Pub Date : 2025-12-01DOI: 10.1016/j.metop.2025.100396
Liaoyuan Zheng , Junli Liu
Lysosomes, the cellular recycling hubs, are indispensable for maintaining homeostasis by degrading misfolded proteins, damaged organelles, and foreign pathogens. Their dysfunction is a hallmark of aging and age-related neurodegenerative diseases, where impaired clearance of toxic protein aggregates drives pathogenesis. Nevertheless, the mechanisms by which lysosomal function can be enhanced to mitigate these detrimental processes remain inadequately understood. A recent study conducted by Li et al. describes a newly identified transcriptional program, the Lysosomal Surveillance Response (LySR), that, when activated, significantly extends healthspan and reduces proteotoxicity in C. elegans. This adaptive transcriptional program, governed by the GATA transcription factor, ELT-2, and modulated by the acetyltransferase CBP-1, operates independently of canonical longevity pathways such as the DAF-2 insulin-like signaling. This work not only unveils a previously unrecognized longevity pathway but also charts a new course for developing therapies targeting aging and neurodegeneration.
{"title":"A lysosomal surveillance response promotes healthspan in C. elegans","authors":"Liaoyuan Zheng , Junli Liu","doi":"10.1016/j.metop.2025.100396","DOIUrl":"10.1016/j.metop.2025.100396","url":null,"abstract":"<div><div>Lysosomes, the cellular recycling hubs, are indispensable for maintaining homeostasis by degrading misfolded proteins, damaged organelles, and foreign pathogens. Their dysfunction is a hallmark of aging and age-related neurodegenerative diseases, where impaired clearance of toxic protein aggregates drives pathogenesis. Nevertheless, the mechanisms by which lysosomal function can be enhanced to mitigate these detrimental processes remain inadequately understood. A recent study conducted by Li et al. describes a newly identified transcriptional program, the Lysosomal Surveillance Response (LySR), that, when activated, significantly extends healthspan and reduces proteotoxicity in <em>C. elegans</em>. This adaptive transcriptional program, governed by the GATA transcription factor, ELT-2, and modulated by the acetyltransferase CBP-1, operates independently of canonical longevity pathways such as the DAF-2 insulin-like signaling. This work not only unveils a previously unrecognized longevity pathway but also charts a new course for developing therapies targeting aging and neurodegeneration.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100396"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1016/j.metop.2025.100424
A.G. Holleboom , S.M. Francque , K. Cusi , C. Caussy
Since liver cirrhosis due to Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) was first described in patients with diabetes mellitus, the prevalence and severity of this liver disease have increased dramatically, driven by the increase in obesity and type 2 diabetes mellitus (T2DM). Strong epidemiological links between MASLD, insulin resistance and T2DM exist: T2DM is associated with higher prevalence and severity of MASLD, up to hepatic decompensation and hepatocellular carcinoma, and MASLD is in turn associated with incident T2DM Mechanistic studies support insulin resistance of metabolic tissues as the root cause of MASLD, whereas hepatic insulin resistance in turn contributes to hyperglycemia. Several pharmacological agents including incretin-based strategies, FGF21 analogues and the panPPAR agonist lanifibranor target the interface of MASLD and T2DM and have thereby shown promise to improve MASH and associated liver fibrosis. In light of the evident close multilevel links between MASLD and T2DM, care development efforts for MASLD in guidelines, local protocols and implementation strategies should aim to involve hepatologists, diabetologists, PCPs and their affiliated care teams in a joint effort to address the growing burden of fibrotic MASLD.
{"title":"Close multilevel links between metabolic dysfunction-associated steatotic liver disease and type 2 diabetes mellitus","authors":"A.G. Holleboom , S.M. Francque , K. Cusi , C. Caussy","doi":"10.1016/j.metop.2025.100424","DOIUrl":"10.1016/j.metop.2025.100424","url":null,"abstract":"<div><div>Since liver cirrhosis due to Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) was first described in patients with diabetes mellitus, the prevalence and severity of this liver disease have increased dramatically, driven by the increase in obesity and type 2 diabetes mellitus (T2DM). Strong epidemiological links between MASLD, insulin resistance and T2DM exist: T2DM is associated with higher prevalence and severity of MASLD, up to hepatic decompensation and hepatocellular carcinoma, and MASLD is in turn associated with incident T2DM Mechanistic studies support insulin resistance of metabolic tissues as the root cause of MASLD, whereas hepatic insulin resistance in turn contributes to hyperglycemia. Several pharmacological agents including incretin-based strategies, FGF21 analogues and the panPPAR agonist lanifibranor target the interface of MASLD and T2DM and have thereby shown promise to improve MASH and associated liver fibrosis. In light of the evident close multilevel links between MASLD and T2DM, care development efforts for MASLD in guidelines, local protocols and implementation strategies should aim to involve hepatologists, diabetologists, PCPs and their affiliated care teams in a joint effort to address the growing burden of fibrotic MASLD.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100424"},"PeriodicalIF":2.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145579096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.metop.2025.100423
Xiaoxuan Tang , Fenglan Wang , Yiran Liu , Yujia Gao , Mengxi Li , Chong Liu , Duanming Zhuang , Bin Zhang
Background
The triglyceride glucose-body mass index (TyG-BMI) is a useful marker for metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease (CVD). However, its ability to differentiate metabolic dysfunction-associated steatohepatitis (MASH) and CVD risk among patients with MASLD requires further investigation. This study evaluates the association between TyG-BMI and MASH/CVD risk in patients with MASLD and applies machine learning (ML) to identify relevant risk factors.
