Cell metabolismPub Date : 2025-02-11DOI: 10.1016/j.cmet.2025.01.009
Jia Li, Chaoqun Cai, Wei Wen Teo, Kai Shin Chin, Yadanar Than Naing, Shengren Song, Franklin Nelson, Li Qiang, Dan Xu, Lei Sun
{"title":"Isoform usage as a distinct regulatory layer driving nutrient-responsive metabolic adaptation","authors":"Jia Li, Chaoqun Cai, Wei Wen Teo, Kai Shin Chin, Yadanar Than Naing, Shengren Song, Franklin Nelson, Li Qiang, Dan Xu, Lei Sun","doi":"10.1016/j.cmet.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.009","url":null,"abstract":"Transcriptome modulation is essential for metabolic adaptation to nutrient environments. However, the role of isoform usage, a crucial transcriptome component, is not yet fully understood. This study outlines the landscape of isoform-usage modulations across major metabolic organs in both mice and monkeys, spanning diverse metabolic states. Our in-depth analysis identifies numerous isoform-usage events, intricately influenced by nutrient challenges and largely independent of gene expression regulation. Comparative analyses of mice and monkeys highlight hundreds of conserved isoform events that exhibit consistent responses to nutrient challenges across species and correlate with human metabolic traits. When analyzing splicing factor-binding motifs in nutrient-regulated events, HuR emerges as the predominant orchestrator of the isoform network in adipocytes, which is validated using an adipose tissue-specific knockout and an Ap2-promoter-driven transgenic mouse model. In summary, our results offer a comprehensive perspective on isoform usage in metabolic regulation, setting a platform for future functional inquiries.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-10DOI: 10.1016/j.cmet.2025.01.002
Nguyen T.B. Nguyen, Sira Gevers, Rutger N.U. Kok, Lotte M. Burgering, Hannah Neikes, Ninouk Akkerman, Max A. Betjes, Marlies C. Ludikhuize, Can Gulersonmez, Edwin C.A. Stigter, Yvonne Vercoulen, Jarno Drost, Hans Clevers, Michiel Vermeulen, Jeroen S. van Zon, Sander J. Tans, Boudewijn M.T. Burgering, Maria J. Rodríguez Colman
{"title":"Lactate controls cancer stemness and plasticity through epigenetic regulation","authors":"Nguyen T.B. Nguyen, Sira Gevers, Rutger N.U. Kok, Lotte M. Burgering, Hannah Neikes, Ninouk Akkerman, Max A. Betjes, Marlies C. Ludikhuize, Can Gulersonmez, Edwin C.A. Stigter, Yvonne Vercoulen, Jarno Drost, Hans Clevers, Michiel Vermeulen, Jeroen S. van Zon, Sander J. Tans, Boudewijn M.T. Burgering, Maria J. Rodríguez Colman","doi":"10.1016/j.cmet.2025.01.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.002","url":null,"abstract":"Tumors arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumors, however, retain some hierarchical organization, maintaining both cancer stem cells (CSCs) and cancer differentiated cells (CDCs). This heterogeneity, coupled with cellular plasticity enabling CDCs to revert to CSCs, contributes to therapy resistance and relapse. Using genetically encoded fluorescent reporters in human tumor organoids, combined with our machine-learning-based cell tracker, CellPhenTracker, we simultaneously traced cell-type specification, metabolic changes, and reconstructed cell lineage trajectories during tumor organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumor dynamics, suppressing CSC differentiation and inducing dedifferentiation into a proliferative CSC state. Mechanistically, lactate increases histone acetylation, epigenetically activating MYC. Given that lactate’s regulation of MYC depends on the bromodomain-containing protein 4 (BRD4), targeting cancer metabolism and BRD4 inhibitors emerge as a promising strategy to prevent tumor relapse.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"47 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-06DOI: 10.1016/j.cmet.2024.12.011
Thibaux Van der Stede, Alexia Van de Loock, Guillermo Turiel, Camilla Hansen, Andrea Tamariz-Ellemann, Max Ullrich, Eline Lievens, Jan Spaas, Nurten Yigit, Jasper Anckaert, Justine Nuytens, Siegrid De Baere, Ruud Van Thienen, Anneleen Weyns, Laurie De Wilde, Peter Van Eenoo, Siska Croubels, John R. Halliwill, Pieter Mestdagh, Erik A. Richter, Wim Derave
