Min Seok Kim, Hyun Young Park, Soo Hyun Choi, Eun-Ju Chang, JaeSang Ko, Jin Sook Yoon
Pentraxin 3 (PTX3) is a prototypic humoral soluble pattern-recognition molecule known to function in immunity-related inflammation. Given the lack of information on the precise functions of PTX3 in the pathogenesis of Graves’ orbitopathy (GO), this study investigated the role of PTX3 in the inflammation and adipogenesis mechanism of GO. We first compared the PTX3 expression between orbital tissues from patients with GO and normal controls, using real-time polymerase chain reaction, which estimated significantly higher PTX3 transcript levels in the GO tissues than in the normal tissues. In addition, PTX3 production was markedly increased upon interleukin (IL)-1β and adipogenic stimulation. We then evaluated the effects of silencing PTX3 in primary orbital fibroblast cultures by analyzing the expression levels of pro-inflammatory cytokines, adipogenesis-related proteins, and downstream transcription factors in cells transfected with or without a small interfering RNA against PTX3, using western blot. Silencing PTX3 attenuated the IL-1β-induced secretion of pro-inflammatory cytokines, including IL-6, IL-8, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and cyclooxygenase-2, and suppressed the IL-1β-mediated activation of p38 kinase, nuclear factor-κB, and extracellular signal-regulated kinase. Moreover, PTX3 knockdown suppressed adipogenic differentiation, as assessed using Oil Red O staining, as well as the expression of adipogenesis-associated transcription factors including peroxisome proliferator activator-γ, CCAAT/enhancer-binding proteins α and β, adipocyte protein 2, adiponectin, and leptin. Thus, this study suggests that PTX3 plays a significant role in the pathogenesis of GO and may serve as a novel therapeutic target for the condition.
五肽 3(Pentraxin 3,PTX3)是一种典型的体液可溶性模式识别分子,已知在与免疫相关的炎症中发挥作用。鉴于缺乏有关PTX3在巴塞杜氏眼眶病(Graves' orbitopathy,GO)发病机制中确切功能的信息,本研究探讨了PTX3在GO的炎症和脂肪生成机制中的作用。我们首先利用实时聚合酶链反应比较了GO患者和正常对照组眼眶组织中PTX3的表达情况,结果发现GO组织中的PTX3转录本水平明显高于正常组织。此外,在白细胞介素(IL)-1β和脂肪生成刺激下,PTX3的产生明显增加。然后,我们在原代眼眶成纤维细胞培养物中沉默了PTX3,利用Western印迹分析了转染或不转染PTX3小干扰RNA的细胞中促炎细胞因子、脂肪生成相关蛋白和下游转录因子的表达水平。沉默PTX3可减少IL-1β诱导的促炎细胞因子(包括IL-6、IL-8、单核细胞趋化蛋白-1、细胞间粘附分子-1和环氧化酶-2)的分泌,并抑制IL-1β介导的p38激酶、核因子κB和细胞外信号调节激酶的活化。此外,用油红 O 染色法评估,PTX3 基因敲除抑制了脂肪生成分化,也抑制了脂肪生成相关转录因子的表达,包括过氧化物酶体增殖激活因子-γ、CCAAT/增强子结合蛋白α和β、脂肪细胞蛋白 2、脂肪连素和瘦素。因此,这项研究表明,PTX3 在 GO 的发病机制中起着重要作用,并可能成为该病的新型治疗靶点。
{"title":"Pentraxin3 mediates inflammation and adipogenesis in Graves’ orbitopathy pathogenesis","authors":"Min Seok Kim, Hyun Young Park, Soo Hyun Choi, Eun-Ju Chang, JaeSang Ko, Jin Sook Yoon","doi":"10.1530/jme-24-0039","DOIUrl":"https://doi.org/10.1530/jme-24-0039","url":null,"abstract":"<p>Pentraxin 3 (PTX3) is a prototypic humoral soluble pattern-recognition molecule known to function in immunity-related inflammation. Given the lack of information on the precise functions of PTX3 in the pathogenesis of Graves’ orbitopathy (GO), this study investigated the role of PTX3 in the inflammation and adipogenesis mechanism of GO. We first compared the PTX3 expression between orbital tissues from patients with GO and normal controls, using real-time polymerase chain