Methods
The study used data from National Health and Nutrition Examination Survey (NHANES) to analyzed associations between TyG-BMI and two clinical outcomes: MASH, defined by the FibroScan-AST (FAST) score ≥0.35, and self-reported CVD. Participants were categorized based on TyG-BMI quartiles: Q1 (<246.79), Q2 (246.79–280.32), Q3 (280.33–323.99), and Q4 (≥324.00). Multivariate survey-weighted logistic regression and restricted cubic splines (RCS) were used to assess relationships and potential nonlinearity. Multiple ML models were employed, with feature importance interpreted via Shapley Additive Explanations (SHAP) analysis.
Results
Among 674 MASLD participants (390 males), higher TyG-BMI was independently associated with increased risks of MASH and CVD risk. Compared with Q1, Q4 had adjusted odds ratios of 24.46 (95 % CI: 2.94–203.31, P = 0.003) for MASH and 3.53 (95 % CI: 1.26–9.90, P = 0.017) for CVD. RCS indicated linear relationships between TyG-BMI and both outcomes. The gradient boosting machine and support vector machine exhibited the optimal performance best in discriminating high-risk MASH (ROC: 0.910) and CVD (ROC: 0.773), confirming TyG-BMI as a significant risk factors.
Conclusion
TyG-BMI effectively identifies MASH and CVD risk in patients with MASLD, offering clinicians a practical tool for risk stratification and management.
{"title":"Association between triglyceride glucose-body mass index and MASH, cardiovascular disease in MASLD patients: a cross-sectional study and machine learning analysis","authors":"Xiaoxuan Tang , Fenglan Wang , Yiran Liu , Yujia Gao , Mengxi Li , Chong Liu , Duanming Zhuang , Bin Zhang","doi":"10.1016/j.metop.2025.100423","DOIUrl":"10.1016/j.metop.2025.100423","url":null,"abstract":"<div><h3>Background</h3><div>The triglyceride glucose-body mass index (TyG-BMI) is a useful marker for metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease (CVD). However, its ability to differentiate metabolic dysfunction-associated steatohepatitis (MASH) and CVD risk among patients with MASLD requires further investigation. This study evaluates the association between TyG-BMI and MASH/CVD risk in patients with MASLD and applies machine learning (ML) to identify relevant risk factors.</div></div><div><h3>Methods</h3><div>The study used data from National Health and Nutrition Examination Survey (NHANES) to analyzed associations between TyG-BMI and two clinical outcomes: MASH, defined by the FibroScan-AST (FAST) score ≥0.35, and self-reported CVD. Participants were categorized based on TyG-BMI quartiles: Q1 (<246.79), Q2 (246.79–280.32), Q3 (280.33–323.99), and Q4 (≥324.00). Multivariate survey-weighted logistic regression and restricted cubic splines (RCS) were used to assess relationships and potential nonlinearity. Multiple ML models were employed, with feature importance interpreted via Shapley Additive Explanations (SHAP) analysis.</div></div><div><h3>Results</h3><div>Among 674 MASLD participants (390 males), higher TyG-BMI was independently associated with increased risks of MASH and CVD risk. Compared with Q1, Q4 had adjusted odds ratios of 24.46 (95 % CI: 2.94–203.31, P = 0.003) for MASH and 3.53 (95 % CI: 1.26–9.90, P = 0.017) for CVD. RCS indicated linear relationships between TyG-BMI and both outcomes. The gradient boosting machine and support vector machine exhibited the optimal performance best in discriminating high-risk MASH (ROC: 0.910) and CVD (ROC: 0.773), confirming TyG-BMI as a significant risk factors.</div></div><div><h3>Conclusion</h3><div>TyG-BMI effectively identifies MASH and CVD risk in patients with MASLD, offering clinicians a practical tool for risk stratification and management.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100423"},"PeriodicalIF":2.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145579095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prostate cancer (PCa) is a major global health concern for men, yet its underlying metabolic mechanisms are not fully understood. Identifying causal metabolites could reveal novel pathways for risk assessment and prevention.
