Metabolism: clinical and experimental最新文献

{"title":"Unraveling the roles of mitochondrial sirtuins in aging-related diseases: From mechanistic insights to therapeutic strategies","authors":"Yanyan Cao ,&nbsp;Yan Wang ,&nbsp;Na Zhao ,&nbsp;Ziyue Yuan ,&nbsp;Lan Zhang ,&nbsp;Peng Jin","doi":"10.1016/j.metabol.2025.156356","DOIUrl":"10.1016/j.metabol.2025.156356","url":null,"abstract":"<div><div>Mitochondrial sirtuins, including SIRT3, SIRT4, and SIRT5, play pivotal roles in maintaining mitochondrial homeostasis by regulating oxidative phosphorylation, energy metabolism, and redox balance. Dysregulation of these enzymes is closely associated with the pathogenesis of aging-related diseases such as neurodegenerative diseases, metabolic diseases, and cardiovascular diseases. SIRT3 has been the most extensively studied, demonstrating protective effects against oxidative stress and metabolic dysregulation. In contrast, while SIRT4 and SIRT5 are less characterized, they are critical for the regulation of insulin sensitivity, nitrogen metabolism, and mitochondrial function. This review focuses on the involvement of mitochondrial sirtuins in modulating cellular metabolism, redox balance, and mitochondrial homeostasis, highlighting their roles in the development and progression of aging-related diseases. Furthermore, we provide an overview of small-molecule modulators targeting mitochondrial sirtuins, which aim to restore cellular function, attenuate aging processes, and offer novel therapeutic strategies for treating aging-related diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156356"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity.","authors":"Christine Mund, Anupam Sinha, Anika Aderhold, Ivona Mateska, Eman Hagag, Sofia Traikov, Bettina Gercken, Andres Soto, Jonathan Pollock, Lilli Arndt, Michele Wölk, Natalie Werner, Georgia Fodelianaki, Pallavi Subramanian, Kyoung-Jin Chung, Sylvia Grossklaus, Mathias Langner, Mohamed Elgendy, Tatyana Grinenko, Ben Wielockx, Andreas Dahl, Martin Gericke, Matthias Blüher, Ünal Coskun, David Voehringer, Maria Fedorova, Mirko Peitzsch, Peter J Murray, Triantafyllos Chavakis, Vasileia Ismini Alexaki","doi":"10.1016/j.metabol.2025.156358","DOIUrl":"10.1016/j.metabol.2025.156358","url":null,"abstract":"<p><strong>Background and aims: </strong>Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology.</p><p><strong>Methods: </strong>We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured.</p><p><strong>Results: </strong>Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2^-/- APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers.</p><p><strong>Conclusions: </strong>Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156358"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Symphony of regulated cell death: Unveiling therapeutic horizons in sarcopenia","authors":"Jie Peng ,&nbsp;Mi Zou ,&nbsp;Qianmingyue Zhang ,&nbsp;Dongcan Liu ,&nbsp;Shuanghong Chen ,&nbsp;Ruiying Fang ,&nbsp;Yuan Gao ,&nbsp;Xiaohua Yan ,&nbsp;Liang Hao","doi":"10.1016/j.metabol.2025.156359","DOIUrl":"10.1016/j.metabol.2025.156359","url":null,"abstract":"<div><div>Sarcopenia is a progressive musculoskeletal condition associated with aging, marked by a decline in muscle mass, strength, and performance. This condition not only compromises functional independence in older individuals but also contributes to escalating healthcare and economic burdens. Although the underlying mechanisms are complex and multifaceted, recent discoveries have emphasized the regulatory influence of multiple forms of programmed cell death—including apoptosis, ferroptosis, necroptosis, and pyroptosis—on skeletal muscle degeneration. These cell death pathways contribute to key pathological features such as muscle fiber loss, proteostasis imbalance, neuromuscular dysfunction, mitochondrial deficits, and persistent inflammation. This review synthesizes current understanding of the molecular underpinnings of regulated cell death (RCD) in sarcopenia and discusses emerging therapeutic interventions aimed at modulating these pathways. These include pharmacological agents (e.g., ferroptosis inhibitors, polyphenols), structured exercise programs (notably resistance), targeted nutritional support (e.g., amino acids, vitamin D), cell-based therapies, and gene-targeted strategies. Despite growing evidence supporting RCD as a viable therapeutic target, the interplay among different cell death modalities and the translation of mechanistic insights into clinical practice remain insufficiently understood. Advancing sarcopenia treatment will require integrated multi-omics analyses, identification of predictive biomarkers, and rigorously designed clinical studies to support personalized and effective therapeutic approaches.