Endocrine Connections最新文献

{"title":"The role of microbiota and toll-like receptors in polycystic ovary syndrome: regulatory mechanisms of androgen metabolism.","authors":"Xueming Huang, Liuyan Wu, Yunxiang Zhang, Xiaowen Lai, Dan Sun","doi":"10.1530/EC-25-0162","DOIUrl":"10.1530/EC-25-0162","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS), a prevalent reproductive endocrine and metabolic disorder in gynecology, has hyperandrogenism (HA) as an essential pathophysiological alteration. PCOS patients, with or without HA, present diverse clinical manifestations. The function of intestinal or reproductive tract microorganisms in PCOS has drawn attention in recent years and is associated with the occurrence of HA. In this article, we review the connection between the microbial alterations in the intestinal and reproductive tracts and androgens in PCOS, and elaborate on the role of TLRs in this process.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186810","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":"Testosterone-induced erythrocytosis: addressing the challenge of metabolic syndrome and widely prescribed SGLT2-inhibitor drugs.","authors":"Federica Tramontana, Azmi Mohammed, Yaasir H Mamoojee, Richard Quinton","doi":"10.1530/EC-24-0695","DOIUrl":"10.1530/EC-24-0695","url":null,"abstract":"<p><p>Testosterone is the cornerstone therapy for men with hypogonadism, and also treats any associated anaemia by promoting erythropoiesis. However, excessive doses cause erythrocytosis (raised red cell mass), especially if other risk factors are present. Erythrocytosis is associated with arterial and venous thrombosis in population studies. Testosterone is now increasingly prescribed to older men with functional hypogonadism and obesity, hypertension or type 2 diabetes, who are anyway at higher risk of both erythrocytosis and thrombosis. Although short-medium term testosterone treatment in these men was not associated with adverse cardiovascular outcomes, there were more cases of pulmonary embolism. Originally envisaged as purely oral hypoglycaemic drugs, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now increasingly prescribed in chronic kidney disease (CKD), ischaemic heart disease and left ventricular impairment, irrespective of glycaemia, and the likelihood of co-prescription with testosterone is thus increased considerably. Crucially, they also increase haematocrit by promoting haematopoiesis. This review focuses on the current best evidence for managing erythrocytosis, in the context of more prevalent obesity and prescriptions of testosterone and SGLT2i in this population. It highlights the need to balance the metabolic and therapeutic benefits against the potential risks. Management strategies include re-evaluating the original treatment indication, addressing modifiable risk factors, switching to transdermal testosterone and/or reducing the testosterone dose. Venesection is not recommended, except for clonal erythrocytosis, due to its potential pro-thrombotic effects. However, combination therapy with testosterone and SGLT2s in men with anaemia of advanced CKD could augment, or even partly supersede, expensive treatment with conventional erythrocytosis-stimulating agents.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289326","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":"Phase 1 clinical trial of eneboparatide, a novel PTH receptor 1 agonist.","authors":"Michel Ovize, Soraya Allas, Michael D Culler, Stephane Milano, Taha Ouldrouis, Mark Sumeray, Jeroen van de Wetering de Rooij, Michael Mannstadt","doi":"10.1530/EC-24-0464","DOIUrl":"10.1530/EC-24-0464","url":null,"abstract":"<p><strong>Objective: </strong>This study evaluated the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of eneboparatide (AZP-3601), a novel agonist of the PTH receptor 1 developed for the treatment of hypoparathyroidism.</p><p><strong>Design: </strong>This was a randomized, double-blind, placebo-controlled study. One-hundred four healthy volunteers were recruited into seven single ascending dose (SAD) and five multiple ascending dose (MAD) cohorts.</p><p><strong>Methods: </strong>PK parameters were time to peak, Cmax, area under the curve (AUC) and half-life. PD parameters included albumin-adjusted serum calcium (sCa), serum phosphorus (sPh), serum endogenous PTH, 24 hr urinary excretion of calcium (24 h-uCa), fractional excretion of calcium (FECa) and bone turnover markers (s-CTX and P1NP).