shi Y … +4 more , Wang A, Zhang Y, Yao X, Li J
Mol Cell Endocrinol · 2025 Oct · PMID 40780684 · Publisher ↗
Polycystic ovary syndrome (PCOS) is often linked with immune dysregulation and chronic inflammation, where immune responses play a significant role. Recent studies have identified IGFBP7 involvement in immune processes,...
Polycystic ovary syndrome (PCOS) is often linked with immune dysregulation and chronic inflammation, where immune responses play a significant role. Recent studies have identified IGFBP7 involvement in immune processes, suggesting its potential role in modulating immune function. However, the involvement of IGFBP7 in immune modulation within the context of PCOS remains underexplored. In this study, we utilized a Dehydroepiandrosterone (DHEA)-induced PCOS mouse model, including both wild-type and IGFBP7 knockout (KO) mice, to investigate the involvement of IGFBP7 in immune regulation related to PCOS. We performed spleen transcriptome sequencing and TCR β CDR3 repertoire sequencing to assess changes in immune gene expression and T cell receptor diversity. Our findings demonstrate that IGFBP7 significantly mitigates PCOS-like symptoms, normalizing estrous cycles and improving ovarian morphology. Transcriptome analysis revealed a substantial downregulated genes in the spleen of IGFBP7 mice, with enrichment in pathways associated with immune function. Additionally, in the DHEA-induced PCOS mouse model, TCR β CDR3 repertoire analysis indicated increased clonality and decreased diversity, alongside alterations in V and J gene usage in IGFBP7 mice. These results highlight the critical role of IGFBP7 in immune regulation within the context of PCOS, offering new insights into the immune mechanisms underlying PCOS pathology.
Sex-specific differences in the influence of maternal obesity on the oxidative and inflammatory status in the maternal-placental-fetal unit: new insights into the placental sphingolipid profile.
Hernández MH, Santos ED, Rodriguez Y … +7 more , Ferchaud-Roucher V, Rousseau-Ralliard D, Frambourg A, Berveiller P, Vialard F, Couturier-Tarrade A, Dieudonne MN
Mol Cell Endocrinol · 2025 Oct · PMID 40780683 · Publisher ↗
Although maternal obesity influences placental and fetal development, the underlying molecular mechanisms have yet to be determined. Oxidative and inflammatory status at the fetal-placental unit appear to be involved in...
Although maternal obesity influences placental and fetal development, the underlying molecular mechanisms have yet to be determined. Oxidative and inflammatory status at the fetal-placental unit appear to be involved in the early fetal metabolic programming. The objective of the present study is to reveal a potential role of sphingolipids in stablishing an oxidative and inflammatory status in the maternal-placental-fetal unit, as function of fetal sex. Term placenta and maternal and fetal plasma were collected from lean (BMI 18-25 kg/m) and obese women (BMI 30-40 kg/m) without gestational diabetes aged from 20 to 40 having undergone a cesarean section. Firstly, key markers of oxidative stress and inflammation were studied with immunoblotting and biochemical assays. Secondly, the maternal-placental-fetal unit's sphingolipid profile was determined by mass spectrometry. Lastly, the placental samples' transcriptome was analyzed by RNA sequencing. Obese mothers showed lower plasma levels of ceramide Cer 20:0 (p = 0.02). Surprisingly, placental ceramide content was not influenced by maternal obesity. Nevertheless, male placentas from obese women showed a higher sphingomyelin content and hypo-inflammation as showed by RNAseq. Both males and female placentas from obese women showed higher levels of oxidative stress as showed by the oxidative stress markers (protein carbonylation and lipid peroxidation). However, RNAseq revealed an upregulation of oxidative stress mechanisms only in female placentas. Whatever the newborn's sex, maternal obesity was associated with higher fetal plasma oxidative stress. In conclusion, our results revealed sex-specific features in the placental transcriptome, highlighted placental metabolic adaptations, and provided insights into the underlying molecular mechanisms of fetal programming.
Mitochondrial dysfunction and defective quality control mechanisms in the kidney are not reversed by high-fat diet withdrawal in early obese mice.
Braga PC, Vitorino R, Ferreira R … +4 more , Marques M, Oliveira PF, Rodrigues AS, Alves MG
Mol Cell Endocrinol · 2025 Oct · PMID 40774607 · Publisher ↗
High fat diet (HFD) induces glomerulopathy and proximal tubule injury. The precise pathophysiological mechanisms triggering obesity-related kidney impairment remain elusive, especially after dietary correction. Male C57B...
