Nature metabolism最新文献

{"title":"FXR's double life in bile ducts.","authors":"Shogo Takahashi,Frank J Gonzalez","doi":"10.1038/s42255-026-01528-6","DOIUrl":"https://doi.org/10.1038/s42255-026-01528-6","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754741","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":"Tissue-trained fibroblasts fuel invasion with lipids.","authors":"Gul Muneer,Sara Zanivan","doi":"10.1038/s42255-026-01501-3","DOIUrl":"https://doi.org/10.1038/s42255-026-01501-3","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"23 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147753030","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":"Tissue-specific fibroblast lipid cues impose the rate of epithelial cancer invasion","authors":"Timothy Budden, Noah Palombo, Shilpa Gurung, Martha Gutteridge, Charlotte Russell, Jair Marques, Alex von Kriegsheim, Lyutong An, Catherine Harwood, Luisa Motta, Claus Jorgensen, Carlos López-Garcîa, Caroline Gaudy-Marqueste, Kevin Harrington, Malin Pedersen, Ben O’Leary, Antonio Rullan, Amaya Virós","doi":"10.1038/s42255-026-01514-y","DOIUrl":"https://doi.org/10.1038/s42255-026-01514-y","url":null,"abstract":"Squamous cell carcinomas (SCCs) originate in epithelial tissues of older individuals who have been exposed to environmental carcinogens. Despite overlapping clinical hallmarks, SCCs from different anatomic sites have different prognoses. Here we show that fibroblasts confer site-specific cues that determine SCC proliferation and invasion. Oral and lung fibroblasts have distinct lipid metabolism, transferring unique lipids to SCC cells that promote epithelial-to-mesenchymal transition, and oral and lung SCC invasion. Whereas oral fibroblasts transfer sphingomyelins, which activate the ceramide–sphingosine-1-phosphate–STAT3 pathway and promote oral SCC invasion, lung fibroblasts transfer triglycerides to lung SCCs, thereby triggering cholesterol synthesis and invasion, which is associated with poor survival. By contrast, dermal fibroblasts are lipid poor, and cutaneous SCC is less invasive. Our data indicate that targeting fibroblast lipid synthesis and SCC lipid uptake or breakdown inhibits oral and lung epithelial cancer invasion.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"21 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751814","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":"Islet cell DNA methylation in human ageing and diabetes","authors":"Emily Hodges, Guoqiang Gu","doi":"10.1038/s42255-026-01502-2","DOIUrl":"10.1038/s42255-026-01502-2","url":null,"abstract":"Ageing and genetic predisposition increase the risk of type 2 diabetes (T2D). Two studies published in this issue of Nature Metabolism show that the DNA methylome in islet α and β cells changes with ageing and the development of T2D. Genes associated with these changes are enriched for those linked to α or β-cell function, and to T2D.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 4","pages":"772-773"},"PeriodicalIF":20.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147739148","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":"Epigenetic adaptation of beta cells across lifespan and disease","authors":"Elisabetta Manduchi, Hélène C. Descamps, Jinping Liu, Jonathan Schug, Tong Da, Deeksha Lahori, Hilana El-Mekkoussi, Michelle Lee, Eseye Feleke, Diana Bernstein, Chengyang Liu, Ali Naji, Benjamin Glaser, Klaus H. Kaestner, Dana Avrahami","doi":"10.1038/s42255-026-01495-y","DOIUrl":"10.1038/s42255-026-01495-y","url":null,"abstract":"Although the prevalence of type 2 diabetes (T2D) increases with age, most adults maintain normoglycaemia despite rising insulin resistance owing to the adaptive capacity of pancreatic beta cells to meet increased metabolic demand. However, persistent insulin resistance can lead to beta cell dysfunction and T2D onset. Here we show the mapping of genome-wide DNA methylation (DNAm) patterns and the epigenomic basis of beta cell adaptations by leveraging cell-type-specific methylome data from the Human Pancreas Analysis Program. In healthy donors, we identify progressive age-related demethylation enriched in cis-regulatory elements at beta cell identity and function genes. By contrast, alpha cells show the opposite trajectory, with subtle, age-related hypermethylation. In T2D beta cells, but not alpha cells, we observed further demethylation compared to healthy controls, underscoring a unique capacity of beta cells to respond to changes in metabolic demand. Together, our findings suggest that DNAm remodelling in healthy beta cells reflects a long-term adaptation to metabolic demand, which, in T2D, is accelerated as part of a compensatory response that ultimately fails under sustained insulin resistance. Mapping of genome-wide DNA methylation patterns in human islet alpha and beta cells highlights age and type 2 diabetes dependent adaptations and compensatory responses to altered metabolic demands.