Metabolism: clinical and experimental最新文献

{"title":"Metabolomic aging clock predicts risk of different cardiovascular diseases in the UK Biobank","authors":"Guochang You ,&nbsp;Kangjie Wang ,&nbsp;Runnan Shen ,&nbsp;Xiong Chen ,&nbsp;Jinjin Jiang ,&nbsp;Yunhao Sun ,&nbsp;Dan Wu ,&nbsp;Jiatang Xu ,&nbsp;Kai Huang ,&nbsp;Chen Yao","doi":"10.1016/j.metabol.2025.156467","DOIUrl":"10.1016/j.metabol.2025.156467","url":null,"abstract":"<div><div>Current metabolomic aging clocks inadequately capture individual heterogeneity in biological aging trajectories, constraining their clinical utility. Here, we developed a metabolomic age clock in the UK Biobank (<em>n</em> = 196,790) using a comprehensive panel of 249 plasma metabolites. This framework was trained to predict phenotypic age (PhenoAge), a validated composite biomarker that integrates clinical chemistry across multiple systems, and was evaluated for its utility to predict incident cardiovascular diseases (CVDs) and dementia. We found that this new measure accurately predicted actual PhenoAge (Pearson's r = 0.90) and was significantly associated with the incidence of seven CVDs, including major adverse cardiovascular events, atherosclerotic cardiovascular disease, myocardial infarction, stroke, aortic stenosis, heart failure, and abdominal aortic aneurysm, but not dementia. Furthermore, metabolomic aging was associated with biological, physical, and cognitive age-related phenotypes, comprising telomere length, frailty index, and reaction time. Incorporating the metabolomic age clock with PREVENT (Predicting Risk of CVD Events) risk score modestly improved the performance, as measured by C-statistic and net reclassification index. Genetic analyses revealed 91 genomic loci and 168 genes (e.g., <em>SERPINA1</em>, <em>FADS</em> cluster), with tissue-enrichment analysis highlighting the liver's significant role in metabolic aging. By bridging metabolomic profiles with multisystem aging information, this framework provides a measure of biological aging that is associated with age-related functional status and cardiovascular risk.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156467"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705560","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 and immune dysfunction at the crossroads between type 1 diabetes and neurodegeneration","authors":"Francesca D'Addio ,&nbsp;Loredana Bucciarelli ,&nbsp;Maria Elena Lunati ,&nbsp;Paolo Fiorina","doi":"10.1016/j.metabol.2025.156471","DOIUrl":"10.1016/j.metabol.2025.156471","url":null,"abstract":"<div><div>A growing body of evidence suggests that neurogenerative disorders are increasingly common in individuals with type 1 diabetes (T1D) and should be considered part of the heterogeneous impairment of the nervous system linked to the T1D condition. The already established association between brain health and blood glucose metabolic control pushes to normalize glycemia in individuals with neurodegenerative diseases as well as in those with T1D. Normoglycemia has, indeed, been associated with reduced brain atrophy and preserved neuronal plasticity and function. Interestingly, immune dysregulation recently demonstrated in neurodegenerative diseases may be highly relevant given the autoimmune nature of T1D. Poor glycemic control and a disrupted immune response may act as common pathogenic mechanisms that increase the incidence of neurodegenerative disorders in individuals with T1D and may unveil new diagnostic and therapeutic paths for future clinical advancements. In this narrative review, we summarize new evidence showing that brain damage and cognitive dysfunction are linked to T1D and delineate the role of altered glycemic control, neuronal loss and immune dysregulation. We also discuss novel therapeutic approaches that target the aforementioned mechanisms and may help prevent the onset of neurodegenerative disorders in individuals with T1D.