reaction, which estimated significantly higher PTX3 transcript levels in the GO tissues than in the normal tissues. In addition, PTX3 production was markedly increased upon interleukin (IL)-1β and adipogenic stimulation. We then evaluated the effects of silencing PTX3 in primary orbital fibroblast cultures by analyzing the expression levels of pro-inflammatory cytokines, adipogenesis-related proteins, and downstream transcription factors in cells transfected with or without a small interfering RNA against PTX3, using western blot. Silencing PTX3 attenuated the IL-1β-induced secretion of pro-inflammatory cytokines, including IL-6, IL-8, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and cyclooxygenase-2, and suppressed the IL-1β-mediated activation of p38 kinase, nuclear factor-κB, and extracellular signal-regulated kinase. Moreover, PTX3 knockdown suppressed adipogenic differentiation, as assessed using Oil Red O staining, as well as the expression of adipogenesis-associated transcription factors including peroxisome proliferator activator-γ, CCAAT/enhancer-binding proteins α and β, adipocyte protein 2, adiponectin, and leptin. Thus, this study suggests that PTX3 plays a significant role in the pathogenesis of GO and may serve as a novel therapeutic target for the condition.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"30 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abigail R. Walker, Holly Ann Parkin, Sung Hye Kim, Vasso Terzidou, David F Woodward, Phillip R Bennett, Aylin C. Hanyaloglu
The prostanoid G protein-coupled receptor (GPCR) EP2 is widely expressed and implicated in endometriosis, osteoporosis, obesity, pre-term labour, and cancer. Internalisation and intracellular trafficking are critical for shaping GPCR activity, yet little is known regarding spatial programming of EP2 signalling and whether this can be exploited pharmacologically. Using three EP2-selective ligands that favour activation of different EP2 pathways, we show that EP2 undergoes limited agonist-driven internalisation but is constitutively internalised via dynamin-dependent, β-arrestin-independent pathways. EP2 was constitutively trafficked to early and very early endosomes (VEE) which was not altered by ligand activation. APPL1, a key adaptor and regulatory protein of the VEE, did not impact EP2 agonist-mediated cAMP. Internalisation was required for ~70% of the acute butaprost- and AH13205-mediated cAMP signalling, yet PGN9856i, a Gαs biased agonist, was less dependent on receptor internalisation for its cAMP signalling, particularly in human term pregnant myometrial cells that endogenously express EP2. Inhibition of EP2 internalisation partially reduced calcium signalling activated by butaprost or AH13205 and had no effect on PGE2 secretion. This indicates an agonist-dependent differential spatial requirement for Gαs and Gαq/11 signalling and a role for plasma membrane initiated Gαq/11-Ca2+-mediated PGE2 secretion. These findings reveal a key role for EP2 constitutive internalisation in its signalling and potential spatial bias in mediating its downstream functions. This in turn could highlight important considerations for future selective targeting of EP2 signalling pathways.