High fat diet (HFD) induces glomerulopathy and proximal tubule injury. The precise pathophysiological mechanisms triggering obesity-related kidney impairment remain elusive, especially after dietary correction. Male C57BL6/J mice (n = 15) were divided in: control group (CTR) fed with standard chow; a group fed with HFD for 200 days (28-29 weeks); and a group fed with HFD for 60 days (8-9 weeks) and then with standard chow (HFDt)(∼21 weeks). Biometric data and whole-body metabolism were assessed. Expression of genes associated with mitochondrial dynamics, mitochondrial complexes and antioxidant defenses were analyzed. Kidney homogenates enriched in mitochondria were prepared and characterized by mass spectrometry-based proteomics. Kidney tissue of mice fed HFD exhibited reduced PGC-1α expression, an imbalance between fusion (increased MFN1 and decreased OPA1) and fission (decreased FIS1 and DRP1) processes. The activity of mitochondrial complex I (CI) was increased, while activity of complex II (CII) was decreased in the kidney after HFD and HFDt. Antioxidant defense Manganese Superoxide dismutase (MnSOD) was decreased in the kidney of HFD, while Glutathione reductase (GR) increased, with both activities being restored upon dietary reversion. Proteomic analysis showed alterations in proteins associated with glutathione and glycine metabolism, fatty acid oxidation (FAO), and peroxisomal function. HFD negatively impacted kidney glutathione related proteins (Gsta3 and Gsr); however dietary correction reverted this condition. Acsm3 protein was downregulated in kidney after HFD and upregulated after dietary correction. Some machinery is shared by mitochondria and peroxisomes, with their network being crucial particularly under stress conditions. A HFD impaired kidney FAO in peroxisomes, as evidenced by downregulation of Pecr after HFD and HFDt. Dietary correction after early-obesity mitigates the systemic metabolic dysfunction and can attenuate mitochondria dysfunction but is unable to completely restore mitochondria dynamics and bioenergetics. The results highlight the integrity of mitochondrial network as a main point for targeted therapeutic strategies aimed at preventing the progression of kidney disease.
Heterogeneity of Sox2-expressing cells in mouse pituitary and their roles in postnatal gonadotroph differentiation.
Smiljanic K, Constantin S, Nessa N … +1 more , Stojilkovic SS
Mol Cell Endocrinol · 2025 Oct · PMID 40774606 · Publisher ↗
Postnatal differentiation of gonadotrophs from Sox2-expressing stem cells is essential for maturation of the hypothalamic-pituitary-gonadal axis, puberty, and reproduction. Here, we examined the differentiation and maint...
Postnatal differentiation of gonadotrophs from Sox2-expressing stem cells is essential for maturation of the hypothalamic-pituitary-gonadal axis, puberty, and reproduction. Here, we examined the differentiation and maintenance of gonadotrophs in developing and adult mice. Gonadotrophs and Sox2-expressing cells were identified by immunostaining, and gonadotrophs were also visualized by specific expression of the fluorescent protein tdTomato during embryonic and postnatal differentiation. Sox2-expressing cells are localized in the anterior parenchyma, marginal zone, and posterior pituitary, regardless of mouse age. Gonadotrophs are localized in the anterior parenchyma separate from Sox2-expressing cells. During the juvenile and prepubertal periods, cells in transition from Sox2 expression to tdTomato expression, as well as numerous differentiated gonadotrophs, were also present in the marginal zone. The size and distribution of the newly differentiated gonadotrophs were consistent with their migration into the parenchyma and maturation into a secretory cell type. Specific knockout of PI4-kinase A in gonadotrophs slowed their postnatal differentiation in the marginal zone, causing a significant reduction in the size of the gonadotroph population. This was accompanied by a progressive loss of specific gene expression in the residual gonadotrophs, leading to an increase in the number of dedifferentiated cells expressing tdTomato. Thus, Sox2 expressing cells in the marginal zone serve as stem cells for postnatal gonadotrophs, and the differentiation and maintenance of these cells require phosphoinositides derived by PI4-kinase A.
Epigenetic regulation of sex: the role of DNA methylation and zbtb38 in zebrafish sex differentiation and heat-induced masculinization.
Pierron F, Heroin D, Daramy F
Mol Cell Endocrinol · 2025 Nov · PMID 40759373 · Publisher ↗
There is increasing evidence that global change can threaten biodiversity by inducing skewed sex ratios. Accumulating evidences support a role of epigenetics, mainly DNA methylation, in sex differentiation. The aim of th...