</p><p><strong>Results: </strong>There were no serious adverse events. All adverse events were of mild-to-moderate intensity. AUC and Cmax of eneboparatide increased with increasing doses. Time to maximum plasma concentration was 5-20 min. SAD showed a dose-dependent increase of sCa and decrease of sPh associated with a reduction of serum endogenous PTH. MAD demonstrated a rapid access to maximal PD effects and maintained levels of sCa throughout the day. Urinary excretion of calcium did not increase as a function of the dose of eneboparatide. P1NP and s-CTX did not change over the treatment period.</p><p><strong>Conclusion: </strong>The PD effects of eneboparatide were prolonged despite the short half-life. These data suggest that eneboparatide may provide sustained control of serum calcium in patients with hypoparathyroidism with once daily dosing. An open-label phase 2 study in patients with hypoparathyroidism has been recently completed and published and a phase 3 study has been initiated.</p><p><strong>Clinical trial registration number: </strong>NCT05239221.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149864","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":"Hyperprolactinemia and cancer risk: a Swedish population-based cohort study.","authors":"Christos Himonakos, Louise Emilsson, Sophie Bensing, Katarina Berinder","doi":"10.1530/EC-25-0108","DOIUrl":"10.1530/EC-25-0108","url":null,"abstract":"<p><strong>Objective: </strong>Prolactin (PRL) promotes cell proliferation, and PRL receptor expression is elevated in various cancer types. However, only a few studies have examined cancer risk in patients with hyperprolactinemia (HPL). The aim of this study was to investigate cancer risk in a nationwide cohort of patients with a diagnosis of HPL, with special emphasis on breast cancer.</p><p><strong>Design: </strong>In this Swedish population-based cohort study, we used nationwide registries to identify 3,837 patients (2,955 (77%) women) with HPL, treated with dopamine agonists (DA), diagnosed between 2006 and 2019, along with 38,370 controls matched by age, sex, calendar year and county of residence at first HPL diagnosis.</p><p><strong>Methods: </strong>Cancer outcomes (overall and specific types), as registered in the Swedish Cancer Register, were analyzed using Cox regression, internally stratified by the matching variables and additionally adjusted for diabetes mellitus, obesity, smoking, alcohol overconsumption, hormone replacement therapy and educational level to estimate adjusted hazard ratios (aHRs).</p><p><strong>Results: </strong>During a median follow-up time of 6.1 years (interquartile range (IQR) 3.4-9.6), 168 (4.6%) new cases of cancer were identified in patients with HPL and 1,608 (4.4%) in the control group (aHR 1.05 (95% CI: 0.89-1.23)). Twenty-eight (0.7%) patients (all women) in the HPL group and 267 (0.7%) in the control group developed breast cancer (aHR 1.02 (95% CI: 0.68-1.51)). Similarly, there was no increased risk of any other site-specific cancer.</p><p><strong>Conclusions: </strong>In this nationwide cohort study of patients with DA-treated HPL, no increased risk of overall cancer, breast cancer or other site-specific malignancies was observed.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247014","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":"The effect of MDMA on anterior pituitary hormones: a secondary analysis of a randomized placebo-controlled trial.","authors":"Cihan Atila, Sara-Jessica Camerin, Matthias E Liechti, Mirjam Christ-Crain","doi":"10.1530/EC-25-0254","DOIUrl":"10.1530/EC-25-0254","url":null,"abstract":"<p><strong>Background: </strong>3,4-Methylenedioxymethamphetamine (MDMA), a psychoactive substance, has been proposed as a novel provocation test for oxytocin deficiency. Limited evidence suggests that MDMA may also stimulate the anterior pituitary. Therefore, this analysis aimed to investigate the acute effect of MDMA on the anterior pituitary in healthy adults.