Molecular and Cellular Endocrinology最新文献

{"title":"Notch signaling modulates Fgf23 expression through crosstalk with hypoxia and PTH pathways in osteogenic cells","authors":"Yoshihiro Tamamura ,&nbsp;Kenta Terai ,&nbsp;Akira Yamaguchi","doi":"10.1016/j.mce.2025.112663","DOIUrl":"10.1016/j.mce.2025.112663","url":null,"abstract":"<div><div>Fibroblast growth factor 23 (Fgf23) is produced by bone and functions primarily as a phosphaturia hormone. We previously reported that overexpression of the Notch intracellular domain (NICD) in osteogenic cells enhances Fgf23 expression in association with osteomalacia <em>in vivo</em>. Here, we investigated the underlying mechanisms using osteogenic cell lines UMR-106 and IDG-SW3 cells. NICD overexpression increased <em>Fgf23</em> levels in both cell types. Manipulating RBPJ-κ activity, either a dominant-negative or constitutively active form, revealed that Notch-mediated <em>Fgf23</em> expression is dependent on RBPJ-κ. Treatment with iron chelator Desferrioxamine (DFO) upregulated <em>Fgf23</em> expression, which was abolished by dominant-negative RBPJ-κ overexpression. This effect was partially attenuated by short hairpin RNA (shRNA) targeting hypoxia-inducible factor (<em>HIF</em>)-2α, but not <em>HIF-1</em>α. DFO treatment also increased expression of Notch1 protein, but not Notch2 and Nocth3, in parallel with upregulation of the Notch target mRNAs, <em>Hes1</em> and <em>Hey1</em>. In addition, DFO elevated the expression of γ<strong><em>-</em></strong>secretase subunits, whereas a γ<strong>-</strong>secretase inhibitor suppressed DFO-induced increases in Notch1 and Fgf23 levels, suggesting that increased γ<strong><em>-</em></strong>secretase expression promotes Notch processing. Moreover, Notch signaling exerted an additive stimulatory effect on parathyroid hormone (PTH)-induced <em>Fgf23</em> expression, at least in part through interaction with the protein kinase A (PKA) pathway. Co-immunoprecipitation assays revealed a physical interaction between NICD and CREB period Collectively, these findings demonstrate that Notch signaling regulates Fgf23 expression through crosstalk with hypoxic and PTH pathways, providing novel insights into Fgf23 regulation and identifying potential therapeutic targets for Fgf23-related disorders.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112663"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OXTR overexpression induces polycystic ovary syndrome-like phenotype via prolactin/p-STAT3 signaling in mice","authors":"Shuilian Wang ,&nbsp;Xinyue Bao ,&nbsp;Ziying Liu ,&nbsp;Mingjun San ,&nbsp;Lingyu Zhang ,&nbsp;Yanjun Liu ,&nbsp;Mingyan Yang ,&nbsp;Yaowu Zheng ,&nbsp;Dan Li","doi":"10.1016/j.mce.2025.112668","DOIUrl":"10.1016/j.mce.2025.112668","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder, represents the most common cause of anovulatory infertility. While the oxytocin receptor (OXTR) is well-characterized in parturition and lactation, its role in follicular development remains undefined. In this study, we establish that global OXTR overexpression in female mice (⁺⁺<em>Oxtr</em>) recapitulates cardinal PCOS features, including hyperandrogenism, oligo-ovulation, and polycystic ovarian changes. ⁺⁺<em>Oxtr</em> females exhibited distinct ovarian pathology marked by follicular atresia, cystic changes, hemorrhage, and deficient corpus luteum formation. These morphological alterations coincided with profound endocrine dysregulation, featuring hyperprolactinemia, suppressed luteinizing hormone (LH) secretion, and progesterone (P) deficiency, contrasting with preserved fertility in ⁺⁺<em>Oxtr</em> males. Mechanistically, we identified an OXTR-prolactin (PRL)-p-STAT3 axis as central to PCOS pathogenesis. Corresponding to hyperprolactinemia, persistent activation of nuclear p-STAT3 (Tyr705) in ⁺⁺<em>Oxtr</em> ovaries - absent in WT controls at pregnancy - upregulated folliculogenesis genes (<em>Lhcgr</em>, <em>Pgr</em>, <em>Leptin</em>, <em>Cyp17a1</em>) while impairing ovulation. Therapeutic intervention with bromocriptine normalized prolactin and progesterone levels, partially restoring ovarian function. Notably, ⁺⁺<em>Oxtr</em> females developed metabolic dysfunction characterized by insulin resistance and gonadal adiposity despite maintaining lean phenotypes. Our findings position OXTR as a novel upstream regulator of PCOS pathogenesis with hyperprolactinemia, suggesting bromocriptine may have therapeutic value in hyperprolactinemic PCOS cases. These insights open new avenues for targeted PCOS interventions.