Nature metabolism最新文献_第5页

Spatial quantitative metabolomics enables identification of remote and sustained ipsilateral cortical metabolic reprogramming after stroke 空间定量代谢组学能够识别中风后远端和持续的同侧皮质代谢重编程

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-08-05 DOI: 10.1038/s42255-025-01340-8

Gangqi Wang, Bernard M. van den Berg, Sarantos Kostidis, Kelsey Pinkham, Marleen E. Jacobs, Arthur Liesz, Martin Giera, Ton J. Rabelink

{"title":"Spatial quantitative metabolomics enables identification of remote and sustained ipsilateral cortical metabolic reprogramming after stroke","authors":"Gangqi Wang, Bernard M. van den Berg, Sarantos Kostidis, Kelsey Pinkham, Marleen E. Jacobs, Arthur Liesz, Martin Giera, Ton J. Rabelink","doi":"10.1038/s42255-025-01340-8","DOIUrl":"10.1038/s42255-025-01340-8","url":null,"abstract":"Mass spectrometry imaging (MSI) has become a cornerstone of spatial biology research. However, various factors that are intrinsic to the technology limit the quantitative capacity of MSI-based spatial metabolomics and thus reliable interpretation. Here we developed an improved quantitative MSI workflow, based on isotopically 13C-labelled yeast extract as internal standards, to overcome these pitfalls. Using brain and kidney tissue, we demonstrate that this approach allows for quantification of more than 200 metabolic features. Applying our workflow to a stroke model allowed us to not only map metabolic remodelling of the infarct and peri-infarct area over time, but also discover hitherto unnoted remote metabolic remodelling in the histologically unaffected ipsilateral sensorimotor cortex. At day 7 post-stroke, increased levels of neuroprotective lysine and reduced excitatory glutamate levels were found when compared with the contralateral cortex. By day 28 post-stroke, lysine and glutamate levels appeared normal, while decreased precursor pools of uridine diphosphate N-acetylglucosamine and linoleate persisted that were previously linked to vulnerability. Importantly, traditional normalization strategies not using internal standards were unable to visualize these differences. Using 13C-labelled yeast extracts as a normalization strategy establishes a paradigm in quantitative MSI-based spatial metabolomics that greatly enhances reliability and interpretive strength. Wang et al. report a workflow to perform quantitative mass spectrometry imaging and provide insight into spatial metabolic remodelling undergone in the mouse brain upon ischaemia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1791-1800"},"PeriodicalIF":20.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01340-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Macrophages say NO to nucleotide synthesis and salvage instead 巨噬细胞对核苷酸合成和打捞产生NO反应

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-08-04 DOI: 10.1038/s42255-025-01322-w

Eloïse Marques, Dylan G. Ryan

引用次数: 0

Lactate signalling leads to aggregation of immune-inflammatory hotspots and SLC5A12 blockade promotes their resolution 乳酸信号传导导致免疫炎症热点聚集，SLC5A12阻断促进其解决

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-08-04 DOI: 10.1038/s42255-025-01331-9

Michelangelo Certo, Elena Pontarini, Sebastian G. Gilbert, Ronny Schmidt, Jason D. Turner, Davide Lucchesi, Daria Apostolo, Giulia Cavallaro, Charlotte G. Smith, Serena Colafrancesco, Joana Campos, Saba Nayar, Christoph Schröder, Benjamin A. Fisher, Fabian Spill, Michele Bombardieri, Claudio Mauro