{"title":"Constitutive internalisation of EP2 differentially regulates G protein signalling","authors":"Abigail R. Walker, Holly Ann Parkin, Sung Hye Kim, Vasso Terzidou, David F Woodward, Phillip R Bennett, Aylin C. Hanyaloglu","doi":"10.1530/jme-23-0153","DOIUrl":"https://doi.org/10.1530/jme-23-0153","url":null,"abstract":"<p>The prostanoid G protein-coupled receptor (GPCR) EP2 is widely expressed and implicated in endometriosis, osteoporosis, obesity, pre-term labour, and cancer. Internalisation and intracellular trafficking are critical for shaping GPCR activity, yet little is known regarding spatial programming of EP2 signalling and whether this can be exploited pharmacologically. Using three EP2-selective ligands that favour activation of different EP2 pathways, we show that EP2 undergoes limited agonist-driven internalisation but is constitutively internalised via dynamin-dependent, β-arrestin-independent pathways. EP2 was constitutively trafficked to early and very early endosomes (VEE) which was not altered by ligand activation. APPL1, a key adaptor and regulatory protein of the VEE, did not impact EP2 agonist-mediated cAMP. Internalisation was required for ~70% of the acute butaprost- and AH13205-mediated cAMP signalling, yet PGN9856i, a Gαs biased agonist, was less dependent on receptor internalisation for its cAMP signalling, particularly in human term pregnant myometrial cells that endogenously express EP2. Inhibition of EP2 internalisation partially reduced calcium signalling activated by butaprost or AH13205 and had no effect on PGE2 secretion. This indicates an agonist-dependent differential spatial requirement for Gαs and Gαq/11 signalling and a role for plasma membrane initiated Gαq/11-Ca2+-mediated PGE2 secretion. These findings reveal a key role for EP2 constitutive internalisation in its signalling and potential spatial bias in mediating its downstream functions. This in turn could highlight important considerations for future selective targeting of EP2 signalling pathways.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"19 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140629693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weiye Zhao, Susanna F Rose, Ryan Blake, Aňze Godicelj, Amy E Cullen, Jack Stenning, Lucy Beevors, Marcel Gehrung, Sanjeev Kumar, Kamal Kishore, Ashley Sawle, Matthew Eldridge, Federico M Giorgi, Katherine S Bridge, Florian Markowetz, Andrew N Holding
The Estrogen Receptor-alpha (ER) drives 75% of breast cancers. On activation, the ER recruits and assembles a 1-2 MDa transcriptionally active complex. These complexes can modulate tumour growth, and understanding the roles of individual proteins within these complexes can help identify new therapeutic targets. Here, we present the discovery of ER and ZMIZ1 within the same multi-protein assembly by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 hours. GSEA analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell cycle genes. Integration of ENCODE data with our RNA-seq results identified that ER and ZMIZ1 both bind the promoter of E2F2. We therefore propose that ER and ZMIZ1 interact to enable the efficient estrogenic response at subset of cell cycle genes via a novel ZMIZ1-ER-E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA and METABRIC, and the proteins are co-localised within the nuclei of tumours cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER-ZMIZ1 interaction in ER-positive patient tumours, supporting potential clinical relevance.
{"title":"ZMIZ1 enhances ERα-dependent expression of E2F2 in breast cancer","authors":"Weiye Zhao, Susanna F Rose, Ryan Blake, Aňze Godicelj, Amy E Cullen, Jack Stenning, Lucy Beevors, Marcel Gehrung, Sanjeev Kumar, Kamal Kishore, Ashley Sawle, Matthew Eldridge, Federico M Giorgi, Katherine S Bridge, Florian Markowetz, Andrew N Holding","doi":"10.1530/jme-23-0133","DOIUrl":"https://doi.org/10.1530/jme-23-0133","url":null,"abstract":"<p>The Estrogen Receptor-alpha (ER) drives 75% of breast cancers. On activation, the ER recruits and assembles a 1-2 MDa transcriptionally active complex. These complexes can modulate tumour growth, and understanding the roles of individual proteins within these complexes can help identify new therapeutic targets. Here, we present the discovery of ER and ZMIZ1 within the same multi-protein assembly by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 hours. GSEA analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell cycle genes. Integration of ENCODE data with our RNA-seq results identified that ER and ZMIZ1 both bind the promoter of E2F2. We therefore propose that ER and ZMIZ1 interact to enable the efficient estrogenic response at subset of cell cycle genes via a novel ZMIZ1-ER-E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA and METABRIC, and the proteins are co-localised within the nuclei of tumours cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER-ZMIZ1 interaction in ER-positive patient tumours, supporting potential clinical relevance.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"238 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140571954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Postmenopausal osteoporosis (OP) is a prevalent skeletal disease with not fully understood molecular mechanisms. This study aims to investigate the role of circular RNA (circRNA) in postmenopausal OP and to elucidate the potential mechanisms of the circRNA-miRNA-mRNA regulatory network. We obtained circRNA and miRNA expression profiles from postmenopausal OP patients from the Gene Expression Omnibus database. By identifying differentially expressed circRNAs and miRNAs, we constructed a circRNA-miRNA-mRNA network and identified key genes associated with OP. Further, through a range of experimental approaches, including dual-luciferase reporter assays, RNA pull-down experiments, and qRT-PCR, we examined the roles of circ_0134120, miR-590-5p, and STAT3 in the progression of OP. Our findings reveal that the interaction between circ_0134120 and miR-590-5p in regulating STAT3 gene expression is a key mechanism in OP, suggesting the circRNA-miRNA-mRNA network ais a potential therapeutic target for this condition.
