Journal of molecular endocrinology最新文献_第2页

PKD and scaffold NHERF1 mediate hypoxia-induced gene expression in 3T3-L1 adipocytes. PKD和支架NHERF1介导缺氧诱导的3T3-L1脂肪细胞的基因表达。

IF 3.8 4区医学

Journal of molecular endocrinology Pub Date : 2025-08-27 Print Date: 2025-08-01 DOI: 10.1530/JME-25-0011

Ying-Yu Wu, Yu-Yao Huang, Juu-Chin Lu

{"title":"PKD and scaffold NHERF1 mediate hypoxia-induced gene expression in 3T3-L1 adipocytes.","authors":"Ying-Yu Wu, Yu-Yao Huang, Juu-Chin Lu","doi":"10.1530/JME-25-0011","DOIUrl":"10.1530/JME-25-0011","url":null,"abstract":"Hypoxia has been implicated as a causal factor in mediating adipocyte dysfunction in obesity. Moreover, protein kinase D 1 (PKD1), a serine/threonine protein kinase, has been shown to contribute to diet-induced adiposity. Therefore, we investigated if PKD isoforms mediate hypoxia-induced dysfunction in 3T3-L1 adipocytes. Hypoxia increased phosphorylation of PKD1 at serine 916 (S916), the autophosphorylation site linked to PKD1 activation, indicating hypoxia-induced activation of PKD1 in adipocytes. Inhibition or depletion of PKD isoforms mitigated hypoxia-induced increase in hypoxia-inducible factor 1α (HIF1α), the master transcription factor mediating hypoxia-induced gene expression, confirming that PKDs modulate the hypoxia-induced mechanism in adipocytes. Surprisingly, depletion of PKD1 and PKD2, but not PKD3, attenuated hypoxia-induced HIF1α target gene expression. Unlike PKD3, PKD1 and PKD2 possess a unique PDZ-binding motif at their C-terminus. Indeed, hypoxia upregulated a PDZ-containing scaffold protein Na+/H+ exchanger regulatory factor 1 (NHERF1) and its interaction with PKD1, whereas NHERF1 depletion attenuated hypoxia-induced PKD1 phosphorylation, HIF1α protein accumulation, and gene expression. Mechanistically, hypoxia induced nuclear import of active PKD1, which phosphorylated histone deacetylase 5 (HDAC5) at S498, promoting cytoplasmic localization of HDAC5. HDAC5 deacetylated heat shock protein 70 (HSP70) at lysine 77, which dissociated HSP70 from HIF1α, allowing HSP90 association that stabilized HIF1α. Interestingly, PKD inhibition reversed hypoxia effects on subcellular localization of PKD1/HDAC5, HSP70 acetylation, and HIF1α/HSP90 association. In summary, our findings reveal an NHERF1-PKD1-HDAC5 mechanism modulating hypoxia-induced gene expression in adipocytes.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835393","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}

引用次数: 0

TNF but not VEGF induces secretion of multiple chemokines and cytokines by uterine artery endothelial cells: potential implications for preeclampsia. TNF而非VEGF诱导子宫动脉内皮细胞分泌多种趋化因子和细胞因子-子痫前期的潜在影响。

IF 3.8 4区医学

Journal of molecular endocrinology Pub Date : 2025-08-22 Print Date: 2025-08-01 DOI: 10.1530/JME-25-0008

L Clemente, C Zhou, K Chaiyakul, J H Adams, J Jacobson, J L Austin, D S Boeldt, I M Ong, I M Bird