{"title":"Lactate signalling leads to aggregation of immune-inflammatory hotspots and SLC5A12 blockade promotes their resolution","authors":"Michelangelo Certo, Elena Pontarini, Sebastian G. Gilbert, Ronny Schmidt, Jason D. Turner, Davide Lucchesi, Daria Apostolo, Giulia Cavallaro, Charlotte G. Smith, Serena Colafrancesco, Joana Campos, Saba Nayar, Christoph Schröder, Benjamin A. Fisher, Fabian Spill, Michele Bombardieri, Claudio Mauro","doi":"10.1038/s42255-025-01331-9","DOIUrl":"10.1038/s42255-025-01331-9","url":null,"abstract":"Ectopic lymphoid structures (ELS) are aggregates of lymphoid cells that often form within inflamed tissues in patients with autoimmune diseases, cancer, infectious diseases and cardiovascular conditions. These structures drive B cell maturation into memory B cells and plasma cells through B cell and T cell co-stimulation, and their role in pathogenesis is increasingly recognized. Understanding how ELS develop and persist in inflamed tissues is essential for elucidating the pathogenesis and treatment responses in diseases in which they have a prominent role. Here we show that metabolic pathways and specific metabolites, in particular lactate, are master regulators of ELS organization in Sjögren’s disease (SjD), the second-most common autoimmune rheumatic disease. Furthermore, inhibiting lactate uptake by lactate transporters, specifically by SLC5A12 blockade, represents a previously unappreciated checkpoint in autoimmune inflammatory diseases. This approach results in multidimensional pro-resolution effects, including reduced inflammatory cytokine levels, enhanced T cell egress from inflamed sites and diminished T cell and B cell areas and their segregation within ELS. Certo, Pontarini et al. provide insight into the metabolic requirements of ectopic lymphoid structure (ELS) assembly in the context of autoimmunity, and show that blocking lactate uptake by SLC5A12 offers therapeutic benefits in a mouse model of Sjögren’s disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1663-1680"},"PeriodicalIF":20.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01331-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144770052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide 经典活化的巨噬细胞在一氧化氮的驱动下进行功能显著的核苷酸代谢重塑

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-08-04 DOI: 10.1038/s42255-025-01337-3

Steven V. John, Gretchen L. Seim, Billy J. Erazo-Flores, James A. Votava, Uzziah S. Urquiza, Nicholas L. Arp, John Steill, Jack Freeman, Lauren N. Carnevale, Isaiah Roberts, Xin Qing, Stuart A. Lipton, Ron Stewart, Laura J. Knoll, Jing Fan

{"title":"Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide","authors":"Steven V. John, Gretchen L. Seim, Billy J. Erazo-Flores, James A. Votava, Uzziah S. Urquiza, Nicholas L. Arp, John Steill, Jack Freeman, Lauren N. Carnevale, Isaiah Roberts, Xin Qing, Stuart A. Lipton, Ron Stewart, Laura J. Knoll, Jing Fan","doi":"10.1038/s42255-025-01337-3","DOIUrl":"10.1038/s42255-025-01337-3","url":null,"abstract":"During an immune response, macrophages specifically reprogramme their metabolism to support functional changes. Here, we revealed that nucleotide metabolism is one of the most significantly reprogrammed pathways upon classical activation. Specifically, de novo synthesis of pyrimidines is maintained up to uridine monophosphate, but blocked at cytidine triphosphate and deoxythymidine monophosphate synthesis; de novo synthesis of purines is shut off at the last step (catalysed by AICAR transformylase/IMP cyclohydrolase, ATIC), and cells switch to increased purine salvage. Nucleotide degradation to nitrogenous bases is upregulated but complete oxidation of purine bases (catalysed by xanthine oxidoreductase, XOR) is inhibited, diverting flux into salvage. Mechanistically, nitric oxide was identified as a major regulator of nucleotide metabolism, simultaneously driving multiple key changes, including the transcriptional downregulation of Tyms and profound inhibition of ATIC and XOR. Inhibiting purine salvage using Hgprt knockout or inhibition alters the expression of many stimulation-induced genes, suppresses macrophage migration and phagocytosis, and increases the proliferation of the intracellular parasite Toxoplasma gondii. Together, these results thoroughly uncover the dynamic reprogramming of macrophage nucleotide metabolism upon classical activation and elucidate the regulatory mechanisms and functional significance of such reprogramming. John et al. show that upon classical activation, macrophages undergo nitric oxide-driven reprogramming of nucleotide metabolism, which affects immune functions and responses.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1681-1702"},"PeriodicalIF":20.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769989","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}

引用次数: 0

BAT mitochondria: whitening meets softening BAT线粒体：美白与软化

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-08-01 DOI: 10.1038/s42255-025-01319-5