绝经后骨质疏松症(OP)是一种流行的骨骼疾病,其分子机制尚未完全明了。本研究旨在探讨环状 RNA(circRNA)在绝经后骨质疏松症中的作用,并阐明 circRNA-miRNA-mRNA 调控网络的潜在机制。我们从基因表达总库数据库中获得了绝经后 OP 患者的 circRNA 和 miRNA 表达谱。通过识别差异表达的 circRNA 和 miRNA,我们构建了 circRNA-miRNA-mRNA 网络,并确定了与 OP 相关的关键基因。此外,我们还通过一系列实验方法,包括双荧光素酶报告实验、RNA牵引实验和qRT-PCR,研究了circ_0134120、miR-590-5p和STAT3在OP进展过程中的作用。我们的研究结果表明,circ_0134120和miR-590-5p在调控STAT3基因表达中的相互作用是OP的一个关键机制,这表明circRNA-miRNA-mRNA网络是该病的一个潜在治疗靶点。
{"title":"circ_0134120: a new frontier in understanding postmenopausal osteoporosis pathogenesis","authors":"Junling Wang, Hongyan Zhang, Yue Cao, Irene Ma, Xuefang Liang, Dongfang Xiang","doi":"10.1530/jme-23-0140","DOIUrl":"https://doi.org/10.1530/jme-23-0140","url":null,"abstract":"<p>Postmenopausal osteoporosis (OP) is a prevalent skeletal disease with not fully understood molecular mechanisms. This study aims to investigate the role of circular RNA (circRNA) in postmenopausal OP and to elucidate the potential mechanisms of the circRNA-miRNA-mRNA regulatory network. We obtained circRNA and miRNA expression profiles from postmenopausal OP patients from the Gene Expression Omnibus database. By identifying differentially expressed circRNAs and miRNAs, we constructed a circRNA-miRNA-mRNA network and identified key genes associated with OP. Further, through a range of experimental approaches, including dual-luciferase reporter assays, RNA pull-down experiments, and qRT-PCR, we examined the roles of circ_0134120, miR-590-5p, and STAT3 in the progression of OP. Our findings reveal that the interaction between circ_0134120 and miR-590-5p in regulating STAT3 gene expression is a key mechanism in OP, suggesting the circRNA-miRNA-mRNA network ais a potential therapeutic target for this condition.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"50 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140572245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-22Print Date: 2024-05-01DOI: 10.1530/JME-23-0112
Marta Santos-Hernández, Frank Reimann, Fiona M Gribble
Enteroendocrine cells located along the gastrointestinal epithelium sense different nutrients/luminal contents that trigger the secretion of a variety of gut hormones with different roles in glucose homeostasis and appetite regulation. The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are involved in the regulation of insulin secretion, appetite, food intake and body weight after their nutrient-induced secretion from the gut. GLP-1 mimetics have been developed and used in the treatment of type 2 diabetes mellitus and obesity. Modulating the release of endogenous intestinal hormones may be a promising approach for the treatment of obesity and type 2 diabetes without surgery. For that reason, current understanding of the cellular mechanisms underlying intestinal hormone secretion will be the focus of this review. The mechanisms controlling hormone secretion depend on the nature of the stimulus, involving a variety of signalling pathways including ion channels, nutrient transporters and G-protein-coupled receptors.
