Molecular Metabolism最新文献

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DIO3 depletion attenuates ovarian cancer growth via reduced glycolysis and alterations in glutamine metabolism. DIO3耗竭通过糖酵解减少和谷氨酰胺代谢改变来减缓卵巢癌的生长。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-10-01 Epub Date: 2025-07-30 DOI: 10.1016/j.molmet.2025.102225
Dotan Moskovich, Daniel Beilinson, Amit Rosemarin, Aileen Cohen, Itai Fabian, Tzuri Lifschytz, Bernard Lerer, Govindasamy Mugesh, Maya Gottfried, Osnat Ashur-Fabian
{"title":"DIO3 depletion attenuates ovarian cancer growth via reduced glycolysis and alterations in glutamine metabolism.","authors":"Dotan Moskovich, Daniel Beilinson, Amit Rosemarin, Aileen Cohen, Itai Fabian, Tzuri Lifschytz, Bernard Lerer, Govindasamy Mugesh, Maya Gottfried, Osnat Ashur-Fabian","doi":"10.1016/j.molmet.2025.102225","DOIUrl":"10.1016/j.molmet.2025.102225","url":null,"abstract":"<p><strong>Objective: </strong>Metabolic reprogramming emerges as a central driver of therapy resistance and survival disadvantage in ovarian cancer. We recently demonstrated that inhibiting the enzyme Deiodinase type 3 (DIO3) reduces ovarian cancer growth, although the underlying mechanism remains unclear.</p><p><strong>Methods: </strong>We studied DIO3 role in metabolism in genetically manipulated ovarian cancer cells using protein expression analysis, integrative proteomics, endogenous and extracellular metabolomics, metabolic assays including lactate and glutamate secretion, reactive oxygen species (ROS) production and the Seahorse Cell Mito Stress test.</p><p><strong>Results: </strong>We reveled that inhibiting DIO3 suppresses glycolysis while enhancing ATP production through oxidative phosphorylation (OXPHOS). We corroborated these findings using two models of ovarian cancer xenografts, demonstrating a marked reduction in glycolytic proteins upon silencing or inhibiting DIO3 using our first in class small molecule. Moreover, altered glutamine metabolism was also documented, favoring urea cycle and TCA cycle engagement over antioxidant production, accompanied by elevated ROS. Intriguingly, DIO3 depletion in fallopian tube cells, the precursor of HGSOC, displayed distinct metabolic adaptations, including enhanced glycolysis and lipid metabolism, suggesting tissue-specific roles for DIO3.</p><p><strong>Conclusions: </strong>These collective findings position DIO3 as a potential regulator of ovarian cancer metabolism, with implications for targeting this enzyme to disrupt tumor energetics as a novel therapeutic approach.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102225"},"PeriodicalIF":6.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to "microRNA-1 regulates metabolic flexibility by programming skeletal muscle pyruvate metabolism" [Mol Metabol 98 (2025) 1-23/102182]. “microRNA-1通过编程骨骼肌丙酮酸代谢调节代谢灵活性”的更正[Mol metabolism 98(2025) 1-23/102182]。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-10-01 Epub Date: 2025-08-07 DOI: 10.1016/j.molmet.2025.102223
Ahmed Ismaeel, Bailey D Peck, McLane M Montgomery, Benjamin I Burke, Jensen Goh, Abigail B Franco, Qin Xia, Katarzyna Goljanek-Whysall, Brian McDonagh, Jared M McLendon, Pieter J Koopmans, Daniel Jacko, Kirill Schaaf, Wilhelm Bloch, Sebastian Gehlert, Kevin A Murach, Kelsey H Fisher-Wellman, Ryan L Boudreau, Yuan Wen, John J McCarthy