Mateus Prates Mori, Oswaldo A. Lozoya, Janine H. Santos

引用次数: 0

2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction 2-羟戊二酸介导棕色脂肪细胞的增白，并偶联线粒体功能障碍的核软化

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-08-01 DOI: 10.1038/s42255-025-01332-8

Harshita Kaul, Lea Isermann, Katharina Senft, Milica Popovic, Theodoros Georgomanolis, Linda Baumann, Pujyanathan Sivanesan, Andromachi Pouikli, Hendrik Nolte, Bojana Lucic, Ximena Hildebrandt, Katrin Seidel, Thorsten Gnad, Felix Gaedke, Ulrike Göbel, Franziska Peters, Maksym Cherevatenko, Joo Hyun Park, Astrid Schauss, Nieves Peltzer, Jens Claus Brüning, Jan-Wilhelm Kornfeld, Alexander Pfeifer, Thomas Langer, Marina Lusic, Sara A. Wickström, Christian Frezza, Aleksandra Trifunovic

{"title":"2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction","authors":"Harshita Kaul, Lea Isermann, Katharina Senft, Milica Popovic, Theodoros Georgomanolis, Linda Baumann, Pujyanathan Sivanesan, Andromachi Pouikli, Hendrik Nolte, Bojana Lucic, Ximena Hildebrandt, Katrin Seidel, Thorsten Gnad, Felix Gaedke, Ulrike Göbel, Franziska Peters, Maksym Cherevatenko, Joo Hyun Park, Astrid Schauss, Nieves Peltzer, Jens Claus Brüning, Jan-Wilhelm Kornfeld, Alexander Pfeifer, Thomas Langer, Marina Lusic, Sara A. Wickström, Christian Frezza, Aleksandra Trifunovic","doi":"10.1038/s42255-025-01332-8","DOIUrl":"10.1038/s42255-025-01332-8","url":null,"abstract":"Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. Here we show that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite d-2-hydroxyglutarate (d-2HG), which in turn promotes lipid droplet enlargement. We further demonstrate that d-2HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2HG are stress responses to mitochondrial dysfunction in BAT. CLPP-deficiency-driven mitochondrial dysfunction in brown adipose tissue leads to the accumulation of d-2-hydroxyglutarate, in turn promoting lipid-droplet enlargement by altering gene expression and epigenetically regulating nuclear stiffness.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1593-1613"},"PeriodicalIF":20.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01332-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Synthetic torpor: advancing metabolic regulation for medical innovations 合成迟钝：促进医学创新的代谢调节

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-07-31 DOI: 10.1038/s42255-025-01345-3

Wenbo Wu, Genshiro A. Sunagawa, Hong Chen

{"title":"Synthetic torpor: advancing metabolic regulation for medical innovations","authors":"Wenbo Wu, Genshiro A. Sunagawa, Hong Chen","doi":"10.1038/s42255-025-01345-3","DOIUrl":"10.1038/s42255-025-01345-3","url":null,"abstract":"Torpor is a naturally occurring state of metabolic suppression that enables animals to adapt and survive extreme environmental conditions. Inspired by this adaptation, researchers have pursued synthetic torpor—an artificially induced, reversible hypometabolic state with transformative medical potential. Achieving synthetic torpor has been pursued for over a hundred years, with earlier work focused on identifying drugs for systemically suppressing metabolism. Breakthroughs in 2020 identified key torpor-regulating neurons in mice, opening new opportunities for neuromodulation-based metabolic control. Synthetic torpor has been applied in animal models for various medical applications, including ischaemic protection, organ preservation, radiation protection and lifespan extension. This Perspective examines the fundamental concepts of natural torpor, advances in approaches to induce synthetic torpor and medical applications of synthetic torpor. The capability of synthetic torpor to suppress whole-body metabolism has the potential to transform medicine by offering novel strategies for medical interventions. Chen et al. provide an overview of historical and more recent approaches for the induction of synthetic torpor, and discuss their potential medical applications.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1511-1523"},"PeriodicalIF":20.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747268","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}

