Molecular and Cellular Endocrinology最新文献

{"title":"Exploratory analysis of differences at the transcriptional interface between the maternal and fetal compartments of the sheep placenta and potential influence of fetal sex","authors":"Katherine M. Halloran ,&nbsp;Nadia Saadat ,&nbsp;Brooke Pallas ,&nbsp;Arpita K. Vyas ,&nbsp;Vasantha Padmanabhan","doi":"10.1016/j.mce.2025.112546","DOIUrl":"10.1016/j.mce.2025.112546","url":null,"abstract":"<div><div>An understanding of the inner workings of the placenta is imperative to elucidate how the maternal and fetal compartments coordinate to mediate fetal development. The two compartments can be separated and studied before term in sheep, a feat not possible in humans, thus providing a valuable translational model. This study investigated differential expression of gene signaling networks in the maternal and fetal compartments of the placenta and explored the potential influence of fetal sex. On approximately gestational day 120 (term: 147 days), ewes were euthanized and fetuses removed and sexed. Placentomes [n = 5 male, n = 3 female] were collected, and caruncles (maternal) and cotyledons (fetal) were separated and sequenced to assess RNA expression. Analysis revealed 2627 differentially expressed genes (FDR&lt;0.01, abslog2FC ≥ 2) contributing to key transcriptional differences between maternal and fetal compartments, which suggested that the maternal compartment drives extracellular signaling at the interface whereas the fetal compartment controls internal mechanisms crucial for fetal-placental development. X-chromosome inactivation equalized expression of a vast majority of X-linked genes in the fetal compartment. Additionally, the female placenta had more fine-tuned regulation of key pathways for fetal-placental development, such as DNA replication, mRNA surveillance, and RNA transport, compared to males, which had enrichment of metabolic pathways including TCA cycle and galactose metabolism. These findings, in addition to supporting differences in expression in the maternal and fetal placental compartments and the possible influence of fetal sex, offer a transcriptional platform to compare placental perturbations that occur at the maternal-fetal interface that contribute to adverse pregnancy outcomes.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"603 ","pages":"Article 112546"},"PeriodicalIF":3.8,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826134","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":"N-acetylcysteine influence on PI3K/Akt/mTOR and sphingolipid pathways in rats with MASLD induced by HFD: a promising new therapeutic purpose","authors":"Klaudia Sztolsztener,&nbsp;Daniel Michalak,&nbsp;Adrian Chabowski","doi":"10.1016/j.mce.2025.112545","DOIUrl":"10.1016/j.mce.2025.112545","url":null,"abstract":"<div><div>Sphingolipid and glucose metabolism play important roles in the induction and progression of severe liver disorders like metabolic dysfunction-associated steatotic liver disease (MASLD). The perturbation in sphingolipid formation may improve the liver structure and functioning and may constitute the potential therapeutic options for the development of simple steatosis and its progression to steatohepatitis. This study aims to assess the influence of N-acetylcysteine (NAC) on the sphingolipid and insulin signaling pathways in rats subjected to standard or high-fat diets. Sphingolipid level was measured using high-performance liquid chromatography (HPLC). A multiplex assay kit determined the level of phosphorylated form of proteins included in the PI3K/Akt/mTOR pathway. The immunoblotting estimated the expression of proteins from sphingolipid and insulin transduction pathways. A histological Oil red O staining was used to assess the hepatic accumulation of lipid droplets. Molecular docking was applied to showcase NAC interaction with PI3K/Akt/mTOR pathway proteins. NAC decreased dihydroceramide and ceramide levels and increased phosphorylation of sphingosine and sphinganine. This antioxidant also enhanced phosphorylated Akt, GSK3α/β, and P70 S6 kinase and decreased phosphorylated S6RP. In silico docking analysis of insulin signaling molecules evidenced the higher binding affinity of NAC with all tested proteins, i.e., IRS1, PTEN, Akt, GSK3α/β, P70 S6 kinase, and S6RP, suggesting a potential protective influence on insulin resistance development, which is one of the criteria for MASLD diagnosing. Based on these data, NAC improved the hepatic insulin sensitivity and sphingolipid synthesis and storage, improving and restoring glucose homeostasis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"603 ","pages":"Article 112545"},"PeriodicalIF":3.