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 4","pages":"941-956"},"PeriodicalIF":20.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01495-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147739146","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":"Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes","authors":"Jones K. Ofori, Sabrina Ruhrmann, Axel Lindström, Alexander Perfilyev, Melina Martin, Alexandros Karagiannopoulos, Lucia Scisciola, Katja Kost, Josefine Jönsson, Åsa Nilsson, Boris Kantor, Monika Dudenhöffer-Pfeifer, Marianne G. Rots, Anna Wendt, Tina Rönn, Lena Eliasson, Karl Bacos, Charlotte Ling","doi":"10.1038/s42255-026-01498-9","DOIUrl":"10.1038/s42255-026-01498-9","url":null,"abstract":"Epigenome-wide studies of pancreatic islets provide valuable insights into type 2 diabetes (T2D) but lack methylomes from individual cell types. Here we show changes to alpha and beta cell-specific methylomes and transcriptomes from people with or without T2D, using whole-genome bisulfite sequencing and RNA sequencing. We discover 22,544 differentially methylated regions annotated to 7,975 genes in alpha versus beta cells, such as INS, GCG, PDX1 and PCSK1, with ~50% showing differential expression. CRISPR–dCas9–DNMT3A-based epigenetic editing increases INS and TH DNA methylation, while CRISPR–dCas9–TET1-based editing decreases GCG methylation, each altering INS, TH or GCG expression and content in beta cells. Pre-T2D/T2D-associated differentially methylated regions in alpha and beta cells overlap 12–18% of T2D-associated genome-wide association study candidates. Additionally, ONECUT2 is epigenetically upregulated in beta cells from people with pre-T2D/T2D and elevated in male Goto-Kakizaki rat islets. ONECUT2 overexpression in beta cells/islets downregulates gene sets impacting insulin secretion and glucose homeostasis, and reduces mitochondrial activity, ATP/ADP ratio and insulin secretion. We also provide ‘alpha-beta-methylome’ ( https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/ ), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D. Mapping of genome-wide DNA methylation patterns in human islet alpha and beta cells highlights age- and type 2 diabetes-dependent adaptations, and CRISPR-based epigenetic editing strategies validate key targets in human islet beta cells.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 4","pages":"957-980"},"PeriodicalIF":20.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01498-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147739147","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":"Measuring eating patterns in real life reveals high variability in timing and choices","authors":"","doi":"10.1038/s42255-026-01503-1","DOIUrl":"10.1038/s42255-026-01503-1","url":null,"abstract":"Using 10–14 days of time-stamped food intake logs on a smartphone app from more than 20,000 adults, this study shows that both meal timing and food choice are highly variable in real-world settings, with only a small fraction of individuals maintaining consistent first and last eating times or eating the same foods regularly.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 4","pages":"776-777"},"PeriodicalIF":20.8,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147735523","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":"The diversity and consistency of what and when people eat","authors":"Tyler Tran, Emily N. C. Manoogian, Zhaoyi Joey Hou, Shweta Varshney, Jialu Sui, Kyla L. Laing, Jason G. Fleischer, Satchidananda Panda","doi":"10.1038/s42255-026-01504-0","DOIUrl":"10.1038/s42255-026-01504-0","url":null,"abstract":"The timing and types of food that people eat, along with associated daily fluctuations, can influence health and wellbeing. However, there are limited data on how eating patterns remain consistent over multiple days. Here we present an exploratory, cross-sectional analysis of over 20,000 adults who recorded more than 2.5 million food logs over 2 weeks using the myCircadianClock app. Our analysis reveals significant variability in food timing and diversity. The time window during which 95% of food and beverages were consumed ranged from 10 h 54 min for the lowest decile to over 16 h for the highest. The median number of unique food and beverage items consumed over the 2 weeks varied from 20 to 86, and only a subset was consistently eaten on multiple days. Many common foods were regularly consumed at specific times of the day, and factors like age, gender and work schedules influenced both eating patterns and food choices. These findings provide a foundation for using longitudinal food records in nutrition and lifestyle research to enhance our understanding of human behaviour and health. An exploratory, observational analysis involving 2.5 million food logs from over 20,000 adults across 2 weeks highlights both consistent and divergent patterns in food habits that may, in turn, influence human health.