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156471"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794290","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":"DC-SIGN+ macrophages alleviate metabolic dysfunction-associated steatotic liver disease via fine-tuning TLR4 signaling and inflammatory secretory profiles","authors":"Jinxia Liu ,&nbsp;Haifeng Wu ,&nbsp;Ling Zhou ,&nbsp;Qin Jin ,&nbsp;Huoyan Ji ,&nbsp;Baoying Hu ,&nbsp;Hongpei Wu ,&nbsp;Ting Chen ,&nbsp;Xun Wang ,&nbsp;Jianwei Hong ,&nbsp;Rongwei Feng ,&nbsp;Xiaojun Zhang ,&nbsp;Jiali Zhou ,&nbsp;Weiliang Zhang ,&nbsp;Xu Wang ,&nbsp;Lishuai Qu ,&nbsp;Chunhua Wan","doi":"10.1016/j.metabol.2025.156453","DOIUrl":"10.1016/j.metabol.2025.156453","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Innate immune receptors play a pivotal role in modulating immune responses during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to comprehensively investigate the role of the C-type lectin receptor DC-specific ICAM3-grabbing non-integrin (DC-SIGN) in MASLD progression.</div></div><div><h3>Methods</h3><div>DC-SIGN expression in liver tissues from patients with MASLD and healthy individuals was examined using immunohistochemical analyses. Immunofluorescence was used to determine DC-SIGN distribution across liver cell types. In vivo, adeno-associated virus (AAV)-mediated transduction of CD68 promoter-driven human <em>DC-SIGN</em> (<em>hDC-SIGN</em>) or a control construct was performed in mice fed either a high-fat, high-cholesterol (HFHC) diet or a normal chow diet (NCD). Additionally, THP-1-differentiated macrophages were used in vitro to investigate the molecular mechanisms by which DC-SIGN modulates Toll-like receptor 4 (TLR4) endocytosis and inflammatory cytokine secretion.</div></div><div><h3>Results</h3><div>DC-SIGN expression was significantly reduced in liver tissues from patients with MASLD and HFHC-fed mice compared to healthy controls and NCD-fed mice. DC-SIGN predominantly co-localized with the macrophage marker CD68. Delivery of <em>CD68</em> promoter-specific <em>hDC-SIGN</em> markedly ameliorated HFHC-induced liver lipotoxicity, steatosis, inflammation, and fibrosis. Mechanistically, DC-SIGN facilitated macrophage TLR4 endocytosis via direct binding to TLR4, suppressing MyD88-dependent pro-inflammatory responses while activating TBK1-dependent IRF3 signaling. Accordingly, Lewis^X (Le^X)-DC-SIGN signaling reduced lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion while simultaneously enhancing anti-inflammatory IL-10 secretion.</div></div><div><h3>Conclusions</h3><div>DC-SIGN plays a key role in modulating TLR4-dependent inflammation in MASLD, suggesting that targeting macrophage DC-SIGN may be a promising therapeutic approach.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156453"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570289","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":"Molecular code of ferroptosis: emerging multi-dimensional modifications and therapeutic targets in hepatic disorders","authors":"Xiaotong Cai ,&nbsp;Yinhao Zhang ,&nbsp;Wenqing Qin ,&nbsp;Xiaojiaoyang Li","doi":"10.1016/j.metabol.2025.156457","DOIUrl":"10.1016/j.metabol.2025.156457","url":null,"abstract":"<div><div>Ferroptosis, a distinct form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a pivotal regulator in the pathogenesis of liver diseases. It functions both as a driver of hepatocyte injury in chronic liver disorders and as a therapeutic vulnerability in hepatocellular carcinoma. This review provides a comprehensive analysis of the regulatory networks of ferroptosis, shaped by both epigenetic and post-translational modifications. Specifically, we detailed how RNA and DNA methylation, non-coding RNAs, histone acetylation and post-translational modifications dynamically modulated the expression, stability and activity of ferroptosis-related molecules, especially for glutathione peroxidase 4, solute carrier family 7 member 11, acyl-CoA synthetase long-chain family member 4 and transferrin receptor 1. By dissecting these multilayered regulatory mechanisms, we delineated how distinct modifications operated, either promoting or suppressing ferroptosis across various liver diseases. Furthermore, we summarized recent advances in therapeutic interventions targeting ferroptosis-related