Methods
We conducted a comprehensive two-sample Mendelian randomization (TSMR) study following STROBE-MR guidelines. Genetic instruments for plasma metabolites were derived from two independent sources, including the METSIM study, a cohort exclusively comprising Finnish men, and the Canadian Longitudinal Study on Aging (CLSA). Summary-level data for PCa were obtained from the PRACTICAL consortium and FinnGen. Inverse variance weighted (IVW) was the primary analysis method, supplemented by sensitivity analyses and Bayesian colocalization (coloc) to assess shared causal genetic variants, a key methodological strength enhancing causal inference.
Results
Our analysis identified four plasma metabolites with a significant causal relationship with PCa risk. Ribitol was associated with a reduced risk, while N2,N5-diacetylornithine, N-acetylarginine, and N-acetylcitrulline were associated with an elevated risk. These findings were consistent across datasets and robust in sensitivity analyses. Colocalization analysis provided strong evidence (PP.H4 > 0.8) for a shared causal variant at the rs10201159 locus between N2,N5-diacetylornithine and PCa.
Conclusion
This study provides robust genetic evidence supporting a causal role of specific plasma metabolites in prostate cancer development. The incorporation of a male-exclusive metabolomic dataset (METSIM) strengthens the validity of our findings for this male-specific cancer. These metabolites represent promising candidates for further mechanistic investigation into prostate cancer etiology and potential translation into clinical biomarkers.
{"title":"Novel causal associations between plasma metabolites and prostate cancer risk revealed by mendelian randomization","authors":"Hanghang Chen , Huiduo Zhao , Bingxin Meng , Qi Liu","doi":"10.1016/j.metop.2025.100421","DOIUrl":"10.1016/j.metop.2025.100421","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) is a major global health concern for men, yet its underlying metabolic mechanisms are not fully understood. Identifying causal metabolites could reveal novel pathways for risk assessment and prevention.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive two-sample Mendelian randomization (TSMR) study following STROBE-MR guidelines. Genetic instruments for plasma metabolites were derived from two independent sources, including the METSIM study, a cohort exclusively comprising Finnish men, and the Canadian Longitudinal Study on Aging (CLSA). Summary-level data for PCa were obtained from the PRACTICAL consortium and FinnGen. Inverse variance weighted (IVW) was the primary analysis method, supplemented by sensitivity analyses and Bayesian colocalization (coloc) to assess shared causal genetic variants, a key methodological strength enhancing causal inference.</div></div><div><h3>Results</h3><div>Our analysis identified four plasma metabolites with a significant causal relationship with PCa risk. Ribitol was associated with a reduced risk, while N2,N5-diacetylornithine, N-acetylarginine, and N-acetylcitrulline were associated with an elevated risk. These findings were consistent across datasets and robust in sensitivity analyses. Colocalization analysis provided strong evidence (PP.H4 > 0.8) for a shared causal variant at the rs10201159 locus between N2,N5-diacetylornithine and PCa.</div></div><div><h3>Conclusion</h3><div>This study provides robust genetic evidence supporting a causal role of specific plasma metabolites in prostate cancer development. The incorporation of a male-exclusive metabolomic dataset (METSIM) strengthens the validity of our findings for this male-specific cancer. These metabolites represent promising candidates for further mechanistic investigation into prostate cancer etiology and potential translation into clinical biomarkers.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100421"},"PeriodicalIF":2.7,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.metop.2025.100418
Zhongpeng Qiu , Dejing Shang
The pathogenesis of type 2 diabetes mellitus (T2DM) is closely associated with chronic inflammation within the islet microenvironment, where pancreatic islet macrophages serve as central orchestrators of local immune regulation. This review provides a systematic overview of the ontogeny, phenotypic heterogeneity, and functional roles of pancreatic islet macrophages in T2DM pathology. Pancreatic islet macrophages contribute to β-cell proliferation and the maintenance of islet homeostasis through the secretion of various growth factors, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Under conditions of metabolic stress, including lipotoxicity and glucotoxicity, these macrophages are polarized toward a pro-inflammatory phenotype. In this state, they impair β-cell function by releasing inflammatory mediators, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, this article discusses potential clinical strategies that target pancreatic islet macrophages—such as anti-inflammatory agents and immunomodulators—highlighting their promise as novel perspectives for precise intervention in T2DM.
{"title":"The role of pancreatic islet macrophages in type 2 diabetes mellitus: from underlying pathological mechanisms to therapeutic target discovery","authors":"Zhongpeng Qiu , Dejing Shang","doi":"10.1016/j.metop.2025.100418","DOIUrl":"10.1016/j.metop.2025.100418","url":null,"abstract":"<div><div>The pathogenesis of type 2 diabetes mellitus (T2DM) is closely associated with chronic inflammation within the islet microenvironment, where pancreatic islet macrophages serve as central orchestrators of local immune regulation. This review provides a systematic overview of the ontogeny, phenotypic heterogeneity, and functional roles of pancreatic islet macrophages in T2DM pathology. Pancreatic islet macrophages contribute to β-cell proliferation and the maintenance of islet homeostasis through the secretion of various growth factors, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Under conditions of metabolic stress, including lipotoxicity and glucotoxicity, these macrophages are polarized toward a pro-inflammatory phenotype. In this state, they impair β-cell function by releasing inflammatory mediators, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, this article discusses potential clinical strategies that target pancreatic islet macrophages—such as anti-inflammatory agents and immunomodulators—highlighting their promise as novel perspectives for precise intervention in T2DM.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100418"},"PeriodicalIF":2.7,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To systematically evaluate the clinical efficacy of probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) on glycemic control in adults with type 2 diabetes (T2D) and related dysglycemia, and to synthesize associated mechanistic changes in microbial metabolites and composition.
Methods
A systematic review was conducted following PRISMA 2020 guidelines. PubMed/MEDLINE, Scopus, and Web of Science were searched from inception through August 2025 for randomized controlled trials (RCTs) in adults with T2D, prediabetes, or metabolic syndrome. Interventions included probiotics, prebiotics, synbiotics, or FMT compared to control. Outcomes were glycemic indices (e.g., HbA1c, HOMA-IR) and mechanistic biomarkers (e.g., SCFAs, bile acids). Risk of bias was assessed using the Cochrane RoB 2 tool. A narrative synthesis was performed.
Results
Thirty studies were included. Multi-strain probiotics, prebiotics, and synbiotics yielded modest but significant improvements in HbA1c (≈−0.2 to −0.4 %), fasting glucose, and HOMA-IR, particularly with durations ≥12 weeks. These benefits were linked to mechanistic shifts, including increased circulating butyrate and ursodeoxycholate, enrichment of SCFA-producing taxa, and reduced endotoxemia. Efficacy was moderated by concomitant medications: metformin use was synergistic, while sulfonylureas attenuated effects. FMT consistently improved clamp-measured insulin sensitivity in insulin-resistant phenotypes, but its effects on HbA1c were less consistent and donor-dependent.
Conclusion
Microbiome-targeted interventions, especially multi-strain probiotics and substrate-matched synbiotics, are effective adjuncts for improving glycemic control, with effects mediated through microbial metabolite production. FMT primarily modulates insulin sensitivity. Clinical outcomes are context-dependent, influenced by intervention design, duration, and pharmacomicrobiomic interactions.
目的系统评价益生菌、益生元、合成菌和粪便微生物群移植（FMT）对成人2型糖尿病（T2D）及相关血糖异常患者血糖控制的临床疗效，并综合相关微生物代谢物及组成变化的机制。方法按照PRISMA 2020指南进行系统评价。我们检索了PubMed/MEDLINE、Scopus和Web of Science从成立到2025年8月的t2dm、糖尿病前期或代谢综合征成人随机对照试验（rct）。与对照组相比，干预措施包括益生菌、益生元、合成菌或FMT。结果是血糖指数（如HbA1c， HOMA-IR）和机制生物标志物（如scfa，胆汁酸）。使用Cochrane RoB 2工具评估偏倚风险。进行了叙事综合。结果共纳入30项研究。多菌株益生菌、益生元和合成菌对HbA1c（≈−0.2至−0.4%）、空腹血糖和HOMA-IR有适度但显著的改善，尤其是持续时间≥12周的患者。这些益处与机制变化有关，包括循环丁酸盐和熊脱氧胆酸盐的增加、scfa生成类群的富集和内毒素血症的减少。联合用药可减缓疗效：二甲双胍的使用具有协同作用，而磺脲类药物可减弱疗效。FMT在胰岛素抵抗表型中持续改善钳测胰岛素敏感性，但其对HbA1c的影响不太一致且依赖于供体。结论以微生物组为目标的干预措施，特别是多菌株益生菌和底物匹配的合生剂，是改善血糖控制的有效辅助手段，其作用通过微生物代谢物的产生介导。FMT主要调节胰岛素敏感性。临床结果依赖于环境，受干预设计、持续时间和药物微生物组相互作用的影响。