{"title":"TNF but not VEGF induces secretion of multiple chemokines and cytokines by uterine artery endothelial cells: potential implications for preeclampsia.","authors":"L Clemente, C Zhou, K Chaiyakul, J H Adams, J Jacobson, J L Austin, D S Boeldt, I M Ong, I M Bird","doi":"10.1530/JME-25-0008","DOIUrl":"10.1530/JME-25-0008","url":null,"abstract":"While pregnancy is known to be an inflammatory condition, preeclampsia (PE) is a more extreme state associated with higher cytokines and/or altered growth factors. It is generally assumed these PE-elevated factors come from stimulation of immune cells and/or hypoxic uterine tissue, but several studies have shown that endothelial cells may also be a source. The goal of this study was to determine to what extent TNF, a factor overproduced by uteroplacental tissue in PE pregnancy, may influence uterine artery endothelial cells to contribute to these other PE-specific factors in the maternal circulation. Herein, we use multiple analytical methods to show that uterine artery endothelial cells from pregnant sheep (P-UAEC) on exposure to cytokines can secrete multiple cytokines and chemokines seen in PE women, which may contribute to production of Th17 cells and attraction of these and other cells to the vessel surface. Furthermore, the factors not significantly increased by TNF include those known to be specifically secreted by proinflammatory T cells. This begs the question if endothelium itself is the initial primary orchestrator of chemokine and cytokine imbalance, acting directly and indirectly to promote the symptoms of impaired vasodilation and reduced uteroplacental blood flow. If so, future preventive therapies for PE should be targeted at endothelium as well as immune cells.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784500","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}

引用次数: 0

Chronic stress-secreted glucocorticoids induce NAFLD-like changes in male rats: oxidative stress/NLRP3 inflammasome signalling. 慢性应激分泌糖皮质激素诱导雄性大鼠nafld样变化：氧化应激/NLRP3炎症小体信号传导

IF 3.8 4区医学

Journal of molecular endocrinology Pub Date : 2025-08-22 Print Date: 2025-08-01 DOI: 10.1530/JME-25-0056

Qi Shao, Chuxin Zhang, Jie Mu, Jing Ji, Changxiang Li, Chongyang Ma, Fafeng Cheng

{"title":"Chronic stress-secreted glucocorticoids induce NAFLD-like changes in male rats: oxidative stress/NLRP3 inflammasome signalling.","authors":"Qi Shao, Chuxin Zhang, Jie Mu, Jing Ji, Changxiang Li, Chongyang Ma, Fafeng Cheng","doi":"10.1530/JME-25-0056","DOIUrl":"10.1530/JME-25-0056","url":null,"abstract":"Graphical abstract: Abstract: The aim of this study was to investigate the mechanism by which chronic stress (CS) induces non-alcoholic fatty liver disease (NAFLD)-like changes, and the role of oxidative stress and the NLRP3 inflammasome in this mechanism. Transcriptomic data extracted from the Sequence Read Archive (SRA) at the NCBI were employed to identify the molecular targets of CS-induced NAFLD. Fifty 8-week-old healthy male Wistar rats were divided into five groups (n = 10 each) as follows: control, CS, CS + mifepristone (CS + Mif), CS + metyrapone (CS + Met), and corticosterone (Cort). The CS, CS + Mif, and CS + Met groups underwent restraint stress training. Rats in the CS + Mif, CS + Met, and Cort groups were administered mifepristone, metyrapone, and corticosterone for 8 weeks. Data showed that CS induced NAFLD-like liver damage via increased glucocorticoids (GCs). Moreover, CS increased malonaldehyde (MDA) levels and decreased superoxide dismutase (SOD) activity in liver and serum samples, suggesting the occurrence of oxidative stress. Furthermore, CS activated various inflammatory pathways via the NLRP3 inflammasome (NLRP3, ASC, caspase-1), which enhanced cytokine levels (IL-1β, IL-6, TNF-α) in liver tissue. Notably, treatment with metyrapone or mifepristone alleviated liver lesions induced by CS, which implies that the GC signalling pathway may be an important mediator of stress-induced liver inflammation. We conclude that GC mediates the development of oxidative stress and inflammation in the liver, and inhibition of GC signalling may be a new therapeutic strategy in NAFLD.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804329","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}

引用次数: 0

Dysregulation of hepatic deiodinase type I in metabolically associated steatotic liver disease. 代谢相关脂肪变性肝病中I型肝脱碘酶的失调

IF 3.8 4区医学

Journal of molecular endocrinology Pub Date : 2025-08-08 Print Date: 2025-08-01 DOI: 10.1530/JME-25-0096