</p><p><strong>Methods: </strong>This secondary analysis utilized data from a double-blind, placebo-controlled, crossover, randomized trial. Healthy participants received a single oral dose of MDMA (100 mg) or placebo in random order. Plasma hormone levels of the anterior pituitary (adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), prolactin, growth hormone (GH)) and their peripheral endocrine glands (cortisol, free thyroxine (fT4), testosterone, and estradiol) were measured at baseline and 120 min after drug-intake. Plasma hormone changes following MDMA vs placebo were compared using the paired Wilcoxon test.</p><p><strong>Results: </strong>Fifteen healthy participants (median (IQR) age: 35 years (26, 48); 53% female) with a mean (SD) BMI of 23.2 kg/m2 (2.1) were included. MDMA stimulated the hypothalamic-pituitary-adrenal (HPA) axis, with plasma ACTH increasing from 12 ng/L (11, 15) at baseline to 38 ng/L (25, 59) at 120 min, resulting in a significant change of ACTH (P < 0.001). This was accompanied by a cortisol increase from 347 nmol/L (252, 409) to 566 nmol/L (457, 701), resulting in a significant change of cortisol (P = 0.006). Prolactin showed a mild change of 4 μg/L (-1, 12) (P = 0.062). No effects of MDMA were observed on the remaining anterior pituitary axes.</p><p><strong>Conclusion: </strong>MDMA strongly activates the HPA axis, in addition to stimulating oxytocin, suggesting that MDMA may serve as a novel stimulation test for assessing the two pituitary axes simultaneously. Further validation in larger patient populations is necessary.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215298","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":"Serum metabolomics reveals systemic metabolic alterations of Graves' disease before and after antithyroid drug treatment.","authors":"Tiantian Li, Luyang Li, Xinpan Wang, Yue Li, Yingyun Gong, Hongwen Zhou, Xuqin Zheng","doi":"10.1530/EC-25-0078","DOIUrl":"10.1530/EC-25-0078","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to utilize untargeted metabolomics to analyze changes of serum metabolites before and after methimazole treatment in patients with Graves' disease (GD).</p><p><strong>Methods: </strong>Total 40 GD patients and 30 healthy volunteers were recruited for the study. Metabolomics analysis was conducted using liquid chromatography-mass spectrometry.</p><p><strong>Results: </strong>A total of 11,590 metabolites were measured. Compared to healthy controls, newly diagnosed untreated GD patients exhibited significant metabolic dysregulation, with 1,805 metabolites upregulated and 1,737 downregulated. After 1 year of methimazole treatment and normalization of thyroid hormone levels, 137 metabolites remained upregulated and 242 remained downregulated, suggesting incomplete metabolic recovery. Pathway enrichment analysis indicated significant alterations in tyrosine metabolism, biosynthesis of alkaloids derived from histidine and purine, and bile secretion pathways in untreated GD patients. In addition, pathways such as ABC transporters, folate biosynthesis, D-amino acid metabolism, anthranilate degradation, and purine metabolism remained significantly dysregulated after treatment. Correlation analysis revealed positive associations between docosatetraenoic acid and citric acid with free triiodothyronine and free thyroxine levels, between 4-hydroxyphenyllactic acid and free triiodothyronine, and between 13Z,16Z-docosadienoic acid and thyroid-stimulating hormone receptor antibody levels.</p><p><strong>Conclusion: </strong>Significant alterations in plasma metabolomic profiles during the transition from hyperthyroidism to euthyroidism in GD patients were identified using untargeted metabolomics, highlighting persistent metabolic disruptions despite clinical recovery.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215294","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":"Retinoid X receptor γ regulates epithelial-mesenchymal transition and tumor immune infiltration in papillary thyroid cancer tumorigenesis: an experimental and in silico study.","authors":"Pihong Li, Wei Zhang, Qiaolin Wu, Xiaohua Zhang, Zhouci Zheng","doi":"10.1530/EC-25-0015","DOIUrl":"10.1530/EC-25-0015","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to elucidate the functional role and underlying molecular mechanisms of retinoid X receptor γ (RXRG) in the pathogenesis of papillary thyroid carcinoma (PTC).