Metabolism: clinical and experimental最新文献

{"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":"2025-07-28","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":"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":"2025-07-24","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":"Alteration of IGF-1 bioavailability due to PAPPA2 deficiency leads to sex-specific metabolic disturbances","authors":"Antonio J. López-Gambero ,&nbsp;Antonio Vargas ,&nbsp;María del Mar Fernández-Arjona ,&nbsp;Leticia Rubio ,&nbsp;Marialuisa de Ceglia ,&nbsp;Carlos Vera-Fernández ,&nbsp;Ana Campillo-Calatayud ,&nbsp;Patricia Rivera ,&nbsp;Fernando Rodríguez de Fonseca ,&nbsp;Vicente Barrios ,&nbsp;Julie A. Chowen ,&nbsp;Jesús Argente ,&nbsp;Juan Suárez","doi":"10.1016/j.metabol.2025.156355","DOIUrl":"10.1016/j.metabol.2025.156355","url":null,"abstract":"<div><h3>Background</h3><div>The growth hormone (GH)/insulin-like growth factor (IGF-1) axis determines optimal growth and affects metabolism and energy homeostasis. Pregnancy-associated plasma protein-A2 (<em>PAPPA2</em>) regulates bioactive IGF-1 availability and patients with <em>PAPPA2</em> deficiency have impaired growth and glucose metabolism. This axis is altered in metabolic disturbances such as obesity and anorexia nervosa in a sex-specific manner, but the mechanisms involved are not completely understood. Here we evaluated how <em>Pappa2</em> deficiency affects energy homeostasis, focusing on male and female differences.</div></div><div><h3>Methods</h3><div>Growth and energy homeostasis were determined in male and female <em>Pappa2</em>^{<em>ko/ko</em>} mice and control <em>Pappa2</em>^{<em>wt/</em>wt} littermates, as well as their response to recombinant human (rh)PAPPA2, rhIGF-1 and rhIBFBP5. Effects of a high-carbohydrate diet (HCHD) on glucose tolerance, fuel partitioning, de novo lipogenesis and energy homeostasis were determined.</div></div><div><h3>Results</h3><div><em>Pappa2</em>^{<em>ko/ko</em>} mice had reduced body weight, bone length and lipid deposition associated with higher energy expenditure and intake. Male <em>Pappa2</em>^{<em>ko/ko</em>} mice had mild glucose intolerance, altered bone mineral properties and higher energy costs for locomotor activity possibly due to inefficient muscle mitochondrial activity; whereas female <em>Pappa2</em>^{<em>ko/ko</em>} mice had enhanced fatty acid oxidation on a normal diet, but not on a HCHD. All <em>Pappa2</em>^{<em>ko/ko</em>} mice had lower hepatic fat deposition associated with lower IGF-1 activity in the liver, while fatty acid metabolism dysregulation in adipose tissue was found only in females.</div></div><div><h3>Conclusion</h3><div>These data reinforce the importance of the GH/IGF-1 axis in metabolic control and emphasize the relevance of its fine-tuned control by <em>Pappa2.</em> Moreover, the differences between sexes in metabolic imbalances underscore the relevance of sex-specific strategies for treatment of metabolic imbalances.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156355"},"PeriodicalIF":10.8,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686829","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":"Flot2 protects against podocyte injury by maintaining the stability of synaptopodin in diabetic nephropathy","authors":"Hong Zhang ,&nbsp;Wenbiao Wang ,&nbsp;Peimin Liu ,&nbsp;Ting Zhang ,&nbsp;Li Zhang ,&nbsp;Zhiming Ye ,&nbsp;Wei Yang ,&nbsp;Xiaoyan Bai ,&nbsp;Xueqing Yu","doi":"10.1016/j.metabol.2025.156354","DOIUrl":"10.1016/j.metabol.2025.156354","url":null,"abstract":"<div><div>Podocyte injury is a major determinant of diabetic nephropathy (DN). Critical structural proteins such as synaptopodin play an important role in maintaining podocyte morphology and function. Herein, we uncover a protective role of Flotillin-2 (Flot2), a lipid microdomain-associated protein, in the development of DN by maintaining the stability of synaptopodin. We found that Flot2 was downregulated in podocytes and its expression was correlated with glomerular filtration rate and proteinuria in patients with DN. Functionally, Flot2 is protective in DN as global and podocyte-specific <em>Flot2</em> knockout (KO) worsened podocyte injury and aggravated the disease as demonstrated by increasing albuminuria, thickening of glomerular basement membrane, and expansion of mesangium matrix in diabetic mice. In contrast, podocyte-specific <em>Flot2</em> overexpression ameliorated diabetes-induced renal dysfunction and pathology. Mechanistically, we found that Flot2 directly interacted with synaptopodin and protected synaptopodin from ubiquitin degradation <em>via</em> the K48-linked polyubiquitination mediated proteasome pathway. Thus, our findings demonstrate that Flot2 is protective in DN and exerts its protective role by stabilizing synaptopodin. Targeting Flot2 may be a potential therapeutic approach in DN.