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112668"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting the fructose transporter GLUT5 boosts testosterone production in a murine mLTC-1 leydig cell line","authors":"Aikaterini Kallianioti ,&nbsp;Guillaume Bourdon ,&nbsp;Claire Chevaleyre ,&nbsp;Christine Péchoux ,&nbsp;Christelle Ramé ,&nbsp;Jérôme Bourgeais ,&nbsp;Olivier Hérault ,&nbsp;Nancy Geoffre ,&nbsp;Thomas Darde ,&nbsp;Ingrid Plotton ,&nbsp;Véronique Douard ,&nbsp;Joëlle Dupont ,&nbsp;Pascal Froment","doi":"10.1016/j.mce.2025.112658","DOIUrl":"10.1016/j.mce.2025.112658","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Over the past few decades, a significant change globally in sugar intake has coincided with a rising incidence of male infertility, which is now a major public health concern. Diets rich in fructose have been implicated in both male infertility and increased susceptibility to metabolic disorders, such as obesity, diabetes, and related heart problems. While fructose is known to be present in seminal fluid and crucial for sperm motility, the precise role of fructose in testicular function remains largely unknown.&lt;/div&gt;&lt;div&gt;GLUT5 is an exclusive fructose transporter essential for dietary fructose uptake in the intestine. It is also expressed mainly in germ and Leydig cells. We recently revealed that disrupting the &lt;em&gt;Glut5&lt;/em&gt; gene in male mice impairs spermatogenesis and steroidogenesis. However, its specific role within Leydig cells remains unexplored. Therefore, we investigated its role by inhibiting GLUT5 in a murine Leydig cell line (mLTC-1) using a specific inhibitor of GLUT5, MSNBA, combined with a multi-omics approach.&lt;/div&gt;&lt;div&gt;Exposing mLTC-1 cells to MSNBA reduced the intracellular fructose content, limited cell proliferation, and enhanced progesterone and androgens production (Δ4-androstenedione and testosterone). The latter was associated with the upregulation of two genes and proteins involved in steroidogenesis, such as &lt;em&gt;Hsd3b&lt;/em&gt; and steroidogenic acute regulatory protein (&lt;em&gt;StAR&lt;/em&gt;). GLUT5 inhibition in mLTC-1 cells also modified lipid and carbohydrate metabolism. Lipidomic analysis showed decreased cholesterol esters and a shift in the ratio of polyunsaturated fatty acids (PUFAs) to monounsaturated fatty acids (MUFAs). These lipid changes correlated with alterations in the expression of mRNA-encoding enzymes involved in lipogenesis, such as ELOVL6. Metabolomics analysis showed a reduction in most glycolysis metabolites, except for pyruvate and lactate. However, pyruvate could conserve its level by a production through an amino acid pathway using the higher branched-chain amino acid content. Nevertheless, the activity of mitochondria measured by seahorse was not altered. The transcriptomic analysis performed by BRB-seq approach revealed an upregulation of several androgen-sensitive genes, such as &lt;em&gt;Akap5, Slc39a9,&lt;/em&gt; an androgen receptor or lactate dehydrogenase A (&lt;em&gt;Ldha&lt;/em&gt;), which produces lactate, and downregulation of several genes associated with the insulin pathway such as &lt;em&gt;Tsc2 or&lt;/em&gt; the hexokinase &lt;em&gt;Hkdc1&lt;/em&gt;.&lt;/div&gt;&lt;div&gt;In conclusion, GLUT5 supported fructose intake in the murine Leydig cell line mLTC-1, leading to a reduction in cell proliferation. The consequences of inhibition of GLUT5 led to an increase in fatty acids cell content, a perturbation in glycolysis and amino-acid metabolism but an enhanced androgen production. Since androgens regulate spermatogenesis, hyperandrogenism induced by a lower fructose content in Leydig cells may be a primary cause leading to the disruption of spe","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112658"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nrf2/Bach1 axis regulates redox homeostasis and energy metabolism to optimize Sertoli cell-mediated efferocytosis","authors":"Di Wu ,&nbsp;Kejia Zhang ,&nbsp;Jiachen Tan ,&nbsp;Faheem Ahmed Khan ,&nbsp;Chunjie Huang ,&nbsp;Fei Sun","doi":"10.1016/j.mce.2025.112661","DOIUrl":"10.1016/j.mce.2025.112661","url":null,"abstract":"<div><div>Efferocytosis is energy-consuming, and continuous efferocytosis imposes metabolic burdens on the phagocytes. Sertoli cells (SCs) are specialized phagocytes in the testis for efferocytosis of non-viable germ cells and residual bodies. What remains elusive is how SCs integrate metabolic adaptations in response to efferocytosis. Here, we identify the Nrf2/Bach1 axis as an important molecular machinery of SC-mediated efferocytosis. Nrf2 activation during efferocytosis stabilizes Bach1 expression. Nrf2 activation or Bach1 overexpression promotes SC-mediated efferocytosis, while the opposite phenotype is incurred by Nrf2 inactivation or Bach1 deficiency, with oxidative stress being a contributing factor. Beyond experiencing attenuated glucose uptake and ATP production, Bach1-deficient SCs exhibit a reduced NAD⁺/NADH ratio, and restraining NAD⁺ consumption by inhibiting serine biosynthesis rescues their impaired efferocytosis. We further observe an up-regulation of anti-ferroptotic genes in SCs upon Bach1 deficiency and demonstrate a protective role of ferroptosis in this scenario. We thus propose that redox homeostasis and energy metabolism lie at the nexus of the Nrf2/Bach1 axis in the regulation of SC-mediated efferocytosis. Our study explores the regulatory role of the Nrf2/Bach1 axis in SC-mediated efferocytosis, which will lead to a better appreciation of SCs in male reproductive health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112661"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced maternal age induced altered FoxO1 activation and cellular senescence in early placenta development in rats","authors":"María Laura Leonardi ,&nbsp;Alejandro Ranieri ,&nbsp;Cintia Romina Gatti ,&nbsp;Evangelina Capobianco ,&nbsp;Alicia Jawerbaum ,&nbsp;Romina Higa","doi":"10.1016/j.mce.2025.112662","DOIUrl":"10.1016/j.mce.2025.112662","url":null,"abstract":"<div><h3>Introduction</h3><div>Advanced maternal age (AMA) is associated with increased risks of adverse pregnancy outcomes partly due to placental dysfunction; however, the underlying mechanisms remain poorly understood. This study aimed to investigate early placental development in AMA pregnancies, focusing on FoxO1 activation and its role in cellular senescence and oxidative stress.</div></div><div><h3>Methods</h3><div>Three-month-old (Control) and 10-month-old (AMA) Wistar rats were mated with young males. On day 12 of pregnancy, FOXO1 activity and the expression of its target genes, oxidative status and morphometry were evaluated in the decidua and developing placenta.</div></div><div><h3>Results</h3><div>AMA rats exhibited a reduced number of implantation sites, fewer viable embryos, and decreased embryonic crown-rump length, indicating restricted growth. Markers of oxidative stress were increased in the decidua. At the molecular level, FOXO1 phosphorylation was reduced in the decidua, suggesting increased FOXO1 activation, whereas in the developing placenta, FOXO1 phosphorylation was elevated, indicating its inactivation. SGK1, a kinase that regulates FOXO1 phosphorylation, showed decreased phosphorylation in the decidua of AMA rats. Moreover, the senescence markers <em>Cdkn1a</em> (P21) and <em>Cdkn2a</em> (P16), known FOXO1 target genes, were upregulated in the decidua and downregulated in the developing placenta. These changes were associated with impaired cell proliferation in the decidua and a reduced syncitiotrophoblast layer in the developing placenta.</div></div><div><h3>Conclusion</h3><div>These findings highlight the differential regulation of FOXO1 in the decidua and placenta during AMA pregnancies. Increased FOXO1 activity in the decidua, likely driven by oxidative stress, and reduced SGK1 phosphorylation, may impair decidual function and contribute to altered placenta development with reduced FOXO1 activity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112662"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endometrial cells and extracellular vesicles response to high body energy reserves in bovine: Insights into miRNA and mRNA regulation before embryo arrival","authors":"Schaienni Fontoura Saldanha ,&nbsp;Natália Marins Bastos ,&nbsp;Juliana Germano Ferst ,&nbsp;Rodrigo Silva Goulart ,&nbsp;Ricardo Perecin Nociti ,&nbsp;Marcos Roberto Chiaratti ,&nbsp;Angélica Camargo dos Santos ,&nbsp;Flávio Vieira Meirelles ,&nbsp;Felipe Perecin ,&nbsp;Juliano Coelho da Silveira","doi":"10.1016/j.mce.2025.112665","DOIUrl":"10.1016/j.mce.2025.112665","url":null,"abstract":"<div><div>Body energy reserves influence reproductive performance in cattle. Previous findings from our laboratory showed that cows with high body energy reserves (HBER) have lower