Nuria Lopez-Alcantara, Alison-Michelle Naujack, Yingfu Chen, Natalie Taege, Cathleen Geißler, Rebecca Oelkrug, Eva K Wirth, Lutz Schomburg, Anita Boelen, Henriette Kirchner, Jens Mittag

{"title":"Dysregulation of hepatic deiodinase type I in metabolically associated steatotic liver disease.","authors":"Nuria Lopez-Alcantara, Alison-Michelle Naujack, Yingfu Chen, Natalie Taege, Cathleen Geißler, Rebecca Oelkrug, Eva K Wirth, Lutz Schomburg, Anita Boelen, Henriette Kirchner, Jens Mittag","doi":"10.1530/JME-25-0096","DOIUrl":"10.1530/JME-25-0096","url":null,"abstract":"Hepatic thyroid hormone action plays an important role in preventing the development and progression of metabolic liver diseases, as evidenced by the recent success of the receptor-specific agonist resmetirom. The liver enzyme deiodinase type I (DIO1) is important for controlling the local availability of thyroid hormone and is upregulated in metabolically associated steatotic liver disease (MASLD), which is thought to be a compensatory mechanism to enhance local hormone action. However, it remains unclear whether this increase is maintained in later stages of MASLD and whether an induction of Dio1 can provide beneficial metabolic effects. Studying mouse models with different stages of MASLD, we show here that Dio1 mRNA expression and activity are rapidly induced within 1 week by high-caloric dietary intervention. In later stages, this increase was less pronounced. Surprisingly, altered Dio1 mRNA concentration became progressively less well associated with altered DIO1 enzyme activity, suggesting uncoupling of mRNA and protein biosynthesis. In order to enhance DIO1 activity in MASLD development, a transgenic strategy was applied by using an adeno-associated virus-based liver-specific gene therapy with either the Dio1 or Socs3 gene. In either model, DIO1 activity was increased, but neither thyroid hormone target genes nor metabolic parameters were positively affected in the time frame of the experiment. We conclude that hepatic DIO1 biosynthesis becomes progressively disturbed with disease progression in MASLD by a decoupling of its transcript and protein levels, highlighting the key importance of translational processes controlling DIO1 in hepatocytes, which are likely affected by local inflammatory mechanisms.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753585","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}

引用次数: 0

Insights into new mechanosensitive behaviors of G protein-coupled receptors. G蛋白偶联受体新的机械敏感行为的见解。

IF 3.8 4区医学

Journal of molecular endocrinology Pub Date : 2025-08-04 Print Date: 2025-08-01 DOI: 10.1530/JME-24-0147

Aakanksha J Shetty, Alexei Sirbu, Paolo Annibale

{"title":"Insights into new mechanosensitive behaviors of G protein-coupled receptors.","authors":"Aakanksha J Shetty, Alexei Sirbu, Paolo Annibale","doi":"10.1530/JME-24-0147","DOIUrl":"10.1530/JME-24-0147","url":null,"abstract":"G protein-coupled receptors (GPCRs) represent a diverse and vital family of membrane proteins that mediate intracellular signaling in response to extracellular stimuli, playing critical roles in physiology and disease. Traditionally recognized as chemical signal transducers, GPCRs have recently been implicated in mechanotransduction, the process of converting mechanical stimuli into cellular responses. This review explores the emerging role of GPCRs in sensing and responding to mechanical forces, with a particular focus on the cardiovascular system. Cardiovascular homeostasis is heavily influenced by mechanical forces such as shear stress, cyclic stretch, and pressure, which are central to both normal physiology and the pathogenesis of diseases such as hypertension and atherosclerosis. GPCRs, including the angiotensin II type 1 receptor (AT1R) and the β2-adrenergic receptor (β2-AR), have demonstrated the ability to integrate mechanical and chemical signals, potentially through conformational changes and/or modulation of lipid interactions, leading to biased signaling. Recent studies highlight the dual activation mechanisms of GPCRs, with β2-AR now serving as a key example of how mechanical and ligand-dependent pathways contribute to cardiovascular regulation. This review synthesizes current knowledge of GPCR mechanosensitivity, emphasizing its implications for cardiovascular health and disease, and explores advancements in methodologies poised to further unravel the mechanistic intricacies of these receptors.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690571","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}