</p><p><strong>Methods: </strong>We analyzed RNA-seq data from The Cancer Genome Atlas database, ONCOMINE database, and Human Protein Atlas. RXRG expression was validated in 47 matched PTC-normal tissue pairs using real-time reverse transcription-polymerase chain reaction. Functional characterization was performed through loss- and gain-of-function experiments, complemented by flow cytometry analysis. Bioinformatics approaches were employed to investigate RXRG's role in tumor immune infiltration.</p><p><strong>Results: </strong>RXRG was significantly upregulated in PTC (P < 0.001). Elevated RXRG expression correlated with aggressive clinicopathological features, including lymph node metastasis (P = 0.041), advanced tumor stage (P = 0.035), BRAFV600E mutation (P < 0.001), and increase in tumor size (P = 0.011). Functional assays revealed that RXRG knockdown suppressed cell proliferation, colony formation, and migration capacity, whereas its overexpression promoted these oncogenic phenotypes. Mechanistically, RXRG regulated epithelial-mesenchymal transition (EMT) through modulation of E-cadherin, N-cadherin, vimentin, and key transcription factors (Snail and Slug). Furthermore, RXRG expression considerably influenced tumor immune infiltration patterns, particularly affecting eosinophils, NK cells, and B cells.</p><p><strong>Conclusion: </strong>Our study identifies RXRG as a novel oncogenic driver in PTC that promotes tumor progression through EMT regulation and immune microenvironment modulation.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224767","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":"Clinical remission in newly diagnosed type 1 diabetes mellitus and HDL function on cholesterol efflux capacity: prospective InLipoDiab1 study.","authors":"Aleksandra Uruska, Maja Mietkiewska-Dolecka, Agata Grzelka-Wozniak, Justyna Flotynska, Suzanne Saldanha, Anand Rohatgi, Dorota Zozulinska-Ziolkiewicz","doi":"10.1530/EC-24-0704","DOIUrl":"10.1530/EC-24-0704","url":null,"abstract":"<p><strong>Summary: </strong>Type 1 diabetes mellitus (DM1) is characterized by high serum HDL, which does not translate into a better prognosis. It is probably related to the impaired function of HDL particles. One of the functions of HDL is reverse cholesterol transport (cholesterol efflux capacity, CEC). Beneficial for management and prognosis in DM1 is the occurrence of partial clinical remission (pCR). It is not known whether the changes in CEC are related to the presence of pCR. The aim was to evaluate the relationship between CEC and pCR in newly diagnosed DM1 during 12 months. The analysis comprised 127 adults (68% men) with newly diagnosed DM1. CEC was assessed in UT Southwestern Medical Center by measuring the efflux of radiolabeled cholesterol from murine J774 macrophages to apolipoprotein B-depleted serum. The study was performed at two points: at disease onset and after 1 year. pCR was defined as insulin dose-adjusted A1C as A1C (percent) + (4 × insulin dose) ≤9. After 1 year of observation, a significant increase in serum HDL concentration and no change in CEC were demonstrated in the whole group (1.28 (1.11-1.41) vs 1.23 (1.14-1.42), P = 0.6). There was a CEC improvement in women with pCR after 1 year 1.28 (1.04-1.38) vs 1.31 (1.08-1.42), P = 0.05. No relationship was revealed between pCR and CEC (OR 1.8 (CI 95% 0.12-26.8), P = 0.7). In DM1, during the first year of the disease, there was no improvement in CEC despite a significant increase in serum HDL cholesterol concentration. There was no relationship between CEC and pCR. Good metabolic control in pCR has a beneficial impact on CEC.</p><p><strong>Article highlights: </strong>Increased HDL serum cholesterol concentration is not associated with improved HDL function. HDL particles are functionally impaired from the onset of type 1 diabetes. There is no relationship between cholesterol efflux capacity and clinical remission of type 1 diabetes. A change in viewpoint on high HDL cholesterol levels in people with type 1 diabetes as a protective factor for the development of diabetes complications and the awareness that HDL cholesterol levels alone are insufficient to assess the cardiovascular risk in this group of patients.</p><p><strong>Clinicaltrials number: </strong>NCT02306005.