位于胃肠道上皮的肠内分泌细胞能感知不同的营养物质/管腔内容物,从而引发多种肠道激素的分泌,这些激素在葡萄糖稳态和食欲调节中发挥着不同的作用。增量激素胰高血糖素样肽-1(GLP-1)和葡萄糖依赖性促胰岛素多肽(GIP)在营养物质诱导下从肠道分泌后,参与调节胰岛素分泌、食欲、食物摄入量和体重。GLP-1 模拟药物已被开发并用于治疗 2 型糖尿病和肥胖症。调节内源性肠道激素的释放可能是不通过手术治疗肥胖症和 2 型糖尿病的一种很有前景的方法。因此,本综述将重点介绍目前对肠道激素分泌的细胞机制的了解。控制激素分泌的机制取决于刺激的性质,涉及多种信号通路,包括离子通道、营养物质转运体和 G 蛋白偶联受体。
{"title":"Cellular mechanisms of incretin hormone secretion.","authors":"Marta Santos-Hernández, Frank Reimann, Fiona M Gribble","doi":"10.1530/JME-23-0112","DOIUrl":"10.1530/JME-23-0112","url":null,"abstract":"<p><p>Enteroendocrine cells located along the gastrointestinal epithelium sense different nutrients/luminal contents that trigger the secretion of a variety of gut hormones with different roles in glucose homeostasis and appetite regulation. The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are involved in the regulation of insulin secretion, appetite, food intake and body weight after their nutrient-induced secretion from the gut. GLP-1 mimetics have been developed and used in the treatment of type 2 diabetes mellitus and obesity. Modulating the release of endogenous intestinal hormones may be a promising approach for the treatment of obesity and type 2 diabetes without surgery. For that reason, current understanding of the cellular mechanisms underlying intestinal hormone secretion will be the focus of this review. The mechanisms controlling hormone secretion depend on the nature of the stimulus, involving a variety of signalling pathways including ion channels, nutrient transporters and G-protein-coupled receptors.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10959011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139491598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-19Print Date: 2024-05-01DOI: 10.1530/JME-23-0131
Nirvay Sah, Francesca Soncin
Trophoblast stem cells (TSCs) are a proliferative multipotent population derived from the trophectoderm of the blastocyst, which will give rise to all the functional cell types of the trophoblast compartment of the placenta. The isolation and culture of TSCs in vitro represent a robust model to study mechanisms of trophoblast differentiation into mature cells both in successful and diseased pregnancy. Despite the highly conserved functions of the placenta, there is extreme variability in placental morphology, fetal-maternal interface, and development among eutherian mammals. This review aims to summarize the establishment and maintenance of TSCs in mammals such as primates, including human, rodents, and nontraditional animal models with a primary emphasis on epigenetic regulation of their origin while defining gaps in the current literature and areas of further development. FGF signaling is critical for mouse TSCs but dispensable for derivation of TSCs in other species. Human, simian, and bovine TSCs have much more complicated requirements of signaling pathways including activation of WNT and inhibition of TGFβ cascades. Epigenetic features such as DNA and histone methylation as well as histone acetylation are dynamic during development and are expressed in cell- and gestational age-specific pattern in placental trophoblasts. While TSCs from different species seem to recapitulate some select epigenomic features, there is a limitation in the comprehensive understanding of TSCs and how well TSCs retain placental epigenetic marks. Therefore, future studies should be directed at investigating epigenomic features of global and placental-specific gene expression in primary trophoblasts and TSCs.
{"title":"Conserved and divergent features of trophoblast stem cells.","authors":"Nirvay Sah, Francesca Soncin","doi":"10.1530/JME-23-0131","DOIUrl":"10.1530/JME-23-0131","url":null,"abstract":"<p><p>Trophoblast stem cells (TSCs) are a proliferative multipotent population derived from the trophectoderm of the blastocyst, which will give rise to all the functional cell types of the trophoblast compartment of the placenta. The isolation and culture of TSCs in vitro represent a robust model to study mechanisms of trophoblast differentiation into mature cells both in successful and diseased pregnancy. Despite the highly conserved functions of the placenta, there is extreme variability in placental morphology, fetal-maternal interface, and development among eutherian mammals. This review aims to summarize the establishment and maintenance of TSCs in mammals such as primates, including human, rodents, and nontraditional animal models with a primary emphasis on epigenetic regulation of their origin while defining gaps in the current literature and areas of further development. FGF signaling is critical for mouse TSCs but dispensable for derivation of TSCs in other species. Human, simian, and bovine TSCs have much more complicated requirements of signaling pathways including activation of WNT and inhibition of TGFβ cascades. Epigenetic features such as DNA and histone methylation as well as histone acetylation are dynamic during development and are expressed in cell- and gestational age-specific pattern in placental trophoblasts. While TSCs from different species seem to recapitulate some select epigenomic features, there is a limitation in the comprehensive understanding of TSCs and how well TSCs retain placental epigenetic marks. Therefore, future studies should be directed at investigating epigenomic features of global and placental-specific gene expression in primary trophoblasts and TSCs.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11008758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139564368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays antidiabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in a gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with a high-fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, MNAM supplementation reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. The NAD+/sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was diminished in placenta by MNAM. In addition, weight of placenta, fetus weight, and litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of glucose tolerance tests by MNAM. Our data provide evidence for the careful usage of MNAM in treatment of GDM.
