Nature metabolism最新文献

{"title":"Short-term effects of high-protein, lower-carbohydrate ultra-processed foods on human energy balance","authors":"Franziska A. Hägele, Catrin Herpich, Jana Koop, Jonas Grübbel, Rebecca Dörner, Svenja Fedde, Oliver Götze, Yves Boirie, Manfred J. Müller, Kristina Norman, Anja Bosy-Westphal","doi":"10.1038/s42255-025-01247-4","DOIUrl":"https://doi.org/10.1038/s42255-025-01247-4","url":null,"abstract":"<p>Protein-enriched ultra-processed foods (UPFs) are generally perceived as a healthy and favourable dietary choice for weight management. However, compared with low-processed foods, the consumption of UPFs has been demonstrated to result in overfeeding and gains in body weight and fat mass. Here we investigate the short-term effects of protein-enriched UPFs on energy intake and energy balance in a single-blind crossover trial involving 21 healthy young adults, who were randomly assigned to 2 UPF diets for 54 hours in a whole-room calorimeter. Participants received either a high-protein (30%) and lower-carbohydrate (29%) diet (HPLC-UPF) or a normal-protein (13%) and normal-carbohydrate (46%) diet (NPNC-UPF). Meals were equally palatable, matched for calories, fat and fibre, and consumed ad libitum. As primary outcomes, compared with NPNC-UPF consumption, the HPLC-UPF diet resulted in a higher energy expenditure (128 ± 98 kcal d⁻¹) and lower energy intake (−196 ± 396 kcal d⁻¹), leading to a less-positive energy balance (18% versus 32%) with gains in protein and carbohydrate balance only. Postprandial ghrelin levels were lower, whereas glucagon and peptide YY levels were higher with HPLC-UPF compared with NPNC-UPF (secondary outcomes). Despite a reduction in energy intake and increased energy expenditure, the short-term consumption of protein-enriched UPFs did not prevent overeating but did favourably affect energy partitioning. ClinicalTrials.gov registration: NCT05337007.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"14 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607962","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":"Glycogen drives tumour initiation and progression in lung adenocarcinoma","authors":"Harrison A. Clarke, Tara R. Hawkinson, Cameron J. Shedlock, Terrymar Medina, Roberto A. Ribas, Lei Wu, Zizhen Liu, Xin Ma, Yi Xia, Yu Huang, Xing He, Josephine E. Chang, Lyndsay E. A. Young, Jelena A. Juras, Michael D. Buoncristiani, Alexis N. James, Anna Rushin, Matthew E. Merritt, Annette Mestas, Jessica F. Lamb, Elena C. Manauis, Grant L. Austin, Li Chen, Pankaj K. Singh, Jiang Bian, Craig W. Vander Kooi, B. Mark Evers, Christine F. Brainson, Derek B. Allison, Matthew S. Gentry, Ramon C. Sun","doi":"10.1038/s42255-025-01243-8","DOIUrl":"https://doi.org/10.1038/s42255-025-01243-8","url":null,"abstract":"<p>Lung adenocarcinoma (LUAD) is an aggressive cancer defined by oncogenic drivers and metabolic reprogramming. Here we leverage next-generation spatial screens to identify glycogen as a critical and previously underexplored oncogenic metabolite. High-throughput spatial analysis of human LUAD samples revealed that glycogen accumulation correlates with increased tumour grade and poor survival. Furthermore, we assessed the effect of increasing glycogen levels on LUAD via dietary intervention or via a genetic model. Approaches that increased glycogen levels provided compelling evidence that elevated glycogen substantially accelerates tumour progression, driving the formation of higher-grade tumours, while the genetic ablation of glycogen synthase effectively suppressed tumour growth. To further establish the connection between glycogen and cellular metabolism, we developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth. Our findings support the conclusion that glycogen accumulation drives LUAD cancer progression and provide a framework for integrating spatial metabolomics with translational models to uncover metabolic drivers of cancer.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"13 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589835","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":"Disrupting cholesterol homeostasis in T cells boosts antitumour responses","authors":"Kelly T. Kennewick,&nbsp;Steven J. Bensinger","doi":"10.1038/s42255-025-01240-x","DOIUrl":"10.1038/s42255-025-01240-x","url":null,"abstract":"A new study identifies a mechanism by which Elovl1 deletion disrupts the canonical feedback inhibition of cholesterol synthesis in T cells. By fundamentally rewiring cholesterol metabolism, Elovl1-depleted T cells gain increased fitness and synergize with anti-PD-1 therapy to enhance antitumour responses.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"441-443"},"PeriodicalIF":18.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-025-01240-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582913","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}