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826135","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":"Maternal dopamine agonist treatment before pregnancy reverses infertility and hyperprolactinemia in hCG-overexpressing mice through lactation: Evidence of generational effects","authors":"Laura D. Ratner ,&nbsp;Agustina Marcial Lopez ,&nbsp;Noelia P. Di Giorgio ,&nbsp;Matti Poutanen ,&nbsp;Ilpo Huhtaniemi ,&nbsp;Susana B. Rulli","doi":"10.1016/j.mce.2025.112538","DOIUrl":"10.1016/j.mce.2025.112538","url":null,"abstract":"<div><div>Dopamine agonists, such as cabergoline (Cab), have demonstrated efficacy in restoring reproductive function in cases of hyperprolactinemia and hormonal dysregulation. This study investigates the long-term consequences of maternal Cab treatment on the reproductive phenotype of the progeny in a female transgenic (TG) mouse model with hyperprolactinemia and infertility due to human chorionic gonadotropin (hCG) β-subunit overexpression. The TG females that received Cab between weeks 3–4 of life exhibited a reversion of hyperprolactinemia and infertility, whereas WT females retained their fertility. When TG-cab- or WT-Cab-treated females were crossed with WT or TG males, respectively, their female TG offspring showed a reversal of precocious puberty, regularization of estrous cycles, fertility, and prevention of hyperprolactinemia and prolactinomas. Despite the persistent high LH/hCG bioactivity, the normalization of prolactin levels led to a reduction in ovarian luteinization markers and progesterone levels. The TG female pups born to either WT-cab- or TG-cab-treated females exhibited a normalized phenotype, thus suggesting that the effects were indeed due to maternal Cab administration, and not to the transgene. Cross-fostering experiments showed that the long-lasting programming effect of maternal Cab on offspring occurred during lactation because the TG female pups from non-treated WT female/TG male pregnancies, but nursed by Cab-treated females, were free from the altered TG phenotype. These results suggest that Cab treatment before pregnancy may have a multigenerational effect on the hypothalamic-pituitary-gonadal axis of the offspring, mediated during lactation. This highlights potential implications for generational health and clinical practices regarding the use of dopamine agonists during lactation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"602 ","pages":"Article 112538"},"PeriodicalIF":3.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786203","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":"The multi-level effect of chlorpyrifos during clownfish metamorphosis","authors":"Mathieu Reynaud ,&nbsp;Stefano Vianello ,&nbsp;Shu-Hua Lee ,&nbsp;Pauline Salis ,&nbsp;Kai Wu ,&nbsp;Bruno Frederich ,&nbsp;David Lecchini ,&nbsp;Laurence Besseau ,&nbsp;Natacha Roux ,&nbsp;Vincent Laudet","doi":"10.1016/j.mce.2025.112535","DOIUrl":"10.1016/j.mce.2025.112535","url":null,"abstract":"<div><div>Chemical pollution in coastal waters, particularly from agricultural runoff organophosphates, poses a significant threat to marine ecosystems, including coral reefs. Pollutants such as chlorpyrifos (CPF) are widely used in agriculture and have adverse effects on marine life and humans. In this paper, we investigate the impact of CPF on the metamorphosis of a coral reef fish model, the clownfish <em>Amphiprion ocellaris</em>, focusing on the disruption of thyroid hormone (TH) signalling pathways. Our findings reveal that by reducing TH levels, CPF exposure impairs the formation of characteristic white bands in clownfish larvae, indicative of metamorphosis progression. Interestingly, TH treatment can rescue these effects, establishing a direct causal link between CPF effect and TH disruption. The body shape changes occurring during metamorphosis are also impacted by CPF exposure, shape changes are less advanced in CPF-treated larvae than in control conditions. Moreover, transcriptomic analysis elucidates CPF's effects on all components of the TH signalling pathway. Additionally, CPF induces systemic effects on cholesterol and vitamin D metabolism, DNA repair, and immunity, highlighting its broader TH-independent impacts. Pollutants are often overlooked in marine ecosystems, particularly in coral reefs. Developing and enhancing coral reef fish models, such as <em>Amphiprion ocellaris</em> (Cuvier, 1830), offers a more comprehensive understanding of how chemical pollution affects these ecosystems. This approach provides new insights into the complex mechanisms underlying CPF toxicity during fish metamorphosis, shedding light on the broader impact of environmental pollutants on marine organisms.