{"title":"N1-methylnicotinamide impairs gestational glucose tolerance in mice.","authors":"Xiaojing Wei, Yutian Tan, Jiaqi Huang, Ximing Dong, Weijie Feng, Tanglin Liu, Zhao Yang, Guiying Yang, Xiao Luo","doi":"10.1530/JME-23-0126","DOIUrl":"10.1530/JME-23-0126","url":null,"abstract":"<p><p>N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays antidiabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in a gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with a high-fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, MNAM supplementation reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. The NAD+/sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was diminished in placenta by MNAM. In addition, weight of placenta, fetus weight, and litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of glucose tolerance tests by MNAM. Our data provide evidence for the careful usage of MNAM in treatment of GDM.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10831565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138460427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-12Print Date: 2024-01-01DOI: 10.1530/JME-23-0104
Harald Jüppner
Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsα exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gsα mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsα expression due to loss of methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gsα function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gsα-coupled receptors.
{"title":"Pseudohypoparathyroidism: complex disease variants with unfortunate names.","authors":"Harald Jüppner","doi":"10.1530/JME-23-0104","DOIUrl":"10.1530/JME-23-0104","url":null,"abstract":"<p><p>Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsα exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gsα mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsα expression due to loss of methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gsα function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gsα-coupled receptors.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10843601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107591503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The exact neural construct underlying the dynamic secretion of gonadotropin-releasing hormone (GnRH) has only recently been identified despite the detection of multiunit electrical activity volleys associated with pulsatile luteinizing hormone (LH) secretion four decades ago. Since the discovery of kisspeptin/neurokinin B/dynorphin, KNDy, neurons in the mammalian hypothalamus there has been much research into the role of this neuronal network in controlling the oscillatory secretion of gonadotropin hormones. In this review, we provide an update of the progressive application of cutting-edge techniques combined with mathematical modelling by the neuroendocrine community, which are transforming the functional investigation of the GnRH pulse generator. Understanding the nature and function of the GnRH pulse generator can greatly inform a wide range of clinical studies investigating infertility treatments.
{"title":"New methods to investigate the GnRH pulse generator","authors":"Deyana Ivanova, Kevin O'Byrne","doi":"10.1530/jme-23-0079","DOIUrl":"https://doi.org/10.1530/jme-23-0079","url":null,"abstract":"<p>The exact neural construct underlying the dynamic secretion of gonadotropin-releasing hormone (GnRH) has only recently been identified despite the detection of multiunit electrical activity volleys associated with pulsatile luteinizing hormone (LH) secretion four decades ago. Since the discovery of kisspeptin/neurokinin B/dynorphin, KNDy, neurons in the mammalian hypothalamus there has been much research into the role of this neuronal network in controlling the oscillatory secretion of gonadotropin hormones. In this review, we provide an update of the progressive application of cutting-edge techniques combined with mathematical modelling by the neuroendocrine community, which are transforming the functional investigation of the GnRH pulse generator. Understanding the nature and function of the GnRH pulse generator can greatly inform a wide range of clinical studies investigating infertility treatments.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"28 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138578993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-18Print Date: 2023-11-01DOI: 10.1530/JME-23-0035
Megan Beetch, Brian Akhaphong, Alicia Wong, Briana Clifton, Seokwon Jo, Ramkumar Mohan, Juan E Abrahante Llorens, Emilyn U Alejandro