{"title":"Corrigendum to \"microRNA-1 regulates metabolic flexibility by programming skeletal muscle pyruvate metabolism\" [Mol Metabol 98 (2025) 1-23/102182].","authors":"Ahmed Ismaeel, Bailey D Peck, McLane M Montgomery, Benjamin I Burke, Jensen Goh, Abigail B Franco, Qin Xia, Katarzyna Goljanek-Whysall, Brian McDonagh, Jared M McLendon, Pieter J Koopmans, Daniel Jacko, Kirill Schaaf, Wilhelm Bloch, Sebastian Gehlert, Kevin A Murach, Kelsey H Fisher-Wellman, Ryan L Boudreau, Yuan Wen, John J McCarthy","doi":"10.1016/j.molmet.2025.102223","DOIUrl":"10.1016/j.molmet.2025.102223","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102223"},"PeriodicalIF":6.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evaluation of the effects of metformin on gut functions and microbiota and their contribution to improving glucose tolerance in diabetic mice 评估二甲双胍对糖尿病小鼠肠道功能和微生物群的影响及其对改善葡萄糖耐量的贡献。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-09-29 DOI: 10.1016/j.molmet.2025.102263
Murielle Godet , Emmanuelle Meugnier , Oriane Vitalis , Nadia Bendridi , Aurélie Vieille-Marchiset , Nathalie Vega , Bérengère Benoit , Claudie Pinteur , Dominique Rainteau , David Cheillan , Marie-Caroline Michalski , Karim Chikh , Hubert Vidal
{"title":"Evaluation of the effects of metformin on gut functions and microbiota and their contribution to improving glucose tolerance in diabetic mice","authors":"Murielle Godet ,&nbsp;Emmanuelle Meugnier ,&nbsp;Oriane Vitalis ,&nbsp;Nadia Bendridi ,&nbsp;Aurélie Vieille-Marchiset ,&nbsp;Nathalie Vega ,&nbsp;Bérengère Benoit ,&nbsp;Claudie Pinteur ,&nbsp;Dominique Rainteau ,&nbsp;David Cheillan ,&nbsp;Marie-Caroline Michalski ,&nbsp;Karim Chikh ,&nbsp;Hubert Vidal","doi":"10.1016/j.molmet.2025.102263","DOIUrl":"10.1016/j.molmet.2025.102263","url":null,"abstract":"<div><h3>Objectives</h3><div>Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, increasing evidence points to a pivotal role of the gut. Aiming to clarify whether metformin-induced changes in the intestinal tract directly contribute to metabolic improvement, we evaluated the effects of escalating doses (from 50 to 200 mg/kg/day) of metformin orally administered for 4 weeks in mice made glucose intolerant by ten weeks of high fat high sucrose diet.</div></div><div><h3>Methods</h3><div>Several intestinal parameters were studied, including caecal microbiota composition and bile acids profile, ileal FXR signaling, abundance of GLP1-producing cells and goblet cells and blood metabolome.</div></div><div><h3>Results</h3><div>Metformin restored glucose tolerance, fasting insulinemia and HOMA-IR index in a dose-dependent manner. Only a subset of gut-related effects, including mucus production and GLP-1 expression, exhibited a parallel dose–response relationship, suggesting a possible contribution to the observed metabolic improvements. In contrast, other changes, including ileal Fxr-Fgf15 inhibition and hepatic ceramide reduction did not scale with dose, suggesting they are not the main drivers of metformin dose-dependent effects on glycemic control. We also pointed out marked differential sensitivity of gut bacteria to metformin supporting complex interactions of the drug with the microbial ecosystem.</div></div><div><h3>Conclusion</h3><div>Finally, metformin enhanced the proliferation of intestinal epithelium, resulting in increased length of ileal villi. Altogether, this study offers new insights into the metformin mechanism of action and revealed potential novel microbial biomarkers and targets for enhancing its therapeutic efficacy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102263"},"PeriodicalIF":6.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Furin may contribute to proglucagon processing and glucagon-like Peptide-1 production in human alpha cells 在人α细胞中,呋喃可能参与胰高血糖素前加工和胰高血糖素样肽-1的产生。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-09-27 DOI: 10.1016/j.molmet.2025.102259
Janyne Koepke, Wentong Long, Amy Barr, Peter E. Light