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"603 ","pages":"Article 112535"},"PeriodicalIF":3.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788498","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":"Establishment of a tri co-culture model for human feto-placental steroidogenesis and investigation of the antidepressant vortioxetine","authors":"Selen Öztürk ,&nbsp;Basak Ezgi Sarac ,&nbsp;Sedat Odabaş ,&nbsp;Cagatay Karaaslan ,&nbsp;Aysun Kılıç Süloğlu","doi":"10.1016/j.mce.2025.112537","DOIUrl":"10.1016/j.mce.2025.112537","url":null,"abstract":"","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"602 ","pages":"Article 112537"},"PeriodicalIF":3.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786154","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":"Follicular fluid profiling unveils anti-Müllerian hormone alongside glycolytic and mitochondrial dysfunction as markers of polycystic ovary syndrome","authors":"Emídio Vale-Fernandes ,&nbsp;David F. Carrageta ,&nbsp;Mafalda V. Moreira ,&nbsp;Bárbara Guerra-Carvalho ,&nbsp;Bárbara Rodrigues ,&nbsp;Daniela Sousa ,&nbsp;Raquel Brandão ,&nbsp;Carla Leal ,&nbsp;Márcia Barreiro ,&nbsp;António Tomé ,&nbsp;Marco G. Alves ,&nbsp;Pedro F. Oliveira ,&nbsp;Mariana P. Monteiro","doi":"10.1016/j.mce.2025.112536","DOIUrl":"10.1016/j.mce.2025.112536","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age, yet the molecular mechanisms influencing its pathophysiology remain poorly defined. A comprehensive prospective case-control study was conducted to elucidate the follicular fluid (FF) hormone and metabolite profile in women with PCOS and its implications for oocyte maturation and fertilization. The study involved 40 age- and body mass index (BMI)-matched women undergoing in vitro fertilization (IVF), including 20 diagnosed with PCOS and 20 controls with infertility due to tubal or male factors. A distinctive hormone profile in the FF of women with PCOS was identified, characterized by significantly higher anti-Müllerian hormone (AMH) levels (24.90 ± 17.61 vs. 16.68 ± 17.67 pmol/L, <em>p</em> = 0.0039) and lower progesterone (8253 ± 4748 vs. 25362 ± 10862 ng/mL, <em>p</em> &lt; 0.0001) and estradiol levels (388.23 ± 210.58 vs. 651.48 ± 390.79 ng/mL, <em>p</em> = 0.0208) compared to normoovulatory controls. Moreover, a metabolite fingerprint associated with glycolytic and mitochondrial dysfunction was observed, as evidenced by lower lactate (4575.44 ± 1507.76 vs. 5595.34 ± 1073.32 μmol/L, <em>p</em> = 0.0182) and formate (64.51 ± 16.06 vs. 75.81 ± 16.63 μmol/L, <em>p</em> = 0.0351) levels and higher citrate levels (136.93 ± 52.53 vs. 109.15 ± 24.17 μmol/L, <em>p</em> = 0.0409) in the FF of women with PCOS. These findings suggest that the molecular profile of the FF in women with PCOS might be related to granulosa cell glycolytic and mitochondrial dysfunction, which can have a negative impact on oocyte fertilization potential. The study provides an integrative analysis of the FF hormone and metabolite profile in women with PCOS, offering insights into the molecular mechanisms underlying the reproductive dysfunctions associated with this condition.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"602 ","pages":"Article 112536"},"PeriodicalIF":3.