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224766","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":"A high FT3 level might protect bone mineral density among euthyroid type 2 diabetes mellitus patients.","authors":"Jiamin Song, Wenxin Li, Guoyue Yuan, Dong Wang, Li Zhao","doi":"10.1530/EC-25-0110","DOIUrl":"10.1530/EC-25-0110","url":null,"abstract":"<p><strong>Objectives: </strong>This research was to investigate the relationship among thyroid function, sensitivity to thyroid hormone indices, and bone mineral density (BMD) in euthyroid individuals with type 2 diabetes mellitus (T2DM).</p><p><strong>Methods: </strong>A total of 536 euthyroid patients with T2DM were included. The subjects were measured for anthropometric parameters, biochemical indicators, and clinical characteristics. Their bone density was tested by dual-energy X-ray, and then they were classified according to their outcomes.</p><p><strong>Results: </strong>In comparison to the normal BMD group, the FT3 level was notably reduced in the low BMD groups (P < 0.05). The patients were sequentially assigned to tri-sectional quantiles according to FT3. Compared with tertile 1, patients in tertile 2 had a higher value of BMD. Spearman correlation analysis showed that the FT3 level was positively associated with BMD. After adjustment in multiple linear regression, FT3 level remained significantly related to decreased BMD. A significant independent association between FT3 and BMD was found by multiple logistic regression analysis after adjusting for potential confounding variables (OR = 0.187, P < 0.05). No significant relation was found between thyroid hormone indices and BMD.</p><p><strong>Conclusion: </strong>FT3 level was independently associated with BMD in euthyroid patients with T2DM. High-normal FT3 may be a protective factor for BMD.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181008","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":"lncRNA RP11-34D15.2 sponges miR-223 to promote the PGC-1α/irisin signaling pathway, contributing to increased FFA and insulin resistance in obese children.","authors":"Shuang Guo, Mengnan Lu, Yuesheng Liu, Hongai Zhang, Biyao Lian, Yanfeng Xiao, Chunyan Yin","doi":"10.1530/EC-25-0028","DOIUrl":"10.1530/EC-25-0028","url":null,"abstract":"<p><strong>Background: </strong>The global surge in pediatric obesity is closely linked to insulin resistance (IR) and type 2 diabetes, where adipose tissue free fatty acid (FFA) overload and mitochondrial dysfunction play pivotal roles. Long non-coding RNAs (lncRNAs) are emerging regulators of metabolic diseases, but their mechanistic contributions to childhood obesity-associated IR remain underexplored.</p><p><strong>Objective: </strong>This study investigates whether lncRNA RP11-34D15.2 modulates FFA-induced IR through the miR-223/PGC-1α/irisin signaling axis in obese children.</p><p><strong>Methods: </strong>We analyzed serum FFA, insulin, irisin, and white adipose tissue (WAT) transcriptomes in 40 obese and 40 normal-weight children. Functional validation included dual-luciferase reporter assays, primary adipocyte models, and high-fat diet (HFD) mice treated with lncRNA-specific shRNA (n = 10 per group). Molecular interactions were verified via RNA immunoprecipitation and western blotting.</p><p><strong>Results: </strong>Obese children exhibited 2.1-fold higher FFA levels and HOMA-IR (P < 0.01), but 38% lower serum irisin compared to controls, with irisin inversely correlating with body fat percentage (r = -0.67, P = 0.003). lncRNA RP11-34D15.2 was downregulated by 4.3-fold in obese WAT and positively correlated with irisin expression (r = 0.603, P = 0.018). Mechanistic studies revealed that lncRNA directly binds miR-223 (RIP-seq fold enrichment = 5.2, P = 0.004), relieving miR-223-mediated suppression of PGC-1α. Overexpressing lncRNA in adipocytes increased PGC-1α (2.8-fold) and irisin (1.9-fold), upregulated mitochondrial genes (CPT-1: 3.1-fold; UCP-1: 2.4-fold, P < 0.01), and reduced extracellular FFA by 44%. In HFD mice, lncRNA knockdown exacerbated glucose intolerance (AUC increased 29%, P = 0.007), whereas irisin supplementation restored insulin sensitivity (P = 0.013).</p><p><strong>Conclusion: </strong>lncRNA RP11-34D15.2 functions as a ceRNA sponging miR-223 to activate PGC-1α/irisin-mediated mitochondrial β-oxidation and FFA clearance, identifying therapeutic targets for childhood obesity.</p>","PeriodicalId":11634,"journal":{"name":"Endocrine Connections","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119254","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}