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156359"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactiplantibacillus plantarum strain 84-3-derived l-glutamine ameliorates glucose homeostasis via AMPK/PPARγ signaling pathway activation in type 2 diabetes","authors":"Tingting Liang ,&nbsp;Tong Jiang ,&nbsp;Zhuang Liang ,&nbsp;Ya Chen ,&nbsp;Tong Chen ,&nbsp;Bo Dong ,&nbsp;Xinqiang Xie ,&nbsp;Bing Gu ,&nbsp;Qingping Wu","doi":"10.1016/j.metabol.2025.156357","DOIUrl":"10.1016/j.metabol.2025.156357","url":null,"abstract":"<div><h3>Background</h3><div>Gut microbiota and their metabolites play an essential role in type 2 diabetes (T2D). However, contributions of individual bacterial strains and their metabolites to T2D pathogenesis remain poorly understood. We investigated T2D regulation by <em>Lactobacillus</em> in various animal models to understand its therapeutic effects.</div></div><div><h3>Methods and results</h3><div>We performed a case-control study of Chinese adults using metabolome profiling and identified an inverse correlation between <span>l</span>-glutamine and T2D serum concentrations. The <em>glnA</em> and <em>GLUL</em> genes encoding glutamine synthetase (GS) in <em>L. plantarum</em> 84–3 were also identified. <em>L. plantarum</em> 84–3 treatment significantly decreased serum inflammation and improved metabolic phenotypes in streptozotocin- or tetraoxypyrimidine-induced T2D rats, including blood glucose, glucose tolerance, insulin resistance, and lipids. We confirmed elevated serum <span>l</span>-glutamine levels in the <em>L. plantarum</em> 84–3 group. RNA sequencing analysis demonstrated that <em>L. plantarum</em> 84–3-derived <span>l</span>-glutamine is a vital bioactive molecule, improving glucose homeostasis by activating the liver AMPK/PPAR signaling pathway and ameliorating T2D. We conducted co-culture fermentation experiments <em>in vitro</em> and <em>in vivo</em>, and metagenomic and metabolomic analyses revealed that resistance starch combined with <em>L. plantarum</em> 84–3 significantly enriched of <em>Lactobacillus</em> abundance and increased the <span>l</span>-glutamine level, affecting of alanine, aspartate, and glutamate metabolism pathways, which was confirmed <em>in vivo</em> in rats. The reduced <em>L. plantarum</em> and <span>l</span>-glutamine levels were validated in a human T2D cohort.</div></div><div><h3>Conclusions</h3><div>These findings revealed a novel therapeutic effect of <em>L. plantarum</em> in alleviating T2D-related glucose homeostasis by increasing circulating <span>l</span>-glutamine, which suggests viable preventive and therapeutic strategies for metabolic disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156357"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.","authors":"Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden","doi":"10.1016/j.metabol.2025.156361","DOIUrl":"10.1016/j.metabol.2025.156361","url":null,"abstract":"<p><p>Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular lipids or enhancing mitochondrial oxidation. Acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin (SM) to CERs, is crucial for muscle repair and development, yet its role in insulin-resistant states and response to exercise remain unclear. We assessed ASM protein and activity, neutral sphingomyelinase (NSM) and sphingolipid species in skeletal muscle of insulin-sensitive (IS, n = 12), insulin-resistant (IR, n = 11) and T2D men (n = 20), before and after a 12-week high-intensity interval training (HIIT). Comprehensive phenotyping comprised hyperinsulinemic-euglycemic clamps, spiroergometry, targeted lipidomics and assessment of markers of mitochondrial quality control. ASM protein was lower at baseline and increased after HIIT only in T2D (p < 0.05), while ASM activity rose across all groups (IS p < 0.01; IR and T2D p < 0.001). HIIT also increased NSM protein in all groups (p < 0.05). Despite lower baseline SM levels in T2D, HIIT led to elevated CERs species in T2D (C16:0, C20:0, C22:0, C24:1, C24:0) and in IR (C16:0, C20:0) (all p < 0.05). Regression analysis suggested that changes in ASM protein and activity relate to changes in mitochondrial fusion and fission as well as AMP-activated protein kinase (AMPK)-mediated mitophagy. In conclusion, HIIT induces expression of both ASM and NSM and alters CER profiles in insulin-resistant skeletal muscle, independently of changes in insulin sensitivity. ASM could therefore rather contribute to exercise-induced mitochondrial remodeling than driving lipotoxicity, warranting further investigation of ASM as a potential target for exercise mimetic therapies.