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 4","pages":"981-997"},"PeriodicalIF":20.8,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01504-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147734044","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 conserved hormonal signalling-H2A.Z axis rapidly reorganizes 3D chromatin interactions in adipocyte thermogenesis.","authors":"Yang Zhang,Rongbin Zheng,Tadataka Tsuji,Chih-Hao Wang,Xiang-Yu Liu,Yu-Hang Xing,Justin Darcy,Matthew D Lynes,Morten Lundh,Rini Arianti,Ferenc Győry,Rui Dong,Brice Emanuelli,Sarah E Johnstone,Miguel N Rivera,Endre Kristóf,C Ronald Kahn,Kaifu Chen,Yu-Hua Tseng","doi":"10.1038/s42255-026-01510-2","DOIUrl":"https://doi.org/10.1038/s42255-026-01510-2","url":null,"abstract":"Three-dimensional genome organization underlies gene regulation, yet how acute hormonal signalling reshapes chromatin structure to control metabolism remains unclear. β3-adrenergic receptor (β3-AR) hormonal signalling drives adipocyte thermogenesis. Here, we show three-dimensional genome maps of mouse and primary human brown adipocytes during thermogenesis using Micro-C. We find that β3-AR signalling rapidly reorganizes chromatin loops within 4 h, with dynamically gained loops coupled to thermogenic gene activation in both species. Mechanistically, β3-AR stimulation promotes histone variant H2A.Z deposition to enhance chromatin accessibility at loop anchors, facilitating the recruitment of bridging factor MED1. Loss of H2A.Z compromises loop formation and thermogenic gene activation across species. Brown fat-specific H2A.Z deficiency in mice impairs thermogenic activity and glucose tolerance. Integration with genome-wide association studies links H2A.Z-occupied loops to genetic variants associated with obesity and related metabolic disorders. Together, our findings uncover a cross-species conserved β3-AR signalling-H2A.Z axis that rapidly reorganizes chromatin interactions in adipocyte thermogenesis, providing mechanistic and translational insights into metabolic regulation.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"22 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731317","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":"Redox rhythms promote fitness by modulating ageing-dependent reprogramming.","authors":"Xiaoman Wang,Shen-Shen Cui,Xun-Kai Li,Si-Yao Qu,Wei-Wei Chang,Ao Tang,Yu Jin,Shi-Juan Peng,He-Ping Wang,Xue-Qin Fang,Li-Yuan Lu,Chen-Xi Lv,Xin Yu,Jing-Yao Peng,Si-Si Wang,Zi-Yu Wei,Yu-Tong Zhu,Hui-Yu Wang,Jia-Qi Fu,Wen-Qi Li,Ying-Ying Jin,Hou-Zao Chen,Jian-Fei Pei,De-Pei Liu","doi":"10.1038/s42255-026-01515-x","DOIUrl":"https://doi.org/10.1038/s42255-026-01515-x","url":null,"abstract":"Ageing leads to diurnal misalignment with a global reduction in physiological fitness, yet the mechanisms underlying such age-related diurnal reprogramming and its role in ageing remain poorly understood. Here we generate diurnal transcriptomes across eight peripheral tissues and reveal that disrupted redox oscillations are common diurnal alterations in organismal ageing. Restoring redox rhythms through the time-restricted application of antioxidants and pro-oxidants markedly improved glucose metabolism, motor performance and ageing-related characteristics of liver and skeletal muscle in male aged mice. Through multi-omics analyses we further reveal that restoring redox rhythms partially rejuvenates the hepatic transcriptome and chromatin accessibility in ageing-associated functional pathways and involves redox modification of CLOCK protein. Perturbing redox-sensitive cysteine 195 of CLOCK causes premature ageing phenotypes and hepatic reprogramming. Overall, our study reveals that redox rhythms ameliorate functional decline by modulating ageing-relevant reprogramming in liver and skeletal muscle and indicates that redox rhythm-based interventions might promote healthy ageing.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"19 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702262","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}