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mass spectrometric profiling of primary estrogens and estrogen metabolites in human stool and plasma partially elucidates the role of the gut microbiome in estrogen recycling","authors":"Vince W. Li ,&nbsp;Tien S. Dong ,&nbsp;Diana Funes ,&nbsp;Laura Hernandez ,&nbsp;Nicole R. Kushnir ,&nbsp;Devika Nair ,&nbsp;Jonathan P. Jacobs ,&nbsp;Srinivasa T. Reddy ,&nbsp;Emeran A. Mayer ,&nbsp;Lin Chang ,&nbsp;David Meriwether","doi":"10.1016/j.mce.2025.112534","DOIUrl":"10.1016/j.mce.2025.112534","url":null,"abstract":"<div><div>Primary estrogens and estrogen metabolites are commonly measured in human plasma and serum, but there exist almost no recent reports for human stool. This knowledge gap limits our understanding of the relationships between systemic and gut estrogens. We developed a highly sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method to determine, in human plasma and stool, the free and conjugated levels of estrone, estradiol, and estriol together with their additional hydroxyestrogen and methoxyestrogen metabolites. We investigated human stool and plasma estrogens in healthy control men; in follicular and luteal phase premenopausal women; and in postmenopausal women. Most estrogens were present in plasma and stool of all groups, while the plasma and stool levels of hydroxyestrogen and methoxyestrogen metabolites but not estrone were correlated. In stool, estrogens were higher in premenopausal women, with estrogens increasing across the menstrual cycle. We combined these LC-MS/MS measures with shotgun metagenomic sequencing of the stool microbiomes. Estrogen deconjugation enzyme gene copy numbers (β-glucuronidase and arylsulfatase) were higher in premenopausal women; while the gene copy number of β-glucuronidase + arylsulfatase, but not β-glucuronidase alone, correlated with deconjugated stool estrogens in all groups. Moreover, β-glucuronidase + arylsulfatase gene copy numbers correlated with combined plasma estrogens in men and with individual plasma estrogen metabolites in men and premenopausal women. These results support the hypothesis that gut microbial β-glucuronidase and arylsulfatase control the deconjugation of gut estrogens while modulating systemic levels through the uptake and recirculation of these deconjugated estrogens. The intestine may thus constitute an important additional compartment in estrogen physiology.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"603 ","pages":"Article 112534"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780781","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":"Obesity prevention by different exercise protocols (HIIT or MICT) involves beige adipocyte recruitment and improved mitochondrial dynamics in high-fat-fed mice","authors":"Daiana Araujo Santana-Oliveira ,&nbsp;Henrique Souza-Tavares ,&nbsp;Aline Fernandes-da-Silva ,&nbsp;Thatiany Souza Marinho ,&nbsp;Flavia Maria Silva-Veiga ,&nbsp;Julio Beltrame Daleprane ,&nbsp;Vanessa Souza-Mello","doi":"10.1016/j.mce.2025.112533","DOIUrl":"10.1016/j.mce.2025.112533","url":null,"abstract":"<div><h3>Aim</h3><div>This study evaluated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on UCP1-dependent and UCP1-independent thermogenic and mitochondrial dynamics markers in the inguinal sWAT of high-fat-fed mice.</div></div><div><h3>Methods</h3><div>Sixty male C57BL/6 mice (3 months old) were divided into six experimental groups: control diet (C), C + HIIT (C-HIIT), C + MICT (C-MICT), high-fat diet (HF), HF + HIIT (HF-HIIT) and HF + MICT (HF-MICT). The diet and exercise protocols started simultaneously and lasted ten weeks.</div></div><div><h3>Results</h3><div>HIIT and MICT prevented body mass gain and fat pad expansion, improved insulin sensitivity, and induced browning in C-fed and HF-fed animals. Chronic intake of a HF diet caused adipocyte hypertrophy with a proinflammatory adipokine profile and impaired the expression of thermogenic and mitochondrial dynamics markers. However, both exercise intensities increased anti-inflammatory adipokine concentrations and improved gene markers of mitochondrial dynamics, resulting in sustained UCP1-dependent and UCP1-independent thermogenic markers and maintenance of the beige phenotype in inguinal sWAT. The principal component analysis placed all trained groups opposite the HF group and near the C group, ensuring the effectiveness of HIIT and MICT to prevent metabolic alterations.</div></div><div><h3>Conclusions</h3><div>This study provides reliable evidence that, regardless of intensity, exercise is a strategy to prevent obesity by reducing body fat accumulation and inducing browning. The anti-inflammatory adipokine profile and the increased expression of UCP1-dependent and UCP1-independent thermogenic markers sustained active beige adipocytes and mitochondrial enhancement to halt metabolic disturbances due to HF-feeding in exercised mice.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"602 ","pages":"Article 112533"},"PeriodicalIF":3.