{"title":"A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours","authors":"Samantha Pretto,&nbsp;Qian Yu,&nbsp;Pierre Bourdely,&nbsp;Sarah Trusso Cafarello,&nbsp;Heleen H. Van Acker,&nbsp;Joren Verelst,&nbsp;Elena Richiardone,&nbsp;Lotte Vanheer,&nbsp;Amir Roshanzadeh,&nbsp;Franziska Schneppenheim,&nbsp;Charlotte Cresens,&nbsp;Maria Livia Sassano,&nbsp;Jonas Dehairs,&nbsp;Martin Carion,&nbsp;Shehab Ismail,&nbsp;Patrizia Agostinis,&nbsp;Susana Rocha,&nbsp;Tobias Bald,&nbsp;Johan Swinnen,&nbsp;Cyril Corbet,&nbsp;Sophia Y. Lunt,&nbsp;Bernard Thienpont,&nbsp;Mario Di Matteo,&nbsp;Massimiliano Mazzone","doi":"10.1038/s42255-025-01233-w","DOIUrl":"10.1038/s42255-025-01233-w","url":null,"abstract":"Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses. Through a functional CRISPR/Cas9 screening, Pretto et al. identify Elovl1 as a target to improve antitumour immunity by remodelling T cell lipid metabolism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"508-530"},"PeriodicalIF":18.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-025-01233-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582918","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}

{"title":"Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men","authors":"Trine S. Nicolaisen,&nbsp;Aslak E. Lyster,&nbsp;Kim A. Sjøberg,&nbsp;Daniel T. Haas,&nbsp;Christian T. Voldstedlund,&nbsp;Anne-Marie Lundsgaard,&nbsp;Jakob K. Jensen,&nbsp;Ea M. Madsen,&nbsp;Casper K. Nielsen,&nbsp;Mads Bloch-Ibenfeldt,&nbsp;Nicolai J. Wewer Albrechtsen,&nbsp;Adam J. Rose,&nbsp;Natalie Krahmer,&nbsp;Christoffer Clemmensen,&nbsp;Erik A. Richter,&nbsp;Andreas M. Fritzen,&nbsp;Bente Kiens","doi":"10.1038/s42255-025-01236-7","DOIUrl":"10.1038/s42255-025-01236-7","url":null,"abstract":"Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue. Dietary protein restriction in healthy, lean men elicits an increased energy intake to maintain body weight, which is driven, at least in part, by FGF21-mediated alterations to adipose tissue mitochondria.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"602-616"},"PeriodicalIF":18.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-025-01236-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560752","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}