{"title":"Furin may contribute to proglucagon processing and glucagon-like Peptide-1 production in human alpha cells","authors":"Janyne Koepke,&nbsp;Wentong Long,&nbsp;Amy Barr,&nbsp;Peter E. Light","doi":"10.1016/j.molmet.2025.102259","DOIUrl":"10.1016/j.molmet.2025.102259","url":null,"abstract":"<div><h3>Objectives</h3><div>While glucagon-like peptide-1 (GLP-1) production has been previously documented in human alpha cells, the steps regulating its production and secretion are poorly characterized. We investigated the enzymes implicated in proglucagon processing, characterizing their expression and localization in primary human alpha cells and αTC1/9 cells.</div></div><div><h3>Methods</h3><div>Human alpha cells and αTC1/9 cells were maintained in control conditions or exposed to proinflammatory and Akt-activating stimuli to enhance GLP-1 levels. Proglucagon and convertase enzyme gene expression, protein content, and subcellular localization were evaluated by qPCR, Western Blot, and immunofluorescent microscopy, respectively.</div></div><div><h3>Results</h3><div>Our data suggests that the canonical GLP-1-producing enzyme, Prohormone Convertase 1/3 (PC1/3), is poorly expressed and localized in alpha cells, while its homologue furin is optimally positioned for GLP-1 production. We also note that GLP-1 and glucagon processing occur in different subcellular compartments, creating two distinct pools of secretory granules which respond to similar secretory stimuli.</div></div><div><h3>Conclusion</h3><div>Our study suggests that furin, rather than PC1/3, is positioned to process proglucagon into GLP-1, and despite coming from the same precursor molecule, GLP-1 and glucagon are separately packaged in primary human alpha cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102259"},"PeriodicalIF":6.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice. 激活素受体类型IIA/IIB阻断增加肌肉质量和力量,但损害小鼠的血糖控制。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-09-27 DOI: 10.1016/j.molmet.2025.102261
Michala Carlsson, Emma Frank, Joan M Màrmol, Mona Sadek Ali, Steffen H Raun, Edmund Battey, Nicoline Resen Andersen, Andrea Irazoki, Camilla Lund, Carlos Henríquez-Olguin, Martina Kubec Højfeldt, Pauline Blomquist, Frederik Duch Bromer, Gabriele Mocciaro, Andreas Lodberg, Christian Brix Folsted Andersen, Marco Eijken, Andreas Mæchel Fritzen, Jonas Roland Knudsen, Erik A Richter, Lykke Sylow
{"title":"Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice.","authors":"Michala Carlsson, Emma Frank, Joan M Màrmol, Mona Sadek Ali, Steffen H Raun, Edmund Battey, Nicoline Resen Andersen, Andrea Irazoki, Camilla Lund, Carlos Henríquez-Olguin, Martina Kubec Højfeldt, Pauline Blomquist, Frederik Duch Bromer, Gabriele Mocciaro, Andreas Lodberg, Christian Brix Folsted Andersen, Marco Eijken, Andreas Mæchel Fritzen, Jonas Roland Knudsen, Erik A Richter, Lykke Sylow","doi":"10.1016/j.molmet.2025.102261","DOIUrl":"10.1016/j.molmet.2025.102261","url":null,"abstract":"<p><strong>Purpose: </strong>Blocking the Activin receptor type IIA and IIB (ActRIIA/IIB) has clinical potential to increase muscle mass and improve glycemic control in obesity, cancer, and aging. However, the impact of blocking ActRIIA/IIB on strength, metabolic regulation, and insulin action remains unclear.</p><p><strong>Methods: </strong>Here, we investigated the effect of short- (10 mg kg<sup>-1</sup> bw, once, 40h) or long-term (10 mg kg<sup>-1</sup> bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB (αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue.</p><p><strong>Results: </strong>Short-term α ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76-105%. Despite this, αActRIIA/IIB-treated mice exhibited 33% elevated blood glucose and glucose intolerance. Long-term αActRIIA/IIB treatment increased muscle mass (+20%) and reduced fat mass (-8%) in obese mice but failed to enhance insulin-stimulated glucose uptake in muscle or adipose tissue. Instead, it induced glucose intolerance, cardiac hypertrophy with glycogen accumulation, and elevated hepatic triacylglycerol and glucose output in response to pyruvate. Concomitantly, long-term αActRIIA/IIB treatment increased strength (+30%) in mouse soleus muscle and prevented activin A-induced loss of tissue strength in engineered human muscle tissue. Surprisingly, long-term α ActRIIA/IIB treatment lowered volitional running (-250%).