pathways, including their pharmacological mechanisms, efficacy in preclinical models and limitations in clinical translation. Special emphasis was also placed on the complexity of modifications, disease-stage specificity and the topology of modification sites in shaping ferroptosis sensitivity. Collectively, this review highlights ferroptosis as a dynamic and therapeutically actionable within liver pathology and underscores the potential of targeting regulatory modifications to refine strategies for disease intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156457"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615593","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":"TMEM41B contributes to atherosclerosis by promoting lipid synthesis in vascular smooth muscle cells via fatty acid synthase stabilization","authors":"Gui-Yan Peng ,&nbsp;Li-Tai Wei ,&nbsp;Ye-Xiang Jing ,&nbsp;Hao-Long Luo ,&nbsp;Zi-Lun Liu ,&nbsp;Run-Chen Wei ,&nbsp;Jun-Jie Ning ,&nbsp;Guang-Qi Chang ,&nbsp;Mian Wang","doi":"10.1016/j.metabol.2025.156456","DOIUrl":"10.1016/j.metabol.2025.156456","url":null,"abstract":"<div><div>Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E–deficient (ApoE^−/−) mice markedly reduced plaque size and macrophage infiltration. Overexpressing TMEM41B in cultured VSMCs altered intracellular lipid profiles by stabilizing fatty acid synthase (FASN), a crucial enzyme in fatty acid synthesis, via inhibiting its ubiquitination and degradation. The TMEM41B–FASN axis drove lipid synthesis, promoted intracellular lipid storage, and facilitated the release of pro-inflammatory cytokines. Further, in cultured VSMCs, herpes simplex virus (HSV) infection amplified TMEM41B expression via OCT-1-mediated transcriptional activation, linking viral infection to lipid metabolic reprogramming in vitro. These findings expand the current understanding of VSMC-derived foam cell formation and suggest that targeting the TMEM41B–FASN axis may represent a promising therapeutic strategy for AS, particularly in the context of HSV infection.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156456"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615594","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":"Prenatal caffeine exposure impairs neurodevelopment via glucocorticoid-driven epigenetic cascade suppressing astrocytic ABCG1 and cholesterol transport","authors":"Gaole Dai ,&nbsp;Mingcui Luo ,&nbsp;Shiyun Dai ,&nbsp;Xinli Zhou ,&nbsp;Sen Zhu ,&nbsp;Mengxi Lu ,&nbsp;Xiaoyi Han ,&nbsp;Fang Yang ,&nbsp;Ying Yu ,&nbsp;Hui Wang ,&nbsp;Dan Xu","doi":"10.1016/j.metabol.2025.156454","DOIUrl":"10.1016/j.metabol.2025.156454","url":null,"abstract":"<div><div>Prenatal caffeine exposure (PCE), stemming from widespread maternal intake of caffeine-containing substances, has emerged as a major pharmacological stressor affecting fetal neurodevelopment. Although epidemiological studies have consistently linked PCE to cognitive impairments and emotional deficits in offspring, the underlying mechanisms have long been confined to direct adenosine receptor antagonism, failing to explain the persistent neurodevelopmental consequences. Here, using cross-species models (rat PCE, astrocyte-specific <em>Abcg1</em> knockout mice, and glucocorticoid-treated zebrafish) and multi-scale analyses, we demonstrate that PCE activates the maternal-fetal glucocorticoid axis, leading to dysregulation of the GR-<em>miR-130b/301b</em>-PPARγ signaling cascade in hippocampal astrocytes. This disrupts expression of the cholesterol transporter— ATP binding cassette subfamily G member 1 (ABCG1), impairing astrocytic cholesterol efflux and depriving neurons of cholesterol-rich microenvironments essential for synaptic development. <em>Abcg1</em> knockout mice recapitulate PCE-induced synaptic defects, while astrocyte-specific ABCG1 overexpression or <em>miR-130b/301b</em> inhibition rescues neuronal cholesterol supply and synaptic structure. Luciferase assays confirm that <em>miR-130b/301b</em> directly suppress <em>Pparγ</em>-mediated <em>Abcg1</em> transcription. Our findings identify the GR-<em>miR-130b/301b</em>-PPARγ-ABCG1 axis as a core mechanism of PCE-induced neurotoxicity, establishing astrocytic cholesterol transport as a potential intervention target and providing a shared molecular framework for evaluating central nervous system risks of glucocorticoid-disruptive agents.