引用次数: 0

Combining a diet rich in fermentable carbohydrates with metformin improves glycaemic control and reshapes the gut microbiota in people with prediabetes 将富含可发酵碳水化合物的饮食与二甲双胍结合起来，可以改善糖尿病前期患者的血糖控制，重塑肠道微生物群

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-07-31 DOI: 10.1038/s42255-025-01336-4

Natural H. S. Chu, James Ling, Emily W. M. Poon, Jimmy Y. S. Lee, Qianbo Song, Zhong Zuo, Jane Muir, Juliana C. N. Chan, Elaine Chow

{"title":"Combining a diet rich in fermentable carbohydrates with metformin improves glycaemic control and reshapes the gut microbiota in people with prediabetes","authors":"Natural H. S. Chu, James Ling, Emily W. M. Poon, Jimmy Y. S. Lee, Qianbo Song, Zhong Zuo, Jane Muir, Juliana C. N. Chan, Elaine Chow","doi":"10.1038/s42255-025-01336-4","DOIUrl":"10.1038/s42255-025-01336-4","url":null,"abstract":"Metformin efficiently lowers blood glucose levels but leads to gastrointestinal side effects. However, whether dietary interventions can improve metformin tolerability and glucose-lowering efficacy remains unknown. Here we investigate the effects of pretreatment with a diet rich in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) in combination with metformin on postprandial glycaemia and gut microbiota in people with prediabetes. In a double-blind, randomised, crossover trial, 26 individuals with prediabetes received an isocaloric diet with moderate or low FODMAPs for 10 d, concomitantly with metformin for 5 d, separated by a washout period of 2 weeks. The primary endpoint is the difference in postprandial glycaemia assessed by total postprandial incremental area under the curve through continuous glucose monitoring. Secondary endpoints are differences in glucose, insulin and glucagon-like peptide 1 (GLP-1) levels after an oral glucose tolerance test, gut microbiota, gastrointestinal symptoms and body weight. We show that moderate FODMAPs with metformin, as compared with low FODMAPs with metformin, result in lower postprandial glycaemia, higher GLP-1 secretion and higher Butyricimonas virosa abundance. We also show that a higher baseline abundance of Dorea formicigenerans predicts gastrointestinal intolerance to metformin. These findings have implications for personalizing nutritional and pharmacological interventions to prevent diabetes. ClinicalTrials.gov registration: NCT05628584 . In this double-blind, randomised, crossover trial, a diet rich in fermentable foods was shown to improve the glucose-lowering efficacy of metformin due, at least in part, to changes in gut microbiota composition.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1614-1629"},"PeriodicalIF":20.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747267","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}

引用次数: 0

Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts 患者肿瘤和匹配异种移植物之间代谢表型的保存和分化

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-07-29 DOI: 10.1038/s42255-025-01338-2

Aparna D. Rao, Ling Cai, Marelize Snyman, Rachel E. Walsdorf, Xiangyi Li, Sophia N. Wix, Gabrielle Gard, Ariel B. Brown, Juliana Kim, Joao Santos Patricio, Sarah Muh, Misty Martin Sandoval, Lauren G. Zacharias, Kristen A. Heimdal, Wen Gu, Jade Homsi, Brittny Tillman, Rohit Sharma, Travis W. Vandergriff, Ashley Solmonson, Brandon Faubert, Thomas P. Mathews, Sean J. Morrison, Ralph J. DeBerardinis, Jennifer G. Gill