</p><p><strong>Conclusions: </strong>Our findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and muscle insulin sensitivity. However, contrary to the improved glycemic control in humans, ActRIIA/IIB blockade in mice causes severe glucose intolerance and lowers voluntary physical activity. Our study underscores the complex metabolic and functional consequences of ActRIIA/IIB blockade, and highlight species differences on glycemic control, which warrant further investigation.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102261"},"PeriodicalIF":6.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dax1 in AgRP neurons regulates thermogenesis via GR-HDAC3-mediated CRFR1 suppression AgRP神经元中的Dax1通过gr - hdac3介导的CRFR1抑制调控产热。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-09-27 DOI: 10.1016/j.molmet.2025.102258
Zhuodu Wei , Jooseon Cha , Seunghee Lee
{"title":"Dax1 in AgRP neurons regulates thermogenesis via GR-HDAC3-mediated CRFR1 suppression","authors":"Zhuodu Wei ,&nbsp;Jooseon Cha ,&nbsp;Seunghee Lee","doi":"10.1016/j.molmet.2025.102258","DOIUrl":"10.1016/j.molmet.2025.102258","url":null,"abstract":"<div><h3>Objectives</h3><div>The arcuate nucleus of the hypothalamus plays a pivotal role in metabolic homeostasis by integrating the functions of AgRP and POMC neurons. Dax1, a nuclear receptor-like transcription factor, is highly enriched in AgRP neurons; however, its role in energy balance regulation remains largely unexplored. Here, we demonstrate the function of Dax1 in hypothalamic AgRP neurons and its contribution to systemic energy homeostasis and thermogenesis in mice.</div></div><div><h3>Methods</h3><div>We generated AgRP neuron-specific Dax1 conditional knockout mice and assessed their physiological and metabolic responses under high-fat diet feeding and cold exposure. Energy expenditure, brown adipose tissue (BAT) thermogenesis, neuronal activation, and neuropeptide expression were evaluated. Molecular mechanisms were investigated by gene expression analysis, chromatin immunoprecipitation, and biochemical assays.</div></div><div><h3>Results</h3><div>We show that conditional deletion of Dax1 in AgRP neurons enhances energy expenditure, stimulates BAT thermogenesis, and confers resistance to diet-induced obesity in female mice. Notably, these mice exhibit blunted AgRP neuron activation upon cold challenge. Mechanistically, corticotropin-releasing factor receptor type 1 (CRFR1), a key regulator of AgRP neuronal excitability, was upregulated in Dax1-deficient AgRP neurons. We further identified that Dax1 recruits the HDAC3 corepressor complex to the glucocorticoid receptor at the glucocorticoid response element within the <em>Crfr1</em> promoter, thereby repressing <em>Crfr1</em> transcription in response to glucocorticoid signaling.</div></div><div><h3>Conclusions</h3><div>Our findings establish Dax1 as a critical transcriptional repressor of <em>Crfr1</em> in AgRP neurons, linking hypothalamic steroid signaling to the regulation of adaptive thermogenesis and systemic energy balance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102258"},"PeriodicalIF":6.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Weight loss reverses obesity-associated impairments in acute gastrointestinal stretch-induced suppression of food intake and glucose homeostasis 在急性胃肠道拉伸诱导的食物摄入和葡萄糖稳态抑制中,体重减轻逆转肥胖相关损伤。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-09-25 DOI: 10.1016/j.molmet.2025.102260
Maigen Bethea , Tyler Cook , Marwa Mommandi , Andrew McClennan , Allison Martin , Jasmine J. Hendrix , Chelsea R. Hutch , Alfor Lewis , Randy J. Seeley , Henning Fenselau , Silvania da Silva Teixeria , Darleen A. Sandoval