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739131","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":"An endocrinological perspective on polycystic ovarian syndrome","authors":"Smarto Basak ,&nbsp;Amit Kumar Dixit ,&nbsp;Ranjit Kumar Dey ,&nbsp;Lalrin Puia ,&nbsp;Manajit Bora ,&nbsp;Sanjay Kumar Y.R. ,&nbsp;Gajji Babu","doi":"10.1016/j.mce.2025.112524","DOIUrl":"10.1016/j.mce.2025.112524","url":null,"abstract":"<div><div>Polycystic ovarian syndrome (PCOS) is a complex endocrinological disorder that involves dysfunctions across multiple endocrine axes, including the hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes. Our review focuses on understanding the pathophysiology of PCOS through an endocrinological perspective, emphasizing the complex interactions between multiple endocrine axes. We have discussed the roles of the HPG, HPA, and HPT axes in PCOS. Dysregulation of the HPG axis, particularly the altered gonadotropin-releasing hormone pulse frequency resulting in elevated ratio of luteinizing hormone to follicle stimulating hormone, is central to the hyperandrogenism and anovulation, observed in PCOS. We have further highlighted the contributions of the HPA and HPT axes, where elevated adrenal androgen levels and hypothyroidism intensifies the phenotypes of PCOS. Additionally, insulin resistance and hyperinsulinemia, commonly associated with PCOS, aggravates hormonal disturbances and heighten the risk of metabolic complications such as type 2 diabetes and cardiovascular diseases. Elevated levels of anti-Müllerian hormone have also been emphasized as a key factor in inhibiting follicular growth, leading to impaired ovarian function and hyperandrogenism. This review further supports that PCOS is a multifactorial condition involving complex feedback mechanisms between the endocrine, metabolic, and reproductive systems. Furthermore, there remains a huge scope for deciphering the precise molecular interactions between the HPG, HPA, and HPT axes in PCOS, which could pave the way for targeted therapies for better management of both the endocrine and metabolic aspects of this disorder. This review will benefit researchers to get an endocrine perspective on PCOS.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"602 ","pages":"Article 112524"},"PeriodicalIF":3.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730675","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":"Exploring the functional, protective, and transcriptomic effects of GIP on cytokine-exposed human pancreatic islets and EndoC-βH5 cells","authors":"Kristine Henriksen ,&nbsp;Anne Jørgensen ,&nbsp;Simranjeet Kaur ,&nbsp;Rebekka Gerwig ,&nbsp;Cecilie Amalie Brøgger Svane ,&nbsp;Filip K. Knop ,&nbsp;Joachim Størling","doi":"10.1016/j.mce.2025.112522","DOIUrl":"10.1016/j.mce.2025.112522","url":null,"abstract":"<div><div>Immune-mediated beta-cell destruction and lack of alpha-cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects, as well as its cytoprotective effects shown in rodent beta cells. To further increase our understanding of GIP's effects on human beta cells, we here examined the functional, protective, and transcriptomic effects of GIP in human EndoC-βH5 beta cells and isolated human islets in the presence or absence of proinflammatory cytokines (interferon (IFN)-γ ± interleukin (IL)-1β) as a mimic of type 1 diabetes.</div><div>GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets at high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis in EndoC-βH5 cells or human islets, and GIP did not protect against cytokine-induced functional impairment in EndoC-βH5 cells. GIP treatment of human islets for 24 h had no effects on the transcriptome and did not modulate cytokine-induced transcriptional changes. However, GIP augmented IL-1β + IFNγ-induced secretion of interleukin (IL)-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10 but increased the secretion of CXCL8, CCL2, CCL4, and CCL11.</div><div>In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our findings indicate that GIP neither exerts cytoprotective effects against cytokines nor modulate the transcriptome of human islets. GIP may, however, exert selective modulatory effects on secreted inflammatory factors from cytokine-exposed beta cells and islets.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"602 ","pages":"Article 112522"},"PeriodicalIF":3.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}