{"title":"Cellular deconstruction of the human skeletal muscle microenvironment identifies an exercise-induced histaminergic crosstalk","authors":"Thibaux Van der Stede, Alexia Van de Loock, Guillermo Turiel, Camilla Hansen, Andrea Tamariz-Ellemann, Max Ullrich, Eline Lievens, Jan Spaas, Nurten Yigit, Jasper Anckaert, Justine Nuytens, Siegrid De Baere, Ruud Van Thienen, Anneleen Weyns, Laurie De Wilde, Peter Van Eenoo, Siska Croubels, John R. Halliwill, Pieter Mestdagh, Erik A. Richter, Wim Derave","doi":"10.1016/j.cmet.2024.12.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.011","url":null,"abstract":"Plasticity of skeletal muscle is induced by transcriptional and translational events in response to exercise, leading to multiple health and performance benefits. The skeletal muscle microenvironment harbors myofibers and mononuclear cells, but the rich cell diversity has been largely ignored in relation to exercise adaptations. Using our workflow of transcriptome profiling of individual myofibers, we observed that their exercise-induced transcriptional response was surprisingly modest compared with the bulk muscle tissue response. Through the integration of single-cell data, we identified a small mast cell population likely responsible for histamine secretion during exercise and for targeting myeloid and vascular cells rather than myofibers. We demonstrated through histamine H1 or H2 receptor blockade in humans that this paracrine histamine signaling cascade drives muscle glycogen resynthesis and coordinates the transcriptional exercise response. Altogether, our cellular deconstruction of the human skeletal muscle microenvironment uncovers a histamine-driven intercellular communication network steering muscle recovery and adaptation to exercise.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"55 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-06DOI: 10.1016/j.cmet.2024.12.016
Fabian S. Passini, Bavat Bornstein, Sarah Rubin, Yael Kuperman, Sharon Krief, Evi Masschelein, Tevie Mehlman, Alexander Brandis, Yoseph Addadi, Shira Huri-Ohev Shalom, Erik A. Richter, Tal Yardeni, Amir Tirosh, Katrien De Bock, Elazar Zelzer
{"title":"Piezo2 in sensory neurons regulates systemic and adipose tissue metabolism","authors":"Fabian S. Passini, Bavat Bornstein, Sarah Rubin, Yael Kuperman, Sharon Krief, Evi Masschelein, Tevie Mehlman, Alexander Brandis, Yoseph Addadi, Shira Huri-Ohev Shalom, Erik A. Richter, Tal Yardeni, Amir Tirosh, Katrien De Bock, Elazar Zelzer","doi":"10.1016/j.cmet.2024.12.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.016","url":null,"abstract":"Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons regulate morphological and physiological properties of brown and beige fat and prevent systemic hypermetabolism. Targeting runt-related transcription factor 3 (Runx3)/parvalbumin (PV) sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat-diet-induced obesity, and caused adipose tissue browning and beiging, likely driven by elevated norepinephrine levels. Finding that brown and beige fat are innervated by Runx3/PV sensory neurons expressing Piezo2 suggests a model in which mechanical signals, sensed by Piezo2 in sensory neurons, protect energy storage and prevent a systemic hypermetabolic phenotype.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"47 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Interplay between gut microbial communities and metabolites modulates pan-cancer immunotherapy responses","authors":"Xiaoqiang Zhu, Muni Hu, Xiaowen Huang, Lingxi Li, Xiaolin Lin, Xiaoyan Shao, Jiantao Li, Xiaoyue Du, Xinjia Zhang, Rongrong Sun, Tianying Tong, Yanru Ma, Lijun Ning, Yi Jiang, Yue Zhang, Yuqi Shao, Zhenyu Wang, Yilu Zhou, Jinmei Ding, Ying Zhao, Haoyan Chen","doi":"10.1016/j.cmet.2024.12.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.013","url":null,"abstract":"Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but remains effective in only a subset of patients. Emerging evidence suggests that the gut microbiome and its metabolites critically influence ICB efficacy. In this study, we performed a multi-omics analysis of fecal microbiomes and metabolomes from 165 patients undergoing anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapy, identifying microbial and metabolic entities associated with treatment response. Integration of data from four public metagenomic datasets (<em>n</em> = 568) uncovered cross-cohort microbial and metabolic signatures, validated in an independent cohort (<em>n</em> = 138). An integrated predictive model incorporating these features demonstrated robust performance. Notably, we characterized five response-associated enterotypes, each linked to specific bacterial taxa and metabolites. Among these, the metabolite phenylacetylglutamine (PAGln) was negatively correlated with response and shown to attenuate anti-PD-1 efficacy <em>in vivo</em>. This study sheds light on the interplay among the gut microbiome, the gut metabolome, and immunotherapy response, identifying potential biomarkers to improve treatment outcomes.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"15 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-04DOI: 10.1016/j.cmet.2025.01.004