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156361"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mini-review of the EAT-Lancet planetary health diet and its role in cardiometabolic disease prevention.","authors":"Anna Stubbendorff, Suzanne Janzi, Juulia Jukkola, Moa Morency, Shunming Zhang, Yan Borné, Emily Sonestedt","doi":"10.1016/j.metabol.2025.156373","DOIUrl":"10.1016/j.metabol.2025.156373","url":null,"abstract":"<p><p>Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a universal reference diet designed to promote human health while minimizing environmental degradation. It is a predominantly plant-based dietary pattern, rich in whole grains, vegetables, fruits, legumes, and nuts, while low in red meat and added sugars. In this mini-review, we summarize findings from prospective cohorts examining the EAT-Lancet diet in relation to mortality and cardiometabolic outcomes. Higher adherence to this diet was generally associated with lower risk of all-cause mortality, cardiovascular disease, and type 2 diabetes. However, the magnitude of associations varied depending on cohort characteristics, scoring systems, and methodological factors. In addition, adherence to the EAT-Lancet diet was generally low in the studies reviewed. These results suggest potential public health benefits of adopting the EAT-Lancet diet but also highlight the need for harmonized definitions and further research on underlying mechanisms.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156373"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1” [Metabolism, Volume 163 (2025), Article Number 156087]","authors":"Teresa Mezza ,&nbsp;Nicolai J. Wewer Albrechtsen ,&nbsp;Gianfranco Di Giuseppe ,&nbsp;Pietro Manuel Ferraro ,&nbsp;Laura Soldovieri ,&nbsp;Gea Ciccarelli ,&nbsp;Michela Brunetti ,&nbsp;Giuseppe Quero ,&nbsp;Sergio Alfieri ,&nbsp;Enrico Celestino Nista ,&nbsp;Antonio Gasbarrini ,&nbsp;Vincenzo Tondolo ,&nbsp;Andrea Mari ,&nbsp;Alfredo Pontecorvi ,&nbsp;Andrea Giaccari ,&nbsp;Jens J. Holst","doi":"10.1016/j.metabol.2025.156372","DOIUrl":"10.1016/j.metabol.2025.156372","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156372"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AEBP1 as a promising therapeutic target for skeletal muscle insulin resistance in type 2 diabetes mellitus: Convergent evidence from Mendelian randomization and functional validation","authors":"Chen Guo ,&nbsp;Jiani Li ,&nbsp;Xiaofei Yang ,&nbsp;Weinan Xie ,&nbsp;Fangxing Zeng ,&nbsp;Keyu Chen ,&nbsp;Wenjing Mi ,&nbsp;Cheng Tang ,&nbsp;Han Wang","doi":"10.1016/j.metabol.2025.156339","DOIUrl":"10.1016/j.metabol.2025.156339","url":null,"abstract":"<div><h3>Background</h3><div>The pathogenesis of type 2 diabetes mellitus (T2DM) is closely related to skeletal muscle insulin resistance (IR). Currently, there is still a lack of relevant treatments. Summary-data-based Mendelian randomization (SMR) is a vital tool for identifying druggable targets in skeletal muscle to develop T2DM treatments.</div></div><div><h3>Methods</h3><div>Potential causative genetic factors in skeletal muscle and blood causally associated with T2DM were identified by SMR analysis. Bayesian colocalisation were used to validate causality. Pleiotropic impact of drug targets was assessed using phenome-wide MR (Phe-MR). Then, targeted overexpression or knockdown of AEBP1 in mouse myoblast cell lines (C2C12) and human skeletal muscle cells (HSkMCs) further validated the functional phenotype. Protein docking, co-IP and SPR were used to demonstrate protein-protein interactions.</div></div><div><h3>Results</h3><div>Both European and Asian populations revealed that AEBP1 was significantly associated with T2DM and its glycemic profile in blood and skeletal muscle, and was identified as a risk factor. Co-localisation analyses suggest that AEBP1 and T2DM originate from the same genetic variants. Meanwhile, targeted AEBP1 therapy has no potential adverse effects. Furthermore, AEBP1 was significantly expressed in <em>in vivo</em> and <em>in vitro</em> IR models and was consistent with the SMR results. Overexpression of AEBP1 further impaired insulin signalling and glucose transport mechanisms, exacerbating skeletal muscle IR. Targeting AEBP1 knockdown reversed these changes. Protein interaction experiments revealed that PI3K (p110β) is a direct target protein for AEBP1 to exert molecular functions.</div></div><div><h3>Conclusion</h3><div>Targeting AEBP1 therapy is expected to be a pivotal approach for the prevention and treatment of T2DM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156339"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MASLD may influence female-specific cancer risk indirectly through shared metabolic pathways rather than direct causation - author's reply","authors":"Xinrong Zhang ,&nbsp;Mindie H. Nguyen","doi":"10.1016/j.metabol.2025.156350","DOIUrl":"10.1016/j.metabol.2025.156350","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156350"},"PeriodicalIF":11.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Exosomal miRNAs in muscle-bone crosstalk: Mechanistic links, exercise modulation and implications for sarcopenia, osteoporosis and osteosarcopenia” [metabolism. 2025 Jun 21:156333]","authors":"Bo Zhang,&nbsp;Yang Chen,&nbsp;Qiaojie Chen,&nbsp;Haijun Zhang","doi":"10.1016/j.metabol.2025.156351","DOIUrl":"10.1016/j.metabol.2025.156351","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156351"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144569805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}