{"title":"Probiotics, prebiotics, synbiotics, and FMT for glycemic control: A systematic review of clinical efficacy and mechanistic readouts in type 2 diabetes and related dysglycemia","authors":"Neda Shalbaf , Soheila Sadeghi , Sina Homaee , Farnaz Saberian","doi":"10.1016/j.metop.2025.100419","DOIUrl":"10.1016/j.metop.2025.100419","url":null,"abstract":"<div><h3>Objective</h3><div>To systematically evaluate the clinical efficacy of probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) on glycemic control in adults with type 2 diabetes (T2D) and related dysglycemia, and to synthesize associated mechanistic changes in microbial metabolites and composition.</div></div><div><h3>Methods</h3><div>A systematic review was conducted following PRISMA 2020 guidelines. PubMed/MEDLINE, Scopus, and Web of Science were searched from inception through August 2025 for randomized controlled trials (RCTs) in adults with T2D, prediabetes, or metabolic syndrome. Interventions included probiotics, prebiotics, synbiotics, or FMT compared to control. Outcomes were glycemic indices (e.g., HbA1c, HOMA-IR) and mechanistic biomarkers (e.g., SCFAs, bile acids). Risk of bias was assessed using the Cochrane RoB 2 tool. A narrative synthesis was performed.</div></div><div><h3>Results</h3><div>Thirty studies were included. Multi-strain probiotics, prebiotics, and synbiotics yielded modest but significant improvements in HbA1c (≈−0.2 to −0.4 %), fasting glucose, and HOMA-IR, particularly with durations ≥12 weeks. These benefits were linked to mechanistic shifts, including increased circulating butyrate and ursodeoxycholate, enrichment of SCFA-producing taxa, and reduced endotoxemia. Efficacy was moderated by concomitant medications: metformin use was synergistic, while sulfonylureas attenuated effects. FMT consistently improved clamp-measured insulin sensitivity in insulin-resistant phenotypes, but its effects on HbA1c were less consistent and donor-dependent.</div></div><div><h3>Conclusion</h3><div>Microbiome-targeted interventions, especially multi-strain probiotics and substrate-matched synbiotics, are effective adjuncts for improving glycemic control, with effects mediated through microbial metabolite production. FMT primarily modulates insulin sensitivity. Clinical outcomes are context-dependent, influenced by intervention design, duration, and pharmacomicrobiomic interactions.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100419"},"PeriodicalIF":2.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.metop.2025.100416
K.G. Sruthi , C. Aditya , Paramjot Panda , Jyoti Ranjan Mohanty , Manas Ranjan Behera
Background
Normal Weight Obesity (NWO) describes individuals with a normal body mass index (BMI) but elevated body fat percentage (BF%), placing them at increased risk for cardiometabolic complications. This condition is particularly relevant in Southeast Asian populations, where visceral adiposity occurs at lower BMI thresholds. However, regional pooled prevalence data are limited.
Methods
A systematic search was conducted in PubMed, EMBASE, Scopus, Web of Science, and Google Scholar for studies published between January 2010 and May 2025. Eligible studies included observational data on adults (≥18 years) from Southeast Asia reporting NWO prevalence, defined by normal BMI (18.5–24.9 kg/m2) with validated surrogate indices indicative of excess adiposity. Two reviewers independently conducted screening, data extraction, and quality appraisal using the Joanna Briggs Institute (JBI) tool. A random-effects meta-analysis was performed using the Freeman-Tukey double arcsine transformation, with heterogeneity assessed via the I2 statistic.
Results
Eight studies involving 9028 participants from five Southeast Asian countries (Philippines, Malaysia, Thailand, Myanmar, Singapore) were included. The pooled prevalence of NWO was 57 % (95 % CI: 37 %–75 %), with study-specific estimates ranging from 22.8 % to 82 %. Heterogeneity was high (I2 = 98.9 %). Most studies used bioelectrical impedance analysis (BIA) for body fat assessment and were rated as moderate to high quality.
Conclusion
NWO is common among adults in Southeast Asia, especially in women and young adults. These findings highlight the limitations of BMI as a screening tool and support the integration of body fat assessments into public health screening and clinical protocols for early risk detection.