引用次数: 0

Evidence for human kisspeptin receptor homo-oligomerisation and its functional relevance. 人类kisspeptin受体同源寡聚化及其功能相关性的证据。

IF 3.8 4区医学

Journal of molecular endocrinology Pub Date : 2025-07-30 Print Date: 2025-08-01 DOI: 10.1530/JME-25-0043

Aishwarya P Chakraborty, Vidhi B Rathod, Shobha Sonawane, Shital R Bhanarkar, Bhakti R Pathak, Antara A Banerjee

{"title":"Evidence for human kisspeptin receptor homo-oligomerisation and its functional relevance.","authors":"Aishwarya P Chakraborty, Vidhi B Rathod, Shobha Sonawane, Shital R Bhanarkar, Bhakti R Pathak, Antara A Banerjee","doi":"10.1530/JME-25-0043","DOIUrl":"10.1530/JME-25-0043","url":null,"abstract":"Graphical abstract: Abstract: The signalling of kisspeptin-1 through the kisspeptin-1 receptor (KISS1R) is central to mammalian reproduction. Naturally occurring heterozygous KISS1R mutations and Kiss1r +/- knockout mice are less affected than their homozygous counterparts, suggesting that the mutant receptors possibly form oligomers with the wild-type (WT) KISS1R, rescuing the receptor function to some extent. To test this hypothesis, the heterozygous KISS1R mutations R38P, P46Q, S125L and R198G, reported in the literature in cases of delayed puberty, were characterised. In silico analysis predicted that all four mutations affected the receptor function to varying extents, which was substantiated by in vitro studies. Determination of cell surface receptor expression and kisspeptin-stimulated signalling response was carried out post transient transfection of the receptor constructs in CHO cells. Results revealed that these mutations (homozygous condition) impaired the cell surface receptor expression, as quantified by flow cytometry, with a concomitant attenuation of inositol phosphate production. Co-transfection of the WT KISS1R with equal amounts of the mutant receptors, to mimic the heterozygous condition of the mutation in the patients, restored the receptor function and, with increasing amounts of mutant receptors, resulted in attenuation of receptor function. As a direct proof of receptor oligomerisation, co-expression of epitope-tagged KISS1R constructs was carried out. Co-immunoprecipitation and imaging FRET studies revealed that KISS1R forms homo-oligomers in a constitutive manner and that the transmembrane domain 7 contributed to the oligomerisation interface, as demonstrated by the impairment in oligomerisation upon deletion of this domain. Thus, characterisation of heterozygous KISS1R mutations corroborated the oligomerisation status of the KISS1 receptor and helped in establishing a genotype-phenotype association.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667792","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}

引用次数: 0

EGF activation of POMC gene transcription is mediated by STAT3. EGF激活POMC基因转录是由STAT3介导的。

IF 3.8 4区医学

Journal of molecular endocrinology Pub Date : 2025-07-26 Print Date: 2025-08-01 DOI: 10.1530/JME-25-0037