Tingting Zhou, Zhiwei Wang, Xiaowang Lv, Mengting Guo, Ning Zhang, Liangju Liu, Li Geng, Jing Shao, Ka Zhang, Mengru Gao, Aiqin Mao, Yifei Zhu, Fan Yu, Lei Feng, Xiaoyan Wang, Qixiao Zhai, Wei Chen, Xin Ma
{"title":"Targeting gut S. aureofaciens Tü117 serves as a new potential therapeutic intervention for the prevention and treatment of hypertension","authors":"Tingting Zhou, Zhiwei Wang, Xiaowang Lv, Mengting Guo, Ning Zhang, Liangju Liu, Li Geng, Jing Shao, Ka Zhang, Mengru Gao, Aiqin Mao, Yifei Zhu, Fan Yu, Lei Feng, Xiaoyan Wang, Qixiao Zhai, Wei Chen, Xin Ma","doi":"10.1016/j.cmet.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.004","url":null,"abstract":"Currently, the regulation of specific gut microbial metabolism for the development and/or treatment of hypertension remains largely unexplored. Here, we show that α-lipomycin, produced by <em>Streptomyces aureofaciens</em> (<em>S. aureofaciens</em>) Tü117, is upregulated in the serum of high-salt diet (HSD) mice and patients with essential hypertension. α-lipomycin causes vasodilation impairment involving transient receptor potential vanilloid 4 (TRPV4)-mediated nitric oxide and endothelium-derived hyperpolarizing factor pathways in mice. We also find that <em>Lactobacillus plantarum</em> (<em>L. plantarum</em>) CCFM639 attenuates the increase in blood pressure (BP) potentially through inhibiting the proliferation of <em>S. aureofaciens</em> Tü117 in mice. An exploratory intervention trial indicates that <em>L. plantarum</em> CCFM639 supplementation reduces BPs in subjects newly diagnosed with pre-hypertension or stage 1 hypertension without antihypertensive medication. Our findings provide evidence for a role of <em>S. aureofaciens</em> Tü117-associated α-lipomycin elevation in the pathogenesis of HSD-induced hypertension, highlighting that targeting gut bacteria serves as a new therapeutic intervention for hypertension.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"199 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-04DOI: 10.1016/j.cmet.2024.12.015
Marcus D. Goncalves, Neil M. Iyengar
{"title":"Fueling metabolic disruption via FMD to boost chemotherapy in TNBC","authors":"Marcus D. Goncalves, Neil M. Iyengar","doi":"10.1016/j.cmet.2024.12.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.015","url":null,"abstract":"Triple-negative breast cancer (TNBC) is highly glycolytic and lacks effective biomarkers for therapy response. The BREAKFAST trial showed that a fasting-mimicking diet (FMD) improved pathological complete response (pCR) rates to 56.6% compared to historical chemotherapy averages (30%–40%), with minimal severe adverse events. FMD’s metabolic and immune-modulating effects warrant further study with immunotherapy.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"8 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-04DOI: 10.1016/j.cmet.2025.01.005
Moniquetta Shafer, Vivien Low, Zhongchi Li, John Blenis
{"title":"The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer","authors":"Moniquetta Shafer, Vivien Low, Zhongchi Li, John Blenis","doi":"10.1016/j.cmet.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.005","url":null,"abstract":"Propionate metabolism dysregulation has emerged as a source of metabolic health alterations linked to aging, cardiovascular and renal diseases, obesity and diabetes, and cancer. This is supported by several large cohort population studies and recent work revealing its role in cancer progression. Mutations in several enzymes of this metabolic pathway are associated with devastating inborn errors of metabolism, resulting in severe methylmalonic and propionic acidemias. Beyond these rare diseases, however, the broader pathological significance of propionate metabolism and its metabolites has been largely overlooked. Here, we summarize earlier studies and new evidence that the alteration of this pathway and associated metabolites are involved in the development of various metabolic diseases and link aging to cancer progression and metastasis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"77 4 Pt 2 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-02-04DOI: 10.1016/j.cmet.2024.12.012
Judy Hirst
{"title":"A new player in the mammalian electron transport chain","authors":"Judy Hirst","doi":"10.1016/j.cmet.2024.12.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.012","url":null,"abstract":"In an evolutionary twist to mammalian bioenergetics, Spinelli and coworkers reveal the presence of rhodoquinones in mammalian mitochondria, expanding the established premise that the mammalian respiratory chain relies uniquely on ubiquinones for catalysis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"7 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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