{"title":"Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts","authors":"Aparna D. Rao, Ling Cai, Marelize Snyman, Rachel E. Walsdorf, Xiangyi Li, Sophia N. Wix, Gabrielle Gard, Ariel B. Brown, Juliana Kim, Joao Santos Patricio, Sarah Muh, Misty Martin Sandoval, Lauren G. Zacharias, Kristen A. Heimdal, Wen Gu, Jade Homsi, Brittny Tillman, Rohit Sharma, Travis W. Vandergriff, Ashley Solmonson, Brandon Faubert, Thomas P. Mathews, Sean J. Morrison, Ralph J. DeBerardinis, Jennifer G. Gill","doi":"10.1038/s42255-025-01338-2","DOIUrl":"10.1038/s42255-025-01338-2","url":null,"abstract":"Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumour metabolism in patients has not been closely examined. We developed a parallel workflow to analyse [U-13C]glucose tracing and metabolomics data from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labelling, similar to levels in human brain tumours. Although levels of TCA cycle labelling in PDXs were similar to those in the original patient tumours, PDXs had higher labelling in glycolytic metabolites. Through metabolomics, we observed consistent alterations of 100 metabolites among PDXs and patient tumours that reflected species-specific differences in diet, host physiology and microbiota. Despite these differences, most of nearly 200 PDXs retained a ‘metabolic fingerprint’ largely durable over six passages and often traceable back to the patient tumour of origin. This study identifies both high- and low-fidelity metabolites in the PDX model system, providing a resource for cancer metabolism researchers. Rao and Cai et al. perform a detailed metabolic comparison between primary tumours from patients and their matching xenografts, which identify conserved as well as divergent metabolic patterns.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1703-1713"},"PeriodicalIF":20.8,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01338-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

The source of dietary fat influences anti-tumour immunity in obese mice 饮食脂肪的来源影响肥胖小鼠的抗肿瘤免疫

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-07-25 DOI: 10.1038/s42255-025-01330-w

Britta Kunkemoeller, Hannah Prendeville, Claire McIntyre, Ayantu Temesgen, Rόisín M. Loftus, Conghui Yao, Lydia Dyck, Linda V. Sinclair, Christina Rollings, Aaron Douglas, Gerard Pernes, Kathleen A. J. Mitchelson, Cathal Harmon, Mathilde Raverdeau, Ross Ward, Harry Kane, Jaclyn Kline, Katie L. O’Brien, Martin Brennan, Frances Smith, Brenneth Stevens, Helen M. Roche, Ed C. Lavelle, David K. Finlay, Doreen A. Cantrell, Edward T. Chouchani, Susan Kaech, Evanna L. Mills, Marcia Haigis, Lydia Lynch

{"title":"The source of dietary fat influences anti-tumour immunity in obese mice","authors":"Britta Kunkemoeller, Hannah Prendeville, Claire McIntyre, Ayantu Temesgen, Rόisín M. Loftus, Conghui Yao, Lydia Dyck, Linda V. Sinclair, Christina Rollings, Aaron Douglas, Gerard Pernes, Kathleen A. J. Mitchelson, Cathal Harmon, Mathilde Raverdeau, Ross Ward, Harry Kane, Jaclyn Kline, Katie L. O’Brien, Martin Brennan, Frances Smith, Brenneth Stevens, Helen M. Roche, Ed C. Lavelle, David K. Finlay, Doreen A. Cantrell, Edward T. Chouchani, Susan Kaech, Evanna L. Mills, Marcia Haigis, Lydia Lynch","doi":"10.1038/s42255-025-01330-w","DOIUrl":"10.1038/s42255-025-01330-w","url":null,"abstract":"Obesity increases the risk of many cancers and impairs the anti-tumour immune response. However, little is known about whether the source or composition of dietary fat affects tumour growth or anti-tumour immunity in obesity. Here, we show that high-fat diets (HFDs) derived from lard, beef tallow or butter accelerate tumour growth in a syngeneic model of melanoma, but HFDs based on coconut oil, palm oil or olive oil do not, despite equivalent obesity. Using butter-based and palm oil-based HFDs as examples, we find that these dietary fat sources differentially regulate natural killer and CD8 T cell infiltration and function within the tumour microenvironment, governed by distinct effects on the plasma metabolome and intracellular metabolism. We identify diet-related lipid intermediates, namely long-chain acylcarnitine species, as immunosuppressive metabolites enriched in mice fed butter compared to palm oil HFD. Together, these results highlight the significance of diet in maintaining a healthy immune system and suggest that modifying dietary fat may improve cancer outcomes in obesity. This study shows that animal-based high-fat diets accelerate tumour growth and impair anti-tumour response to melanoma in obese mice, whereas plant-based high-fat diets do not.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1630-1645"},"PeriodicalIF":20.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01330-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144702018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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