{"title":"Prevalence of normal weight obesity among adults in Southeast Asia: Insights from a systematic review and meta-analysis","authors":"K.G. Sruthi , C. Aditya , Paramjot Panda , Jyoti Ranjan Mohanty , Manas Ranjan Behera","doi":"10.1016/j.metop.2025.100416","DOIUrl":"10.1016/j.metop.2025.100416","url":null,"abstract":"<div><h3>Background</h3><div>Normal Weight Obesity (NWO) describes individuals with a normal body mass index (BMI) but elevated body fat percentage (BF%), placing them at increased risk for cardiometabolic complications. This condition is particularly relevant in Southeast Asian populations, where visceral adiposity occurs at lower BMI thresholds. However, regional pooled prevalence data are limited.</div></div><div><h3>Methods</h3><div>A systematic search was conducted in PubMed, EMBASE, Scopus, Web of Science, and Google Scholar for studies published between January 2010 and May 2025. Eligible studies included observational data on adults (≥18 years) from Southeast Asia reporting NWO prevalence, defined by normal BMI (18.5–24.9 kg/m<sup>2</sup>) with validated surrogate indices indicative of excess adiposity. Two reviewers independently conducted screening, data extraction, and quality appraisal using the Joanna Briggs Institute (JBI) tool. A random-effects meta-analysis was performed using the Freeman-Tukey double arcsine transformation, with heterogeneity assessed via the I<sup>2</sup> statistic.</div></div><div><h3>Results</h3><div>Eight studies involving 9028 participants from five Southeast Asian countries (Philippines, Malaysia, Thailand, Myanmar, Singapore) were included. The pooled prevalence of NWO was 57 % (95 % CI: 37 %–75 %), with study-specific estimates ranging from 22.8 % to 82 %. Heterogeneity was high (I<sup>2</sup> = 98.9 %). Most studies used bioelectrical impedance analysis (BIA) for body fat assessment and were rated as moderate to high quality.</div></div><div><h3>Conclusion</h3><div>NWO is common among adults in Southeast Asia, especially in women and young adults. These findings highlight the limitations of BMI as a screening tool and support the integration of body fat assessments into public health screening and clinical protocols for early risk detection.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100416"},"PeriodicalIF":2.7,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.metop.2025.100417
Chencheng Hu , Qian Yang , Runzhi Yu , Shuwei Hu , Bing Meng , Yanyong Xu
Background
Activating transcription factor 3 (ATF3) is known to play a key role in regulating lipid and lipoprotein metabolism. However, the effects of hepatic ATF3 on systemic inflammation and the underlying mechanisms remain unclear.
Methods
An adeno-associated virus with hepatocyte-specific promoter was used to construct mouse models with hepatocyte-specific overexpression or knockdown of ATF3.
Results
Overexpression of human ATF3 in hepatocytes prevented high-fat (HF) diet-induced systemic inflammation in C57BL/6J mice and reversed systemic inflammation in db/db mice. Conversely, hepatocyte-specific loss of ATF3 aggravated diet-induced systemic inflammation. In co-culture studies, the anti-inflammatory effect of hepatocyte ATF3 on adipose tissue was found to be dependent on the presence of free fatty acids mixture. Mechanistically, ATF3 ameliorated HF diet-induced hepatic lipid accumulation and lipotoxicity likely mediated through AMPKα activation.
Conclusion
Our findings collectively indicate that hepatocyte ATF3 alleviates systemic inflammation by reducing hepatic lipotoxicity, a mechanism that may involve the activation of AMPKα. Targeting hepatic ATF3 represents a promising therapeutic strategy for systemic inflammation induced by hepatic lipotoxicity.
{"title":"Hepatic activating transcription factor 3 protects against systemic inflammation by attenuating lipotoxicity","authors":"Chencheng Hu , Qian Yang , Runzhi Yu , Shuwei Hu , Bing Meng , Yanyong Xu","doi":"10.1016/j.metop.2025.100417","DOIUrl":"10.1016/j.metop.2025.100417","url":null,"abstract":"<div><h3>Background</h3><div>Activating transcription factor 3 (ATF3) is known to play a key role in regulating lipid and lipoprotein metabolism. However, the effects of hepatic ATF3 on systemic inflammation and the underlying mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>An adeno-associated virus with hepatocyte-specific promoter was used to construct mouse models with hepatocyte-specific overexpression or knockdown of ATF3.</div></div><div><h3>Results</h3><div>Overexpression of human ATF3 in hepatocytes prevented high-fat (HF) diet-induced systemic inflammation in <em>C5</em>7BL<em>/6J</em> mice and reversed systemic inflammation in <em>db/db</em> mice. Conversely, hepatocyte-specific loss of ATF3 aggravated diet-induced systemic inflammation. In co-culture studies, the anti-inflammatory effect of hepatocyte ATF3 on adipose tissue was found to be dependent on the presence of free fatty acids mixture. Mechanistically, ATF3 ameliorated HF diet-induced hepatic lipid accumulation and lipotoxicity likely mediated through AMPKα activation.</div></div><div><h3>Conclusion</h3><div>Our findings collectively indicate that hepatocyte ATF3 alleviates systemic inflammation by reducing hepatic lipotoxicity, a mechanism that may involve the activation of AMPKα. Targeting hepatic ATF3 represents a promising therapeutic strategy for systemic inflammation induced by hepatic lipotoxicity.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100417"},"PeriodicalIF":2.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.metop.2025.100412
