Nature metabolism最新文献

{"title":"Short-chain fatty acids","authors":"Aygul Dagbasi, Mingzhu Cai, Aanya Hirdaramani, Aylin Hanyaloglu, Douglas J. Morrison, Gary Frost","doi":"10.1038/s42255-026-01579-9","DOIUrl":"10.1038/s42255-026-01579-9","url":null,"abstract":"Short-chain fatty acids (SCFAs), principally acetate, propionate and butyrate, are produced by the gut microbiota through the fermentation of non-digestible carbohydrates. Beyond serving as energy substrates, SCFAs act as signalling molecules that influence metabolism, immune function and physiological homeostasis across multiple organ systems. This Review consolidates the fragmented literature on SCFAs and provides an overview of their production, metabolism and physiological actions. We discuss the microbial and dietary determinants of SCFA production, including the roles of the gut microbiome, cross-feeding interactions and dietary carbohydrates. We then examine the mechanisms through which SCFAs exert their effects, focusing on receptor-mediated signalling, epigenetic regulation and tissue-specific physiological functions. Finally, we evaluate the current evidence linking SCFAs to metabolic health and disease and consider the translational potential of targeting SCFA pathways through dietary and therapeutic approaches. At a time when inadequate dietary fibre intake is a growing public health concern, this Review highlights the physiological importance of SCFAs and their potential role in metabolic health and disease prevention. This Review provides an overview of the biology of short-chain fatty acids, with a focus on their synthesis, signalling and physiological effects, highlighting their translational potential for metabolic and inflammatory diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1652-1668"},"PeriodicalIF":27.5,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620527","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":"Microbial catalysts unlock vitamin bioproduction","authors":"Alejandro I. Ramirez, Lukas Ernst, Jay D. Keasling","doi":"10.1038/s42255-026-01584-y","DOIUrl":"10.1038/s42255-026-01584-y","url":null,"abstract":"The sustainable production of vitamin E in microbial cell factories has been restricted to tocotrienol derivatives. In this issue of Nature Metabolism, Zhang, Li and Cao et al. leverage non-classical enzymatic catalysts that are endogenous to Rhodobacter species to engineer a microbial chassis that produces tocopherols at gram scale.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1636-1637"},"PeriodicalIF":27.5,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605609","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 non-classical biosynthetic route enables tocopherol synthesis in bacteria","authors":"Yang Zhang, Zhizhen Li, Lichuang Cao, Yan Wang, Junyi Wang, Haofeng Chen, Wenhao Li, Xinyu Gao, Qingchen Li, Zhengxin Chen, Kaixuan Xu, Xiangpeng Yang, Xiangrui Wu, Jintao Luo, Jianzhong Liu, Jifeng Yuan","doi":"10.1038/s42255-026-01576-y","DOIUrl":"10.1038/s42255-026-01576-y","url":null,"abstract":"Tocopherols have been widely applied in healthcare, medicine, animal feed and other fields. However, microbial synthesis of tocopherols with industrial potential has not been accomplished yet. Here we report a non-classical biosynthetic route for tocopherol synthesis in Rhodobacter species that bypasses the classical α-tocopherol pathway requiring the 2,3-dimethyl-5-phytyl-1,4-benzoquinone (DMPBQ) as an intermediate. In particular, a Rhodobacter methyltransferase with bifunctional γ/β-tocopherol methyltransferase activities is identified, which can directly synthesize α-tocopherol from δ-tocopherol and γ/β-tocopherols. Furthermore, geranylgeranyl pyrophosphate reductase (GR) plays an important role in reducing tocotrienols into tocopherols. Through systematic metabolic engineering, the engineered Rhodobacter sphaeroides produced a total titer of 508.21 mg l−1 tocopherols in shake flasks, and 3.51 g l−1 under the fed-batch fermentation after process optimization. Taken together, these results offer a non-classical biosynthetic pathway for efficient tocopherol biosynthesis, which would pave the way for future commercial production of tocopherols by microbial fermentation. The study reports a non-classical tocopherol pathway in Rhodobacter that enables heterologous α-tocopherol synthesis by bypassing DMPBQ via a γ/β-tocopherol methyltransferase.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1805-1817"},"PeriodicalIF":27.5,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605533","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":"Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism","authors":"Jo Edward Lewis, Mireia Montaner, Danae Nuzzaci, Paula-Peace James-Okoro, Norio Harada, Nobuya Inagaki, W. Scott Dodson, Patrick J. Knerr, Jonathan D. Douros, Fiona Mary Gribble, Frank Reimann","doi":"10.1038/s42255-026-01575-z","DOIUrl":"10.1038/s42255-026-01575-z","url":null,"abstract":"The development of dual agonists for the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has been a landmark moment in the treatment of type 2 diabetes and obesity. However, for reasons that are incompletely understood, in preclinical and clinical studies, adding either a GIPR agonist or GIPR antagonist to GLP-1R agonism causes additional weight loss1. Here we show that distinct brain regions mediate the appetite-suppressing effects of GIPR agonists and the synergistic weight loss effects conferred by GIPR antagonists. We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide. GiprAP-KO mice exhibit partial protection against diet-induced obesity, reduced responsiveness to the appetite-suppressing effects of acyl-GIP and a reduced ability of acyl-GIP to prevent avoidance triggered by peptide YY. Weight loss effects of liraglutide are comparable in GiprAP-KO and control mice, and the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups. Giprhypo-KO mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice. Giprhypo-KO also abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide—an effect that is not mediated by nucleus tractus solitarius preproglucagon neurons. GIPR antagonism and Giprhypo-KO also sensitise to cagrilintide-induced weight loss. Overall, our results suggest that the AP is responsible for the appetite-suppressing effects of GIPR agonism but that GIP receptors in the hypothalamus underlie the ability of GIPR antagonism to enhance the weight loss effects of GLP-1R and amylin receptor agonists. The study employs region-specific knockout of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in either the area postrema or hypothalamus of mice to determine how GIPR agonism and antagonism regulate food intake and body weight via distinct brain regions.