{"title":"Weight loss reverses obesity-associated impairments in acute gastrointestinal stretch-induced suppression of food intake and glucose homeostasis","authors":"Maigen Bethea ,&nbsp;Tyler Cook ,&nbsp;Marwa Mommandi ,&nbsp;Andrew McClennan ,&nbsp;Allison Martin ,&nbsp;Jasmine J. Hendrix ,&nbsp;Chelsea R. Hutch ,&nbsp;Alfor Lewis ,&nbsp;Randy J. Seeley ,&nbsp;Henning Fenselau ,&nbsp;Silvania da Silva Teixeria ,&nbsp;Darleen A. Sandoval","doi":"10.1016/j.molmet.2025.102260","DOIUrl":"10.1016/j.molmet.2025.102260","url":null,"abstract":"<div><h3>Objective</h3><div>Chemical and mechanical signals from the gastrointestinal tract are critical for regulating satiety and glucose metabolism. While both nutrient sensing in the intestine and gastric distension has been well studied, the role of intestinal stretch in these metabolic processes remain unclear. This study evaluates the role of intestinal stretch in regulating food intake and glucose homeostasis in the context of normal body weight, obesity, and weight loss occurring via both dietary intervention and vertical sleeve gastrectomy (VSG).</div></div><div><h3>Methods</h3><div>We used the nonnutritive substance mannitol to selectively induce intestinal stretch in conscious mice. We assessed food intake, glucose tolerance, and neuronal activation in mice with normal body weight, obesity, or after dietary or surgically-induced weight loss. We employed chemogenetic approaches to inhibit GLP-1R and OxtR-expressing vagal afferents, and genetic and pharmacological strategies to ablate GLP-1 signaling to explore mechanisms for mannitol-induced suppression of feeding.</div></div><div><h3>Results</h3><div>Mannitol-induced intestinal stretch acutely suppressed food intake and improved oral glucose tolerance independent of GLP-1 signaling and vagal intestinal mechanosensation. Diet induced obesity impairs mannitol-induced intestinal stretch reductions in food intake and attenuates neuronal activation in the nucleus of the solitary tract (NTS) upon induction of intestinal stretch. Both dietary and surgical weight loss restored intestinal stretch-induced feeding suppression and enhanced NTS neuronal activation. Importantly, VSG heightened NTS neuronal activation in response to oral but not IP glucose.</div></div><div><h3>Conclusions</h3><div>Together, these data demonstrate that intestinal stretch contributes to the regulation of feeding and glucose metabolism independently of intestinal nutrient-sensing or classical gut hormones.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102260"},"PeriodicalIF":6.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Periodic fasting induced reconstitution of metabolic flexibility improves albuminuria in patients with type 2 diabetes 周期性禁食诱导的代谢灵活性重建可改善2型糖尿病患者的蛋白尿。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-09-24 DOI: 10.1016/j.molmet.2025.102257
Alba Sulaj , Phong B.H. Nguyen , Gernot Poschet , Elisabeth Kliemank , Thomas Fleming , Lea Henke , Wiebke Neibig , Stefan Kopf , Rüdiger Hell , Valter D. Longo , Stephan Herzig , Peter P. Nawroth , Michael P. Menden , Julia Szendroedi
{"title":"Periodic fasting induced reconstitution of metabolic flexibility improves albuminuria in patients with type 2 diabetes","authors":"Alba Sulaj ,&nbsp;Phong B.H. Nguyen ,&nbsp;Gernot Poschet ,&nbsp;Elisabeth Kliemank ,&nbsp;Thomas Fleming ,&nbsp;Lea Henke ,&nbsp;Wiebke Neibig ,&nbsp;Stefan Kopf ,&nbsp;Rüdiger Hell ,&nbsp;Valter D. Longo ,&nbsp;Stephan Herzig ,&nbsp;Peter P. Nawroth ,&nbsp;Michael P. Menden ,&nbsp;Julia Szendroedi","doi":"10.1016/j.molmet.2025.102257","DOIUrl":"10.1016/j.molmet.2025.102257","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic inflexibility has been shown to be associated with type 2 diabetes (T2D) and diabetic nephropathy (DN). However, data are lacking, proving that reconstitution of metabolic flexibility by using a 6-month periodic fasting (PF) regimen may improve albuminuria.