Ryhem Gam, Kevin Sochodolsky, Aurélio Balsalobre, Yves Gauthier, Jacques Drouin

{"title":"EGF activation of POMC gene transcription is mediated by STAT3.","authors":"Ryhem Gam, Kevin Sochodolsky, Aurélio Balsalobre, Yves Gauthier, Jacques Drouin","doi":"10.1530/JME-25-0037","DOIUrl":"10.1530/JME-25-0037","url":null,"abstract":"Classical activation of the hypothalamic-pituitary-adrenal axis is exerted by the stimulation of pituitary POMC gene transcription and ACTH release by the hypothalamic hormone CRH. In parallel, inflammatory cytokines such as IL6 and LIF also stimulate ACTH release and POMC transcription through the JAK/STAT pathway. In recent years, a particular interest in the role of the EGF pathway for POMC activation was sparked by the identification of causative mutations in the USP8 gene that have been implicated in the formation of pituitary corticotroph adenomas that are the hallmark of Cushing's disease. These mutations were associated with the persistent upregulation of the EGF/EGFR pathway and its putative role in ACTH hypersecretion. In the present work, we reassessed the signaling pathways that are activated in response to EGF in pituitary corticotroph cells using the AtT20 cell model. We confirmed the activation of the MAP kinase pathway by EGF and also showed the activation of the AKT/mTOR and JAK/STAT pathways. Whereas activation of all three pathways appears essential for the stimulation of cell proliferation, only the JAK/STAT pathway, and more specifically STAT3, enhances POMC gene transcription. This action is mapped to a single STAT-binding element of the POMC promoter in contrast to the activation by the other STAT-activating cytokines LIF and IL6. Furthermore, EGF signaling is specifically enhanced by STAT3 but not STAT1 in contrast to LIF-dependent activation. All together, the data identified a unique STAT3-dependent target on the POMC promoter that mediates EGF activation of POMC gene transcription.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591480","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}

引用次数: 0

Mechanistic insights of Rhodiola crenulata in treating diabetic kidney disease via network pharmacology. 红景天治疗糖尿病肾病的网络药理学机制探讨。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2025-06-30 Print Date: 2025-07-01 DOI: 10.1530/JME-25-0006

Junhan Li, Yuying Cui, Jinming Yao, Congcong Guo, Mingwen Jiao

{"title":"Mechanistic insights of Rhodiola crenulata in treating diabetic kidney disease via network pharmacology.","authors":"Junhan Li, Yuying Cui, Jinming Yao, Congcong Guo, Mingwen Jiao","doi":"10.1530/JME-25-0006","DOIUrl":"10.1530/JME-25-0006","url":null,"abstract":"Rhodiola crenulata (RC) has been traditionally used for its therapeutic benefits, including alleviating high-altitude sickness, fatigue, and diabetes. Diabetic kidney disease (DKD), a severe complication of diabetes, often leads to progressive renal fibrosis. This study explored the protective effects of RC against kidney fibrosis in DKD rat models, identifying active compounds and their therapeutic targets, with a focus on salidroside (SAL), a key component of RC. After administering RC to DKD rats, network pharmacology analysis identified 22 core components and 141 DKD-related therapeutic targets, with TGFB1 emerging as a primary target in kidney fibrosis. In vivo experiments demonstrated that RC reduced fibrosis markers by decreasing glomerular mesangial expansion, collagen deposition, and myofibroblast proliferation, alongside lowering TGF-β1 levels. In vitro analyses revealed that SAL inhibited high glucose-induced fibroblast activation and suppressed TGF-β1 expression in proximal renal tubular epithelial cells (PTECs), suggesting its direct role in slowing fibrosis progression. These findings indicate that the antifibrotic effects of RC in DKD may be attributed to SAL's ability to regulate fibroblast activity and suppress TGF-β1, highlighting its potential as a therapeutic component for DKD management.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285032","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}

引用次数: 0

Effect of metformin on the endometrial proteome of diet-induced obese mice. 二甲双胍对饮食性肥胖小鼠子宫内膜蛋白质组的影响。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2025-04-24 Print Date: 2025-05-01 DOI: 10.1530/JME-24-0098

Maria-Nefeli Malliou-Becher, Eva-Maria Turnwald, Lara Skupin, Tobias Kretschmer, Andrea Mesaros, Martin Purrio, Maria Wohlfarth, Marion Handwerk, Simone Kalis, Dirk Gründemann, Jörg Dötsch, Ariane Germeyer, Sarah Appel