There is increasing evidence that global change can threaten biodiversity by inducing skewed sex ratios. Accumulating evidences support a role of epigenetics, mainly DNA methylation, in sex differentiation. The aim of the present work was to investigate the potential role of zbtb38, a transcriptional factor that binds to methylated promoters, in sex differentiation and/or maintenance in zebrafish. We analyzed the methylation and transcription level of zbtb38 in males, females and undifferentiated individuals raised at standard or high temperature, a masculinizing factor. Results were compared to those obtained for genes already known to be involved in sex differentiation/maintenance (cyp19a1a, foxl2a, dmrt1). All genes presented a sex-specific pattern of DNA methylation and transcription but the most significant differences between sexes were observed for zbtb38. Moreover, a highly significant positive correlation was observed between the methylation level of zbtb38 and cyp19a1a, which encodes an enzyme that converts androgens into estradiol. However, while the hypermethylation of cyp19a1a was associated with its down-regulation, an inverse relationship was observed for zbtb38, providing a basis for mutual antagonism. Furthermore, zbtb38 was the only gene for which its transcription level was affected by temperature, being up-regulated in females that escaped to masculinization. Finally, despite embryos presented a paternal methylome, zbtb38 was the only gene for which its methylation level rapidly changed during early development to reach intermediate values between males and females at the larval stage, ie a bi-potential state. Our results strongly support a strategic role of DNA methylation and zbtb38 in sex differentiation and maintenance.
Pirin knockdown alleviates the progression of metabolic dysfunction-associated steatotic liver disease by inhibiting hepatic lipid deposition, inflammation, and fibrosis.
Wang Y, Xu Y, Liu Y … +3 more , Lin J, Hong X, Yan S
Mol Cell Endocrinol · 2025 Oct · PMID 40754200 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global disease with a broad spectrum of symptoms. Pirin (PIR) is involved in a variety of biological and molecular processes. However, the role of PIR...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global disease with a broad spectrum of symptoms. Pirin (PIR) is involved in a variety of biological and molecular processes. However, the role of PIR in MASLD remains unclear. Rats were fed with high-fat and high-cholesterol (HFC) diet to induce MASLD. Time-course results showed that liver in HFC-fed rats exhibited a progressive increase in hepatic tissue damage over time (3, 6, and 9 weeks), and developed in obvious hepatic fibrosis and steatosis at week 9. Meanwhile, HFC feeding also gradually increased PIR expression in liver. In vitro, PIR expression was up-regulated in palmitic acid (PA)-induced Hep3B cells. PIR knockdown using PIR shRNA plasmid inhibited steatosis and expression of ACLY, FASN, and XBP1 in PA-induced Hep3B cells. Knocking down PIR inhibited hepatocyte inflammation by inhibiting phosphor-NF-κB p65 into the nucleus, which inhibited the expression of TNF-α and IL-1β. In MASLD, hepatocyte inflammation activates hepatic stellate cell, thereby leading to hepatic fibrosis. Supernatant from PA-treated Hep3B with PIR knockdown inhibited LX-2 activation, as evidenced by decreased expression of Col1A1 and α-SMA in LX-2 cells. Together, these results suggested that PIR knockdown might alleviate the progression of MASLD by inhibiting liver lipid deposition and inflammation, further inhibiting liver fibrosis. Transcriptome data analysis suggested that alteration in the expression of lipid metabolism-related pathways and genes might be a potential cause of PIR regulation in MASLD progression. These findings may reveal a novel target for MASLD therapy.
PACAP inhibits high fat-induced NLRP3 inflammasome-mediated pyroptosis in vascular endothelial cells by regulating the SIRT1/ROS pathway.
Dong J, Ma T, Qu Y … +5 more , Ye R, Feng J, Bai G, Hong A, Ma Y
Mol Cell Endocrinol · 2025 Oct · PMID 40754199 · Publisher ↗
High-fat diet (HFD)-induced obesity leads endothelial dysfunction and contributes to cardiovascular diseases. NLRP3-mediated pyroptosis plays a key role in endothelial injury induced by HFD. Pituitary adenylate cyclase a...