</div></div><div><h3>Methods</h3><div>In this post hoc analysis of a randomized-controlled trial, we investigated whether the PF regimen enhanced metabolic flexibility in individuals with T2D and DN showing improvement of albuminuria (responders) compared to non-responders. Participants followed every month either a 5-day fasting-mimicking diet or a Mediterranean diet for 6 months. LC-MS/MS-based comprehensive metabolic profiling was performed in plasma samples before, during, and after the intervention. Changes in metabolomic patterns and enriched signalling pathways were analysed between study groups.</div></div><div><h3>Results</h3><div>PF induced a sustained shift toward enhanced fatty acid oxidation, lipid utilization, and amino acids turnover, particularly in responders. Responders exhibited persistent elevations in short-chain acylcarnitines and cholesteryl esters, indicating more efficient lipid oxidation and tighter integration of lipid metabolism with the tricarboxylic acid cycle. Increased glycine and serine levels suggested enhanced cellular maintenance, a protein-sparing effect, and a metabolic shift favouring lipid over carbohydrate. In contrast, non-responders demonstrated only transient and limited metabolic shifts. Unsupervised clustering identified distinct metabolic response patterns, reinforcing the potential of personalized dietary interventions.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that diet-induced restoration of metabolic flexibility is associated with improved albuminuria in T2D, suggesting broader implications for precise nutritional strategies in diabetes management.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102257"},"PeriodicalIF":6.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice 在LDLR缺陷小鼠中,通过全身OPA1过表达增加线粒体融合可促进血脂异常和动脉粥样硬化。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-09-22 DOI: 10.1016/j.molmet.2025.102256
Lorenzo Da Dalt , Francesca Fantini , Giulia Giancane , Annalisa Moregola , Silvia Roda , Monika Svecla , Silvia Pedretti , Giovanni Battista Vingiani , Jiangming Sun , Andreas Edsfeldt , Isabel Goncalves , Patrizia Uboldi , Elena Donetti , Andrea Baragetti , Nico Mitro , Luca Scorrano , Giuseppe Danilo Norata
{"title":"Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice","authors":"Lorenzo Da Dalt ,&nbsp;Francesca Fantini ,&nbsp;Giulia Giancane ,&nbsp;Annalisa Moregola ,&nbsp;Silvia Roda ,&nbsp;Monika Svecla ,&nbsp;Silvia Pedretti ,&nbsp;Giovanni Battista Vingiani ,&nbsp;Jiangming Sun ,&nbsp;Andreas Edsfeldt ,&nbsp;Isabel Goncalves ,&nbsp;Patrizia Uboldi ,&nbsp;Elena Donetti ,&nbsp;Andrea Baragetti ,&nbsp;Nico Mitro ,&nbsp;Luca Scorrano ,&nbsp;Giuseppe Danilo Norata","doi":"10.1016/j.molmet.2025.102256","DOIUrl":"10.1016/j.molmet.2025.102256","url":null,"abstract":"<div><h3>Objective</h3><div>Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, and the synthesis of sterols and bile acids (BAs). Emerging evidence suggests that mitochondrial dynamics including biogenesis, fusion, fission, and mitophagy critically influence cardiometabolic diseases, yet their role in atherogenesis remain poorly understood. Mitochondrial fusion ensures metabolic flexibility and stress adaptation, processes highly relevant to lipid handling and vascular cell plasticity. OPA1, a key regulator of inner mitochondrial membrane fusion, has been implicated in metabolic remodeling and cellular stress responses. We therefore investigated whether modulation of OPA1 expression affects lipid homeostasis and plaque formation in LDL receptor-deficient (LDLR KO) mice and in human carotid atherosclerosis.