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156454"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596635","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":"Obesity rewires CD8+ T cell iron metabolism in adipose tissue to fuel metabolic inflammation","authors":"Jinfen Dai ,&nbsp;Zixuan Zeng ,&nbsp;Lishuan Wang ,&nbsp;Wei Yuan ,&nbsp;Karina Cunha e Rocha ,&nbsp;Junho Park ,&nbsp;Garam An ,&nbsp;Ke Wang ,&nbsp;Jisoo Song ,&nbsp;Qian Xiang ,&nbsp;Ying Duan ,&nbsp;Chengjia Qian ,&nbsp;Varsha Beldona ,&nbsp;Whasun Lim ,&nbsp;Enfu Hui ,&nbsp;Michael Karin ,&nbsp;Wei Ying","doi":"10.1016/j.metabol.2025.156438","DOIUrl":"10.1016/j.metabol.2025.156438","url":null,"abstract":"<div><div>Sufficient nutrient supply is important for the maintenance of non-lymphoid tissue resident CD8+ T cell homeostasis, but the role of labile iron remains unclear. Here, we find adipose tissue CD8+ T cells exhibit elevated labile iron and mitochondrial Fe2+ compared to splenic counterparts, driving high ROS and IFNγ production. In obesity, an increase in Fe2+ influx into mitochondria enhances adipose tissue CD8+ cell functions, but weight loss normalizes CD8+ cell iron metabolism. <em>Ncoa4</em> knockout reduces labile iron, blunting ROS and IFNγ production, while <em>Fth1</em> knockout elevates Fe2+ and ROS, elevating IFNγ production. CD8+ cell-specific activation of NRF2 restores iron homeostasis by upregulating ferritin and promoting oxidative detoxification, suppressing adipose tissue CD8+ T cell accumulation and IFNγ production. Finally, NRF2 overexpression in CD8+ T cells attenuates obesity-related adipose tissue inflammation and metabolic disorders. These results highlight the crucial role of labile iron supply in adipose tissue CD8+ T cell homeostasis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156438"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530875","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":"Epicardial adipose tissue produces L-3-hydroxybutyrate in advanced heart failure: direct analysis of fat metabolic remodeling","authors":"Martin Riecan ,&nbsp;Barbora Judita Kasperova ,&nbsp;Michaela Vondrackova ,&nbsp;Petra Janovska ,&nbsp;Eliska Haasova ,&nbsp;Katerina Adamcova ,&nbsp;Peter Ivak ,&nbsp;Daniel Hlavacek ,&nbsp;Katerina Kroupova ,&nbsp;Tomas Cajka ,&nbsp;Jan Kopecky ,&nbsp;Soňa Štemberková Hubáčková ,&nbsp;Milos Mraz ,&nbsp;Ivan Netuka ,&nbsp;Vojtech Melenovsky ,&nbsp;Martin Haluzik ,&nbsp;Ondrej Kuda","doi":"10.1016/j.metabol.2025.156465","DOIUrl":"10.1016/j.metabol.2025.156465","url":null,"abstract":"<div><h3>Background</h3><div>Heart failure (HF) progression involves complex metabolic and multi-organ alterations, but the specific adaptations in adipose tissue are not fully understood.</div></div><div><h3>Aims</h3><div>We aimed to characterize the metabolic remodeling of epicardial (EAT) and subcutaneous (SAT) adipose tissues in HF with reduced ejection fraction (HFrEF), focusing on lipid metabolism, fatty acid oxidation, and ketogenesis.</div></div><div><h3>Methods</h3><div>Clinical and metabolomic profiling were performed on metabolically stable controls (<em>n</em> = 34), patients with mild HFrEF (<em>n</em> = 45), and severe HFrEF (<em>n</em> = 129). Metabolomics profiling identified over 800 metabolites in EAT and SAT. Clustering and pathway enrichment analyses defined depot-specific metabolic shifts across HF stages, while gene expression analyses provided mechanistic support.