{"title":"Effect of metformin on the endometrial proteome of diet-induced obese mice.","authors":"Maria-Nefeli Malliou-Becher, Eva-Maria Turnwald, Lara Skupin, Tobias Kretschmer, Andrea Mesaros, Martin Purrio, Maria Wohlfarth, Marion Handwerk, Simone Kalis, Dirk Gründemann, Jörg Dötsch, Ariane Germeyer, Sarah Appel","doi":"10.1530/JME-24-0098","DOIUrl":"https://doi.org/10.1530/JME-24-0098","url":null,"abstract":"Obesity is known to have detrimental effects on female fertility, influencing both ovarian and endometrial functions. There is evidence that endometrial function is altered in obese and/or insulin-resistant women. Metformin, an insulin-sensitizing drug, has shown potential in treating metabolic and reproductive disorders, including polycystic ovary syndrome (PCOS) and may enhance fertility outcomes by improving endometrial dysfunction. Using a mouse model, this study aimed to investigate how a high-fat diet impacts endometrial-specific protein expression and whether metformin can mitigate these effects. C57BL/6N mice were fed a standard or high-fat diet and either received metformin treatment or did not. Proteomic analyses revealed significant alterations in endometrial protein expression due to the high-fat diet, while metformin administration appeared to restore many of these changes to normal levels. Metformin's impact was evident through alterations in specific proteins associated with reproductive health and metabolic functions, such calcium-independent phospholipase A2-gamma, ATP-binding cassette sub-family D member 1, RAC-beta serine/threonine-protein kinase, acyl-CoA:lysophosphatidylglycerol acyltransferase 1, O-GlcNAcase, scavenger receptor class A member 3, protein kinase C beta type, sortilin, beta-2-microglobulin and apolipoprotein C-III. These results suggest a potential therapeutic role for metformin in normalizing endometrial protein expression, providing insights into how this drug could improve fertility outcomes in obese or insulin-resistant females, besides normalizing ovulation patterns. Overall, this study enhances our understanding of the relationship among obesity, endometrial function and metformin's therapeutic potential, offering a foundation for further research into reproductive health and metabolic disorders.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"74 4","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014944","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}

引用次数: 0

Identification of anti-resorptive GPCRs by high-content imaging in human osteoclasts. 利用高含量显像技术鉴定人破骨细胞的抗再吸收gpcr。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2025-04-22 Print Date: 2025-05-01 DOI: 10.1530/JME-24-0143

Maria L Price, Rachael A Wyatt, Joao Correia, Zakia Areej, Maisie Hinds, Ana Crastin, Rowan S Hardy, Morten Frost, Caroline M Gorvin

{"title":"Identification of anti-resorptive GPCRs by high-content imaging in human osteoclasts.","authors":"Maria L Price, Rachael A Wyatt, Joao Correia, Zakia Areej, Maisie Hinds, Ana Crastin, Rowan S Hardy, Morten Frost, Caroline M Gorvin","doi":"10.1530/JME-24-0143","DOIUrl":"https://doi.org/10.1530/JME-24-0143","url":null,"abstract":"Osteoporosis diagnoses are increasing in the ageing population, and although some treatments exist, these have several disadvantages, highlighting the need to identify new drug targets. G protein-coupled receptors (GPCRs) are transmembrane proteins whose surface expression and extracellular activation make them desirable drug targets. Our previous studies have identified 144 GPCR genes to be expressed in primary human osteoclasts, which could provide novel drug targets. The development of high-throughput assays to assess osteoclast activity would improve the efficiency at which we could assess the effect of GPCR activation on human bone cells and could be utilised for future compound screening. Here, we assessed the utility of a high-content imaging (HCI) assay that measured cytoplasmic-to-nuclear translocation of the nuclear factor of activated T cells-1 (NFATc1), a transcription factor that is essential for osteoclast differentiation, and resorptive activity. We first demonstrated that the HCI assay detected changes in NFATc1 nuclear translocation in human primary osteoclasts using GIPR as a positive control, and then developed an automated analysis platform to assess NFATc1 in nuclei in an efficient and unbiased manner. We assessed six GPCRs simultaneously and identified four receptors (FFAR2, FFAR4, FPR1 and GPR35) that reduced osteoclast activity. Bone resorption assays and measurements of TRAP activity verified that activation of these GPCRs reduced osteoclast activity, and that receptor-specific antagonists prevented these effects. These studies demonstrate that HCI of NFATc1 can accurately assess osteoclast activity in human cells, reducing observer bias and increasing efficiency of target detection for future osteoclast-targeted osteoporosis therapies.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"74 4","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997181","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}

引用次数: 0