High-fat diet (HFD)-induced obesity leads endothelial dysfunction and contributes to cardiovascular diseases. NLRP3-mediated pyroptosis plays a key role in endothelial injury induced by HFD. Pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide belonging to the secretin family, has demonstrated diverse beneficial effects. However, its impact on a high-fat-induced pyroptosis remains unexplored. The purpose of this study is to evaluate the effect of PACAP in alleviating high-fat-induced pyroptosis of human umbilical vein endothelial cells (HUVECs) and to elucidate its potential mechanisms. The results show that palmitic acid (PA) induces HUVECs injury and pyroptosis, while PACAP alleviates PA-induced HUVECs injury and pyroptosis. In addition, PACAP also has a protective effect on vascular damage in the thoracic aorta of obese mice. We further found that PACAP reduced PA-induced intracellular Reactive Oxygen Species (ROS) in HUVECs, while also mitigating PA-induced HUVECs pyroptosis. Moreover, PACAP can inhibit PA-induced ROS and pyroptosis through activation of SIRT1, and the effects of PACAP are reversed by a SIRT1 inhibitor. In conclusion, our study demonstrates that PACAP can inhibit PA-induced oxidative stress and pyroptosis in HUVECs, and its action is closely related to the SIRT1 pathway.
The effect of Semaglutide on mitochondrial function and insulin sensitivity in a myotube model of insulin resistance.
Spry ER, Travis KB, Ragland KJ … +3 more , Klein AJ, Zimmerman JM, Vaughan RA
Mol Cell Endocrinol · 2025 Oct · PMID 40752656 · Publisher ↗
AIMS: Semaglutide (SEMA) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that has recently emerged as a popular pharmacological treatment for type 2 diabetes and insulin resistance due to its weight loss properti...
AIMS: Semaglutide (SEMA) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that has recently emerged as a popular pharmacological treatment for type 2 diabetes and insulin resistance due to its weight loss properties. Previous studies have examined the metabolic effects of SEMA using supra-pharmacokinetically (but not pharmacokinetically attainable) concentrations. The aim of the present study was to determine the metabolic effects of pharmacokinetically attainable levels of SEMA on mitochondrial function and metabolism, which are often reduced during insulin resistance. METHODS: C2C12 myotubes were treated for 24 h with SEMA at 10 nM which approximates pharmacokinetically attainable blood concentrations in vivo. Metabolic gene expression was measured using qRT-PCR. pAkt expression was assessed using Western blot. Seahorse metabolic assays were also used to measure mitochondrial and glycolytic metabolism. Fluorescent staining was used to assess mitochondrial and lipid content. RESULTS: Treatment with SEMA did not alter mitochondrial function, content, or related gene expression. Similarly, SEMA had no significant effect on glycolytic metabolism or related gene expression, nor did it alter cellular lipid content or lipogenic signaling. CONCLUSIONS: High concentrations of SEMA may promote mitochondrial function during in vitro experiments, however the findings from the present report suggest pharmacokinetically attainable levels of SEMA do not alter myotube metabolism or expression of related molecular targets. Disparities in the present report and past observations may be a result of the lower concentrations of SEMA used in the present experiments. Further in vivo studies will be necessary to elucidate the full metabolic effects of SEMA on skeletal muscle.
Corrigendum to "The BRAF mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia" [Mol. Cell. Endocrinol. 581 (2024) 112113].
Ma CX, Ma XN, Liu JJ … +5 more , Guan CH, Li YD, Zhao N, Mauricio D, Fu SB
Mol Cell Endocrinol · 2025 Oct · PMID 40750504 · Publisher ↗
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The sex-chromosomes related cellular dimorphism in physiology and pathology.
Antinozzi C, Sgrò P, Di Luigi L
Mol Cell Endocrinol · 2025 Oct · PMID 40749744 · Publisher ↗
Sex-based biological differences have a profound impact on health and disease. Historically, these disparities were primarily attributed to differences in gonadal hormones. Recent advances in biochemistry and molecular b...
Sex-based biological differences have a profound impact on health and disease. Historically, these disparities were primarily attributed to differences in gonadal hormones. Recent advances in biochemistry and molecular biology, however, have revealed additional contributing mechanisms-most notably, the critical role of genes located on the X and Y chromosomes. The expression of Y-linked genes, increased dosage of X-linked genes in XX compared to XY cells due to incomplete X-chromosome inactivation, genomic imprinting, and the presence of non-coding and micro-RNAs on the X chromosome are all factors that require consideration in the development of in vitro models addressing sex dimorphism. In the present narrative review, we propose studies showing sex differences in vascular and cardiac cells, skeletal muscle cells, adipose tissue, liver, immune cells, cancer tissues and brain tissues. Given the absence of appropriate experimental methodologies for reproducing in vitro the sex differences observed in vivo and the limited research conducted at the cellular and molecular level to elucidate the mechanisms responsible for the observed dimorphism, the present review has two objectives. Firstly, it aims to emphasize the necessity of incorporating sex as a variable in preclinical research. Secondly, it highlights the importance of sex chromosome differences as a biological variable that can influence cell physiology and biological responses, which is crucial when conducting in vitro studies.
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