ovulation and embryo recovery rates compared to cows with moderate reserves (MBER). To investigate whether these reproductive differences are associated with changes in the uterine environment, Nelore cows from the same herd were assigned to MBER or HBER groups through nutritional management. Following estrous synchronization and artificial insemination, animals were slaughtered ∼120 h after ovulation induction. Samples from the uterotubal junction (UTJ) and anterior uterine horn (ANT) were collected. Extracellular vesicles (EVs) were isolated from uterine fluid by flushing, and endometrial tissue was sampled for molecular analysis. Nanoparticle tracking analysis revealed no differences in EV concentration or size between groups. However, when comparing MBER and HBER groups, miRNA profiling identified 8 and 9 differentially expressed miRNAs between MBER and HBER in EVs from the UTJ and ANT, respectively, and 2 differentially expressed miRNAs in endometrial cells from the UTJ, suggesting potential differences in molecular profiles. Transcriptomic analysis of endometrial cells revealed 430 and 35 differentially expressed genes (DEGs) in the UTJ and ANT, respectively, between MBER and HBER groups. The higher number of DEGs in the UTJ may suggest a greater molecular response, which is reflected by more extensive pathway enrichment compared to the ANT. miRNA–mRNA integration, performed by intersecting predicted miRNA targets with the differentially expressed mRNAs from our RNA-seq data, suggests that differentially expressed genes may be regulated by miRNAs altered between groups, indicating miRNA-mediated effects of metabolic condition on the uterine transcriptome. These findings suggest that high body energy reserves are associated with enrichment of immune and metabolism related pathways in the uterine environment, especially in the UTJ, which may reflect a pro-inflammatory, metabolically altered state potentially impairing early embryo development and maternal-embryonic communication.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112665"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of novel amino acid substituted and acylated spexin analogues on pancreatic beta-cell function, appetite and glucose homeostasis","authors":"Daniel M. Gallagher ,&nbsp;Md Zahidul Islam Khan ,&nbsp;Steven Patterson ,&nbsp;Finbarr P.M. O'Harte ,&nbsp;Nigel Irwin","doi":"10.1016/j.mce.2025.112657","DOIUrl":"10.1016/j.mce.2025.112657","url":null,"abstract":"<div><h3>Objective</h3><div>The neuropeptide spexin is recognised as a satiety-inducing hormone, but overall effects on metabolism are less characterised. Rapid enzymatic metabolism means elucidating biological effects of spexin is challenging, because the bioactive profile is short.</div></div><div><h3>Methods</h3><div>Therefore, in the present study, an Asp¹ for Asn¹ substituted spexin analogue, D¹Spx, alongside two related fatty acid derivatised analogues, (γGlu-Pal)-D¹Spx and (K¹¹γGlu-Pal)-D¹Spx, were synthesised and effects on pancreatic beta-cell secretory function and health investigated together with impact on appetite and glucose homeostasis in mice.</div></div><div><h3>Results</h3><div>Spexin immunoreactivity was initially confirmed in BRIN-BD11 beta-cells. Interestingly, like native spexin, D¹Spx was liable to plasma enzyme degradation, but the fatty acid derivatised molecules remained intact. None of the peptides augmented insulin secretion from BRIN-BD11 cells. Moreover, the spexin peptides inhibited alanine‐induced insulin secretion, with native spexin having no effect on intracellular calcium. However, all spexin peptides (10⁻⁸ and 10⁻⁶ M) promoted beta-cell proliferation, whilst native spexin and (γGlu-Pal)-D¹Spx protected against cytokine-induced beta-cell apoptosis. When administered intraperitoneally to mice, spexin peptides lacked effects on appetite regulation, even at elevated doses of 250 nmol/kg. Following conjoint injection with saline, none of the spexin peptides affected blood glucose levels barring a negligible increase by D¹Spx. When administered together with glucose, (γGlu-Pal)-D¹Spx slightly increased blood glucose at 30 min post-injection, but there was no overall difference between the spexin peptides when compared to glucose alone.