</div></div><div><h3>Methods</h3><div>OPA1<sup>TG</sup>/LDLR KO and OPA1<sup>ΔHep</sup>/LDLR KO were fed with a Western-type diet (WTD) for 12 weeks. The development of atherosclerosis was compared to that of LDLR KO mice. In humans, the impact of OPA1 was investigated in asymptomatic and symptomatic subjects from the Carotid Plaque Imaging Project (CPIP) biobank.</div></div><div><h3>Results</h3><div>OPA1<sup>TG</sup>/LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1<sup>TG</sup>/LDLR KO display a reduction of unconjugated bile acids and higher percentage of conjugated bile acids leading to an increased lipid adsorption. This phenotype was associated with increased atherosclerosis in the aortic root. OPA1 overexpression also resulted in an altered vascular smooth muscle cell (VSMC) cellular metabolism and differentiation, promoting a shift from a contractile/synthetic phenotype toward a more proliferative and metabolically active state. Concordantly, the deletion of OPA1 in hepatocytes improved systemic lipoprotein metabolism protecting from atherosclerosis. Concordantly in humans, plaque OPA1 mRNA levels are associated with metabolic and smooth muscle cell related pathways.</div></div><div><h3>Conclusions</h3><div>Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism and vascular smooth muscle cell biology.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102256"},"PeriodicalIF":6.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Insulin evokes release of endozepines from astrocytes of the NTS to modulate glucose metabolism in male rats 在雄性大鼠中,胰岛素唤起NTS星形胶质细胞释放内啡肽来调节葡萄糖代谢。
IF 6.6 2区 医学
Molecular Metabolism Pub Date : 2025-09-19 DOI: 10.1016/j.molmet.2025.102255
Lauryn E. New , Niannian Wang , Holly E. Smith , Ross Birks , Shabbir Khan Afridi , Joanne C. Griffiths , Ryan Hains , Jamie Johnston , Beatrice M. Filippi
{"title":"Insulin evokes release of endozepines from astrocytes of the NTS to modulate glucose metabolism in male rats","authors":"Lauryn E. New ,&nbsp;Niannian Wang ,&nbsp;Holly E. Smith ,&nbsp;Ross Birks ,&nbsp;Shabbir Khan Afridi ,&nbsp;Joanne C. Griffiths ,&nbsp;Ryan Hains ,&nbsp;Jamie Johnston ,&nbsp;Beatrice M. Filippi","doi":"10.1016/j.molmet.2025.102255","DOIUrl":"10.1016/j.molmet.2025.102255","url":null,"abstract":"<div><div>The central nervous system (CNS) plays a key role in regulating metabolic functions, but conditions like obesity and diabetes can disrupt this balance. Within the CNS, the nucleus of the solitary tract (NTS) in the dorsal vagal complex (DVC) senses insulin and regulates feeding behaviour and hepatic glucose production. However, we still know little about which cells in the NTS are sensitive to insulin. We show that in male rats insulin receptors in astrocytes are crucial for the NTS's ability to regulate glucose production in the liver. We demonstrate that insulin evokes the release of endozepines from primary astrocytes and direct infusion of endozepines into the NTS mimics the effects of insulin. Inhibition of the benzodiazepine binding site of GABA<sub>A</sub> receptors prevents action of both insulin and endozepines. The effect of endozepines within the NTS is mimicked by GABA<sub>A</sub> antagonists and prevented by an agonist, suggesting that insulin prompts astrocytes to release endozepines, which then attenuate GABA<sub>A</sub> receptor activity, ultimately reducing glucose production in the liver. We also show that high-fat-diet-induced insulin resistance in the NTS can be circumvented by endozepine administration.</div><div>Our study is the first to show that insulin–dependent release of endozepines from NTS-astrocytes is fundamental to control blood glucose levels.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102255"},"PeriodicalIF":6.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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