Suboptimal in utero environments such as poor maternal nutrition and gestational diabetes can impact fetal birth weight and the metabolic health trajectory of the adult offspring. Fetal growth is associated with alterations in placental mechanistic target of rapamycin (mTOR) signaling; it is reduced in fetal growth restriction and increased in fetal overgrowth. We previously reported that when metabolically challenged by a high-fat diet, placental mTORKO (mTORKOpl) adult female offspring develop obesity and insulin resistance, whereas placental TSC2KO (TSC2KOpl) female offspring are protected from diet-induced obesity and maintain proper glucose homeostasis. In the present study, we sought to investigate whether reducing or increasing placental mTOR signaling in utero alters the programming of adult offspring metabolic tissues preceding a metabolic challenge. Adult male and female mTORKOpl, TSC2KOpl, and respective controls on a normal chow diet were subjected to an acute intraperitoneal insulin injection. Upon insulin stimulation, insulin signaling via phosphorylation of Akt and nutrient sensing via phosphorylation of mTOR target ribosomal S6 were evaluated in the offspring liver, white adipose tissue, and skeletal muscle. Among tested tissues, we observed significant changes only in the liver signaling. In the male mTORKOpl adult offspring liver, insulin-stimulated phospho-Akt was enhanced compared to littermate controls. Basal phospho-S6 level was increased in the mTORKOpl female offspring liver compared to littermate controls and did not increase further in response to insulin. RNA sequencing of offspring liver identified placental mTORC1 programming-mediated differentially expressed genes. The expression of major urinary protein 1 (Mup1) was differentially altered in female mTORKOpl and TSC2KOpl offspring livers and we show that MUP1 level is dependent on overnutrition and fasting status. In summary, deletion of placental mTOR nutrient sensing in utero programs hepatic response to insulin action in a sexually dimorphic manner. Additionally, we highlight a possible role for hepatic and circulating MUP1 in glucose homeostasis that warrants further investigation.
{"title":"Impact of placental mTOR deficiency on peripheral insulin signaling in adult mice offspring.","authors":"Megan Beetch, Brian Akhaphong, Alicia Wong, Briana Clifton, Seokwon Jo, Ramkumar Mohan, Juan E Abrahante Llorens, Emilyn U Alejandro","doi":"10.1530/JME-23-0035","DOIUrl":"10.1530/JME-23-0035","url":null,"abstract":"<p><p>Suboptimal in utero environments such as poor maternal nutrition and gestational diabetes can impact fetal birth weight and the metabolic health trajectory of the adult offspring. Fetal growth is associated with alterations in placental mechanistic target of rapamycin (mTOR) signaling; it is reduced in fetal growth restriction and increased in fetal overgrowth. We previously reported that when metabolically challenged by a high-fat diet, placental mTORKO (mTORKOpl) adult female offspring develop obesity and insulin resistance, whereas placental TSC2KO (TSC2KOpl) female offspring are protected from diet-induced obesity and maintain proper glucose homeostasis. In the present study, we sought to investigate whether reducing or increasing placental mTOR signaling in utero alters the programming of adult offspring metabolic tissues preceding a metabolic challenge. Adult male and female mTORKOpl, TSC2KOpl, and respective controls on a normal chow diet were subjected to an acute intraperitoneal insulin injection. Upon insulin stimulation, insulin signaling via phosphorylation of Akt and nutrient sensing via phosphorylation of mTOR target ribosomal S6 were evaluated in the offspring liver, white adipose tissue, and skeletal muscle. Among tested tissues, we observed significant changes only in the liver signaling. In the male mTORKOpl adult offspring liver, insulin-stimulated phospho-Akt was enhanced compared to littermate controls. Basal phospho-S6 level was increased in the mTORKOpl female offspring liver compared to littermate controls and did not increase further in response to insulin. RNA sequencing of offspring liver identified placental mTORC1 programming-mediated differentially expressed genes. The expression of major urinary protein 1 (Mup1) was differentially altered in female mTORKOpl and TSC2KOpl offspring livers and we show that MUP1 level is dependent on overnutrition and fasting status. In summary, deletion of placental mTOR nutrient sensing in utero programs hepatic response to insulin action in a sexually dimorphic manner. Additionally, we highlight a possible role for hepatic and circulating MUP1 in glucose homeostasis that warrants further investigation.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 4","pages":""},"PeriodicalIF":3.6,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10620464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49678605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}