</div></div><div><h3>Conclusions</h3><div>Acylation creates stable spexin analogues with similar bioactivity as native spexin, including promotion of beta-cell proliferation and partial protection against apoptosis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112657"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of sex: the role of DNA methylation and zbtb38 in zebrafish sex differentiation and heat-induced masculinization","authors":"Fabien Pierron,&nbsp;Débora Heroin,&nbsp;Flore Daramy","doi":"10.1016/j.mce.2025.112636","DOIUrl":"10.1016/j.mce.2025.112636","url":null,"abstract":"<div><div>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 <em>zbtb38,</em> a transcriptional factor that binds to methylated promoters, in sex differentiation and/or maintenance in zebrafish. We analyzed the methylation and transcription level of <em>zbtb38</em> 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 (<em>cyp19a1a</em>, <em>foxl2a</em>, <em>dmrt1</em>). All genes presented a sex-specific pattern of DNA methylation and transcription but the most significant differences between sexes were observed for <em>zbtb38</em>. Moreover, a highly significant positive correlation was observed between the methylation level of <em>zbtb38</em> and <em>cyp19a1a</em>, which encodes an enzyme that converts androgens into estradiol. However, while the hypermethylation of <em>cyp19a1a</em> was associated with its down-regulation, an inverse relationship was observed for <em>zbtb38</em>, providing a basis for mutual antagonism. Furthermore, <em>zbtb38</em> 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, <em>zbtb38</em> 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 <em>zbtb38</em> in sex differentiation and maintenance.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112636"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ox-LDL-stimulated macrophage-derived exosomes regulate adipose tissue remodeling and promote the progression of atherosclerosis","authors":"Xiaoyu Liu ,&nbsp;Guoyan Xu ,&nbsp;Yunlu Xu ,&nbsp;Yuling Xu","doi":"10.1016/j.mce.2025.112660","DOIUrl":"10.1016/j.mce.2025.112660","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis (AS) is a chronic vascular disease, and perivascular adipose tissue dysfunction is an important cause of the arterial plaque formation involved. However, the underlying mechanism has not been fully elucidated. The aim of this study was to investigate the mechanism of oxidized low-density lipoprotein (ox-LDL) stimulation of macrophage-derived exosomes in the development of AS.</div></div><div><h3>Methods</h3><div>We isolated exosomes from ox-LDL-treated macrophages and injected them into Western diet-fed ApoE^−/− mice. We assessed AS, lipid metabolism, and endothelial function by histology, ELISA, qPCR, and western blotting, and examined BMP7 and OPA1 regulation in brown fat and vascular endothelium.</div></div><div><h3>Results</h3><div>Macrophage-derived exosomes were extracted, and their size was determined by transmission electron microscopy. Additionally, CD9, CD63, and TSG101 protein expression within these macrophages was determined. Compared with the control group, the exosomes group showed increased expression of AP2 and PPAR and decreased expression of UCP-1, PGC-1α, and BMP7. Furthermore, when BMP7 was knocked down, the expression of the lipid metabolites FASN, SCD1, HSL, and ATGL as well as of OPA1 decreased. In an ApoE^−/− mouse model, compared to the control group, increased arterial plaques and plaque lesion formation were observed in the exosome group, along with elevated expression of the lipid metrics TC, TG, LDL-C, and HDL-C and significant increases in the expression of the proinflammatory factors VCAM1, ICAM1, MCP-1, and IL-6. Consequently the progression of AS was aggravated in this group.</div></div><div><h3>Conclusions</h3><div>This study demonstrated that ox-LDL stimulated exosome secretion from macrophages, accelerating the AS process. It also showed that, mechanistically, BMP7 regulates the expression of OPA1 and affects the normal lipid metabolism, thereby accelerating AS.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112660"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Linolenic acid rich-chia seed improves glucose tolerance, modulates gluconeogenic pathway and hepatic insulin signaling in an experimental model of metabolic syndrome","authors":"Michelle Berenice Vega Joubert ,&nbsp;María Eugenia Oliva ,&nbsp;Paola Ingaramo ,&nbsp;María Eugenia D'Alessandro","doi":"10.1016/j.mce.2025.112643","DOIUrl":"10.1016/j.mce.2025.112643","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112643"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}