Qianqian Cha , Wenrui Zhao , Liyuan Ran , Yu Wang , Xiaofei Wang , Fei Xu , Zichao Yu , Yingjie Wu
Despite the rising global incidence of non-obese non-alcoholic fatty liver disease (NAFLD), this condition has received limited attention. Unsaturated alginate oligosaccharides (UAOS) have shown promising potential in the management of metabolic diseases. In this study, we used liver-specific growth hormone receptor (GHR) knockout mice as a model for non-obese NAFLD and treated them with UAOS. Our findings demonstrated that UAOS effectively ameliorated insulin resistance and hepatic steatosis in GHR-deficient mice. Additionally, UAOS improved intestinal barrier integrity, altered gut microbiota composition, and increased the relative abundance of beneficial bacteria, including Dubosiella, Akkermansia, Lachnoclostridium, Faecalibaculum, Romboutsia, and Turicibacter, while reducing the prevalence of harmful bacteria. Fecal metabolomics analysis revealed significant reductions in taurohyodeoxycholic acid and isodeoxycholic acid. Furthermore, UAOS may modulate the synthesis and secretion of secondary bile acids through the gut microbiota, potentially inhibiting hepatic bile acid synthesis and contributing to the maintenance of bile acid homeostasis via the FGF15-FGFR4-CYP7A1 signaling pathway. These mechanisms ultimately contributed to improved hepatic lipid metabolism. Together, these results position UAOS as a promising prebiotic candidate for the treatment of non-obese NAFLD.
{"title":"Unsaturated alginate oligosaccharides alleviate insulin resistance and fatty liver in non-obese NAFLD mice by regulating bile acid metabolism through gut microbiota","authors":"Qianqian Cha , Wenrui Zhao , Liyuan Ran , Yu Wang , Xiaofei Wang , Fei Xu , Zichao Yu , Yingjie Wu","doi":"10.1016/j.metop.2025.100412","DOIUrl":"10.1016/j.metop.2025.100412","url":null,"abstract":"<div><div>Despite the rising global incidence of non-obese non-alcoholic fatty liver disease (NAFLD), this condition has received limited attention. Unsaturated alginate oligosaccharides (UAOS) have shown promising potential in the management of metabolic diseases. In this study, we used liver-specific growth hormone receptor (GHR) knockout mice as a model for non-obese NAFLD and treated them with UAOS. Our findings demonstrated that UAOS effectively ameliorated insulin resistance and hepatic steatosis in GHR-deficient mice. Additionally, UAOS improved intestinal barrier integrity, altered gut microbiota composition, and increased the relative abundance of beneficial bacteria, including <em>Dubosiella</em>, <em>Akkermansia</em>, <em>Lachnoclostridium</em>, <em>Faecalibaculum</em>, <em>Romboutsia</em>, and <em>Turicibacter</em>, while reducing the prevalence of harmful bacteria. Fecal metabolomics analysis revealed significant reductions in taurohyodeoxycholic acid and isodeoxycholic acid. Furthermore, UAOS may modulate the synthesis and secretion of secondary bile acids through the gut microbiota, potentially inhibiting hepatic bile acid synthesis and contributing to the maintenance of bile acid homeostasis via the FGF15-FGFR4-CYP7A1 signaling pathway. These mechanisms ultimately contributed to improved hepatic lipid metabolism. Together, these results position UAOS as a promising prebiotic candidate for the treatment of non-obese NAFLD.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100412"},"PeriodicalIF":2.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.metop.2025.100415
Mark D. DeBoer , Matthew J. Gurka , Marieke K. Jones , Mark E. Smolkin
Background
While the severity of the metabolic syndrome (MetS) is associated with type 2 diabetes and cardiovascular disease (CVD) in research cohorts, it is unclear if this association remains when using clinically-collected data, which is more subject to error and bias.
Methods
We used a previously-validated MetS-severity z-score (MetS-Z) to compare the degree of cardiometabolic derangement between clinically-collected data from the electronic health-record (EHR) in the All-of-Us cohort (N = 101,676) with research-collected data from NHANES 2017–2020 (n = 3470). We assessed (separately) the odds of current diabetes and CVD in each cohort based on MetS z-score, adjusted for sex, race/ethnicity, education and income.