</div></div><div><h3>Results</h3><div>Advancing HF was associated with declining cardiac function, systemic congestion, and a metabolic shift toward catabolism. Metabolomics revealed depot-specific adaptations: SAT transitioned smoothly to enhanced lipolysis, whereas EAT demonstrated impaired triacylglycerol replenishment and disrupted final turn of β-oxidation spiral. Both depots increased reliance on acylcarnitine degradation and lipolysis; however, EAT was uniquely characterized by late-stage impairment in mitochondrial and peroxisomal fatty acid oxidation, leading to elevation of 3-hydroxybutyrate and hydroxybutyrylcarnitine tissue levels. Ex vivo analyses of EAT explants showed significantly increased fraction of L-3-hydroxybutyrate enantiomer, produced by EAT, compared to D-3-hydroxybutyrate enantiomer originating from the liver.</div></div><div><h3>Conclusions</h3><div>HF progression drives major, depot-specific metabolic remodeling in adipose tissue. In advanced HF, EAT shows impaired fatty acid oxidation and enhanced local production of L-3-hydroxybutyrate in the vicinity of myocardium, highlighting the close metabolic cooperation in nutrient supply between EAT and the heart muscle through the coronary circulation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156465"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681146","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":"Inhibition of microglial Slc2a5 attenuates ischemic brain injury","authors":"Daosheng Ai ,&nbsp;Baoshan Qiu ,&nbsp;Xing-jun Chen ,&nbsp;Fengzhi Li ,&nbsp;Di Yao ,&nbsp;Huijie Mi ,&nbsp;Jun-Liszt Li ,&nbsp;Bing Zhou ,&nbsp;Jian Zuo ,&nbsp;Yilong Wang ,&nbsp;Woo-ping Ge ,&nbsp;Wenzhi Sun","doi":"10.1016/j.metabol.2025.156429","DOIUrl":"10.1016/j.metabol.2025.156429","url":null,"abstract":"<div><div>Acute ischemic stroke (AIS) is one of the leading causes of mortality and disability globally. Despite its complex pathological mechanisms, effective neuroprotective strategies are still lacking in clinical practice. Microglia and their metabolic processes play a pivotal role in the pathogenesis of AIS, yet the impact and underlying mechanisms of microglial fructose metabolism remain unclear. In this study, we identified <em>Slc2a5</em> (also known as <em>Glut5</em>), a crucial regulator of fructose metabolism in microglia, as a key factor contributing to the early progression of AIS. Conditional deletion of <em>Slc2a5</em> in microglia significantly alleviated brain injury in a mouse model of AIS. Single-cell transcriptomic (scRNA-seq) analysis demonstrated that the deletion of <em>Slc2a5</em> promoted the differentiation of microglia into stroke-associated subpopulations with neuroprotective properties. Moreover, in vitro experiments indicated that this microglial differentiation process was primarily mediated by the activity of pyruvate kinase M2 (PKM2). Collectively, our findings unveil a novel microglial <em>Slc2a5</em>-mediated fructose metabolism pathway that exacerbates brain injury after AIS. This study provides evidence for SLC2A5 as a promising therapeutic target for the clinical treatment of AIS by offering insights into its critical role in microglial metabolism and neuroprotection.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156429"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476654","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":"BCAA catabolism in TRH neurons of paraventricular nucleus regulates energy expenditure","authors":"Xing Ming ,&nbsp;Jialin Tan ,&nbsp;Miaomiao Yuan ,&nbsp;Xiaoqin Ma ,&nbsp;Feiye Zhou ,&nbsp;Shushu Wang ,&nbsp;Qianqian Lyu ,&nbsp;Wenzhi Xue ,&nbsp;Tingting Bo ,&nbsp;Yunxia Liu ,&nbsp;Xuejiao Zhang ,&nbsp;Fuhua Yan ,&nbsp;Jie Hong ,&nbsp;Jie Zheng ,&nbsp;Guang Ning ,&nbsp;Weiqing Wang ,&nbsp;Jiqiu Wang ,&nbsp;Haipeng Sun ,&nbsp;Libin Zhou ,&nbsp;Xiao Wang","doi":"10.1016/j.metabol.2025.156435","DOIUrl":"10.1016/j.metabol.2025.156435","url":null,"abstract":"<div><div>The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (<em>Bckdha</em>^f/f;RIP-Cre) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVN^TRH neurons displays a similar metabolic phenotype to <em>Bckdha</em>^f/f;RIP-Cre mice. TRH supplementation ameliorates the abnormal phenotypes of <em>Bckdha</em>^f/f;RIP-Cre mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the <em>Trh</em> promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156435"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145505679","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}