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156354"},"PeriodicalIF":10.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667998","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":"Time for a change? Threshold for obesity in contemporary Japanese population","authors":"Kenya Kasahara ,&nbsp;Yodai Ichikawa ,&nbsp;Junya Hironaka ,&nbsp;Tomohiro Shinozaki ,&nbsp;Hiroshi Okada ,&nbsp;Hanako Nakajima ,&nbsp;Emi Ushigome ,&nbsp;Masahide Hamaguchi ,&nbsp;Kazushiro Kurogi ,&nbsp;Hiroaki Murata ,&nbsp;Eri Tsuda ,&nbsp;Naoki Yoshida ,&nbsp;Masato Ito ,&nbsp;Michiaki Fukui","doi":"10.1016/j.metabol.2025.156352","DOIUrl":"10.1016/j.metabol.2025.156352","url":null,"abstract":"<div><h3>Background</h3><div>The obesity criteria for Japanese population are defined based on a cross-sectional study conducted 30 years ago. We aimed to examine the validity of a BMI of 25 kg/m² as a determinant of obesity in the Japanese population by assessing the association between BMI and the lifestyle-related diseases in a large and long-term cohort.</div></div><div><h3>Methods</h3><div>This cohort study included 162,136 individuals aged ≥40 years who participated in a medical health checkup program at Panasonic Corporation covering 166 operational sites from 2008 to 2023. The associations between BMI and the development of lifestyle-related diseases during the follow-up period were assessed using a multivariate Cox proportional hazards model. A restricted cubic spline function was applied to model the associations between BMI and disease risk. The BMI values associated with the doubling of HRs (compared with a reference BMI of 22 kg/m²) were examined.</div></div><div><h3>Findings</h3><div>The average follow-up duration ranged from 6 to 8 years depending on the outcome. Restricted cubic spline curves showed BMI values (kg/m²) associated with an HR of 2 (vs. 22 kg/m²): 24.6 for diabetes, 26.8 for hypertension, 32.3 for hypertriglyceridemia, 26.4 for low high-density lipoprotein cholesterol, 25 for high low-density lipoprotein cholesterol, 30.8 for coronary artery disease, 32.0 for stroke, and 25 for CKD after adjusting for covariates. Similar results were observed in subgroup analyses stratified by gender and age.</div></div><div><h3>Conclusion</h3><div>The appropriateness of the conventional BMI threshold of 25 kg/m² in Japan warrants reconsideration.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156352"},"PeriodicalIF":10.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656186","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":"Metabolic regulation of tissue-resident immune cells: Molecular mechanisms and therapeutic implications","authors":"Zixiang Chen ,&nbsp;Fan Xiao ,&nbsp;Xiaoxia Zhu ,&nbsp;Wenhao Zhou ,&nbsp;Ke Rui ,&nbsp;Liwei Lu ,&nbsp;Jie Tian","doi":"10.1016/j.metabol.2025.156349","DOIUrl":"10.1016/j.metabol.2025.156349","url":null,"abstract":"<div><div>Many innate and adaptive immune cells are resident in non-lymphoid tissues and do not participate in peripheral circulation. These tissue-resident immune cells not only rapidly recognize and respond to local infections or injuries but also contribute to the maintenance of tissue homeostasis and immune balance. Immune cell function is closely associated with their metabolic state. Recent studies reveal that tissue-resident immune cells undergo unique metabolic reprogramming to adapt to their specific tissue microenvironment. This metabolic adaptation is crucial for their long-term survival, differentiation, and function. In this review, we systematically elaborate on the metabolic characteristics and tissue-specific regulatory mechanisms of CD8⁺ tissue-resident memory T cells (T_RM) and tissue-resident macrophages (TRMφs). Based on an in-depth analysis of the critical role of immunometabolic pathways in infection, cancer, and autoimmune diseases, we further summarize therapeutic strategies targeting these metabolic pathways and discuss their efficacy, potential side effects, and the challenges facing clinical translation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156349"},"PeriodicalIF":10.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144605330","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":"2025-07-07","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}

{"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":"2025-07-04","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":"2025-07-03","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":"Reply to: Finerenone in the SGLT2i era: redundancy or complementarity?","authors":"John Hakim","doi":"10.1016/j.metabol.2025.156338","DOIUrl":"10.1016/j.metabol.2025.156338","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156338"},"PeriodicalIF":11.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567542","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}