Results
Mean MetS-Z-scores in All of Us (vs. NHANES) were higher overall (0.41 vs. 0.15), including being slightly higher among those without diabetes (0.03 vs. −0.09) and similar among those with diagnosed diabetes (1.42 vs. 1.50). In All of Us (vs. NHANES) MetS-Z was higher among those without CVD (0.36 vs. 0.10) but similar among those with CVD (0.72 vs. 0.66). Adjusted odds of diagnosed diabetes and CVD based on MetS-Z remained significant when using clinically-collected data in All of Us (diabetes: 3.41 [95 % confidence interval 3.34, 3.49]; CVD: 1.20 [1.18, 1.21]), though not as high as in NHANES (diabetes: 5.83 [4.52, 7.51]; CVD: 1.43 [1.27, 1.61]).
Conclusion
While EHR data is limited by selection bias and data accuracy concerns (e.g. lack of fasting laboratory testing), we found overall similar relationships between MetS-severity, diabetes and CVD in EHR-based and research-based cohorts, supporting utility of these data in risk algorithms.
虽然代谢综合征（MetS）的严重程度在研究队列中与2型糖尿病和心血管疾病（CVD）相关，但在使用临床收集的数据时，尚不清楚这种关联是否仍然存在，这些数据更容易出现误差和偏倚。方法：我们使用先前验证的MetS-severity z-score （MetS-Z）来比较All-of-Us队列中电子健康记录（EHR）的临床收集数据（N = 101,676）与NHANES 2017-2020的研究收集数据（N = 3470）之间的心脏代谢紊乱程度。我们根据MetS z-score分别评估了每个队列中当前糖尿病和心血管疾病的几率，并根据性别、种族/民族、教育和收入进行了调整。结果All of Us （vs. NHANES）的平均met - z评分总体较高（0.41 vs. 0.15），其中非糖尿病患者的平均met - z评分略高（0.03 vs. - 0.09），诊断为糖尿病的患者的平均met - z评分相似（1.42 vs. 1.50）。在All of Us中（与NHANES相比），met - z在没有心血管疾病的患者中较高（0.36比0.10），但在有心血管疾病的患者中相似（0.72比0.66）。在All of Us中使用临床收集的数据时，基于MetS-Z的诊断糖尿病和CVD的调整几率仍然显著（糖尿病：3.41[95%可信区间3.34,3.49];CVD: 1.20[1.18, 1.21]），尽管没有NHANES的高（糖尿病：5.83 [4.52,7.51];CVD: 1.43[1.27, 1.61]）。结论：尽管电子病历数据受到选择偏差和数据准确性问题（例如缺乏禁食实验室测试）的限制，但我们发现基于电子病历和基于研究的队列中met -严重程度、糖尿病和心血管疾病之间的总体关系相似，支持这些数据在风险算法中的实用性。
{"title":"Using metabolic syndrome severity in the “real world”: Associations with diabetes and cardiovascular disease in all of us vs. NHANES","authors":"Mark D. DeBoer , Matthew J. Gurka , Marieke K. Jones , Mark E. Smolkin","doi":"10.1016/j.metop.2025.100415","DOIUrl":"10.1016/j.metop.2025.100415","url":null,"abstract":"<div><h3>Background</h3><div>While the severity of the metabolic syndrome (MetS) is associated with type 2 diabetes and cardiovascular disease (CVD) in research cohorts, it is unclear if this association remains when using clinically-collected data, which is more subject to error and bias.</div></div><div><h3>Methods</h3><div>We used a previously-validated MetS-severity z-score (MetS-Z) to compare the degree of cardiometabolic derangement between clinically-collected data from the electronic health-record (EHR) in the All-of-Us cohort (N = 101,676) with research-collected data from NHANES 2017–2020 (n = 3470). We assessed (separately) the odds of current diabetes and CVD in each cohort based on MetS z-score, adjusted for sex, race/ethnicity, education and income.</div></div><div><h3>Results</h3><div>Mean MetS-Z-scores in All of Us (vs. NHANES) were higher overall (0.41 vs. 0.15), including being slightly higher among those without diabetes (0.03 vs. −0.09) and similar among those with diagnosed diabetes (1.42 vs. 1.50). In All of Us (vs. NHANES) MetS-Z was higher among those without CVD (0.36 vs. 0.10) but similar among those with CVD (0.72 vs. 0.66). Adjusted odds of diagnosed diabetes and CVD based on MetS-Z remained significant when using clinically-collected data in All of Us (diabetes: 3.41 [95 % confidence interval 3.34, 3.49]; CVD: 1.20 [1.18, 1.21]), though not as high as in NHANES (diabetes: 5.83 [4.52, 7.51]; CVD: 1.43 [1.27, 1.61]).</div></div><div><h3>Conclusion</h3><div>While EHR data is limited by selection bias and data accuracy concerns (e.g. lack of fasting laboratory testing), we found overall similar relationships between MetS-severity, diabetes and CVD in EHR-based and research-based cohorts, supporting utility of these data in risk algorithms.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100415"},"PeriodicalIF":2.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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