{"title":"ASPiring metabolic-immunotherapy by ASParaginase","authors":"Rushil Shah, Ruoning Wang","doi":"10.1038/s42255-025-01241-w","DOIUrl":"https://doi.org/10.1038/s42255-025-01241-w","url":null,"abstract":"l-Asparaginase (L-ASP) is a standard therapy for leukemias but not solid tumours. In a compassionate-use trial for nasopharyngeal carcinoma, Chang et al. report that L-ASP enhances the anti-tumour T cell response with clinical benefits when combined with pembrolizumab. This study provides proof of concept for ‘metabolic-immunotherapy’ in cancer.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"10 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546243","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":"Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations","authors":"Hsuan-Chia Chang, Chung-Ying Tsai, Cheng-Lung Hsu, Tzong-Shyuan Tai, Mei-Ling Cheng, Yu-Ming Chuang, Hsiang-Yu Tang, Kun-Ju Lin, Jia-Jin Chen, Szu-Han Chang, Yi-Ching Ko, Yu-Wen Chi, Hsuan Liu, Bertrand Chin-Ming Tan, Chia-Rui Shen, Chih-Wei Yang, Ping-Chih Ho, Huang-Yu Yang","doi":"10.1038/s42255-025-01245-6","DOIUrl":"https://doi.org/10.1038/s42255-025-01245-6","url":null,"abstract":"<p>Preclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of <span>l</span>-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The use of <span>l</span>-asparaginase notably enhances immune-checkpoint blockade therapy in patients by strengthening CD8⁺T cell fitness. Our study shows that this combination is a promising avenue for clinical application and provides further mechanistic insight into how asparagine restriction rewires T cell metabolism.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"35 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546247","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":"A western dietary pattern during pregnancy is associated with neurodevelopmental disorders in childhood and adolescence","authors":"David Horner,&nbsp;Jens Richardt M. Jepsen,&nbsp;Bo Chawes,&nbsp;Kristina Aagaard,&nbsp;Julie B. Rosenberg,&nbsp;Parisa Mohammadzadeh,&nbsp;Astrid Sevelsted,&nbsp;Nilo Vahman,&nbsp;Rebecca Vinding,&nbsp;Birgitte Fagerlund,&nbsp;Christos Pantelis,&nbsp;Niels Bilenberg,&nbsp;Casper-Emil T. Pedersen,&nbsp;Anders Eliasen,&nbsp;Sarah Brandt,&nbsp;Yulu Chen,&nbsp;Nicole Prince,&nbsp;Su H. Chu,&nbsp;Rachel S. Kelly,&nbsp;Jessica Lasky-Su,&nbsp;Thorhallur I. Halldorsson,&nbsp;Marin Strøm,&nbsp;Katrine Strandberg-Larsen,&nbsp;Sjurdur F. Olsen,&nbsp;Birte Y. Glenthøj,&nbsp;Klaus Bønnelykke,&nbsp;Bjørn H. Ebdrup,&nbsp;Jakob Stokholm,&nbsp;Morten Arendt Rasmussen","doi":"10.1038/s42255-025-01230-z","DOIUrl":"10.1038/s42255-025-01230-z","url":null,"abstract":"Despite the high prevalence of neurodevelopmental disorders, the influence of maternal diet during pregnancy on child neurodevelopment remains understudied. Here we show that a western dietary pattern during pregnancy is associated with child neurodevelopmental disorders. We analyse self-reported maternal dietary patterns at 24 weeks of pregnancy and clinically evaluated neurodevelopmental disorders at 10 years of age in the COPSAC2010 cohort (n = 508). We find significant associations with attention-deficit hyperactivity disorder (ADHD) and autism diagnoses. We validate the ADHD findings in three large, independent mother–child cohorts (n = 59,725, n = 656 and n = 348) through self-reported dietary modelling, maternal blood metabolomics and foetal blood metabolomics. Metabolome analyses identify 15 mediating metabolites in pregnancy that improve ADHD prediction. Longitudinal blood metabolome analyses, incorporating five time points per cohort in two independent cohorts, reveal that associations between western dietary pattern metabolite scores and neurodevelopmental outcomes are consistently significant in early–mid-pregnancy. These findings highlight the potential for targeted prenatal dietary interventions to prevent neurodevelopmental disorders and emphasise the importance of early intervention. Leveraging four large, longitudinal, prospectively-followed mother–child cohorts, this study shows that a western diet in early–mid-pregnancy is associated with neurodevelopmental disorders in the offspring.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"586-601"},"PeriodicalIF":18.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-025-01230-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532499","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}

{"title":"Gases define redox signalling: NO, H2S, O2 … and cyanide","authors":"Zachary W. Grimmett,&nbsp;Joseph C. Schindler,&nbsp;Jonathan S. Stamler","doi":"10.1038/s42255-025-01229-6","DOIUrl":"10.1038/s42255-025-01229-6","url":null,"abstract":"Discovery of cyanide as an endogenous gas in mammals underscores the common defining principles of redox signalling.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"444-446"},"PeriodicalIF":18.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532864","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":"Regulation of mammalian cellular metabolism by endogenous cyanide production","authors":"Karim Zuhra,&nbsp;Maria Petrosino,&nbsp;Lucia Janickova,&nbsp;Jovan Petric,&nbsp;Kelly Ascenção,&nbsp;Thibaut Vignane,&nbsp;Moustafa Khalaf,&nbsp;Thilo M. Philipp,&nbsp;Stella Ravani,&nbsp;Abhishek Anand,&nbsp;Vanessa Martins,&nbsp;Sidneia Santos,&nbsp;Serkan Erdemir,&nbsp;Sait Malkondu,&nbsp;Barbara Sitek,&nbsp;Taha Kelestemur,&nbsp;Anna Kieronska-Rudek,&nbsp;Tomas Majtan,&nbsp;Luis Filgueira,&nbsp;Darko Maric,&nbsp;Stefan Chlopicki,&nbsp;David Hoogewijs,&nbsp;György Haskó,&nbsp;Andreas Papapetropoulos,&nbsp;Brian A. Logue,&nbsp;Gerry R. Boss,&nbsp;Milos R. Filipovic,&nbsp;Csaba Szabo","doi":"10.1038/s42255-025-01225-w","DOIUrl":"10.1038/s42255-025-01225-w","url":null,"abstract":"Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide. Zuhra and Petrosino et al. report evidence that cyanide acts as a regulatory gasotransmitter in mammalian cells, where it is shown to affect cellular bioenergetics, most likely via protein S-cyanylation.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"531-555"},"PeriodicalIF":18.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-025-01225-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532737","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}