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1669-1678"},"PeriodicalIF":27.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01575-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148585037","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":"Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer","authors":"Deborah Y. Moss, Connor N. Brown, Andrew M. Shaw, Christopher McCann, Nikita Lewis, Matilda Downs, Rebecca Wurelly, Ciara Cunningham, Aaron Philips, Niamh Doherty, Sarah Gallagher, William J. McDaid, Andrew Roe, Aisling Y. Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Sudhir B. Malla, Alexandra J. Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Aoife Leonard, Peter F. Gallagher, Arindam Banerjee, Sandra Van Schaeybroeck, Sufyan Pandor, Brian Quinn, Brett Greer, Christopher Elliott, Sarah Maguire, Aideen E. Ryan, Philip D. Dunne, Mary Mallon, Stephanie Craig, Omar Aftab, Laura C. Greaves, Bryan P. Marzullo, Daniel A. Tennant, Vicky Coyle, Ian G. Mills, Owen Sansom, Tríona Ní Chonghaile, Daniel B. Longley, Simon S. McDade, Melissa J. LaBonte, Emma M. Kerr","doi":"10.1038/s42255-026-01578-w","DOIUrl":"10.1038/s42255-026-01578-w","url":null,"abstract":"Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes. Mitochondrial oxidative metabolism is found to strongly affect the response of colorectal cancer (CRC) cells to the chemotherapeutic drug 5-fluorouracil (5FU). Targeting mitochondrial metabolism sensitizes CRC cells to 5FU.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1751-1771"},"PeriodicalIF":27.5,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01578-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579367","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":"Lipids in ovarian cancer ascites impair T cell activation by disrupting TCR dynamics","authors":"Erica G. Brown, Ewoud B. Compeer, Zhiyang Gan, Andre R. Kelly, Alexander A. Shestov, Laura Córdoba-Espejo, Mitchell T. Evans, Alan Y. Liu, Noelle H. Naughton, Tanay S. Parnaik, Jemma H. Larson, Bruce R. Blazar, Caroline R. Bartman, Joshua D. Rabinowitz, Michael L. Dustin, Daniel J. Powell Jr, Roddy S. O’Connor","doi":"10.1038/s42255-026-01557-1","DOIUrl":"10.1038/s42255-026-01557-1","url":null,"abstract":"T cell-based therapies have limited success against ovarian cancer for poorly understood reasons. Here we show that lipids in ovarian cancer ascites fluid disrupt nanoscale T cell receptor dynamics-driven T cell activation. T cells stimulated in ascites of patients with ovarian cancer have an altered lipid profile, including changes in phosphatidylcholine (PC) and phosphatidylethanolamine content, and disrupted membrane properties. Using untargeted lipidomics, we reveal which lipid species are consumed by T cells in ascites and show that 18:0–18:2 PC impairs T cell activation at physiological concentrations. Mechanistically, we uncover that lipids in ascites, including 18:0–18:2 PC, disrupt nanoscale T cell receptor clustering in immunological synapses. Importantly, pre-activated T cells overcome these lipid-induced barriers, highlighting a promising strategy to enhance adoptive T cell-based therapies for ovarian cancer. These findings provide mechanistic insights into lipid-mediated immune suppression in the tumour microenvironment and an actionable strategy to overcome these barriers. This study demonstrates that lipids in ascites impair T cell activation through disrupting TCR dynamics, which has translational implications for adoptive T cell therapies.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1508-1527"},"PeriodicalIF":27.5,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148552311","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":"Ascites-derived lipid barrier at the T cell synapse","authors":"Teresa Manzo","doi":"10.1038/s42255-026-01564-2","DOIUrl":"10.1038/s42255-026-01564-2","url":null,"abstract":"Ovarian cancer ascites can blunt T cell attack, but the earliest steps affected have remained unclear. In this issue of Nature Metabolism, Brown et al. show that ascites-derived lipids disrupt T cell receptor organization and early activation, revealing a synaptic barrier to immunity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1455-1456"},"PeriodicalIF":27.5,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148552300","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 impact of microbial metabolites on host chromatin and epigenetic regulation","authors":"Tohfa Kabir, Zoe K. Lawler, Leah A. Gates","doi":"10.1038/s42255-026-01577-x","DOIUrl":"10.1038/s42255-026-01577-x","url":null,"abstract":"The chemical diversity of histone post-translational modifications (PTMs), or histone marks, has been greatly expanded with the discovery of understudied and emerging modifications. The microbiome and microbial metabolites have been identified as crucial regulators of these novel PTMs, many of which have key roles in gene regulation. Thus, select histone marks represent a mechanism of host–microbe interaction via chromatin. This Perspective details the emerging roles of histone marks in gene regulation and host physiology. We discuss how these PTMs are regulated by microbial metabolism and the molecular mechanisms of how these microbiota-dependent histone PTMs affect host gene expression. We also highlight examples of the functional roles of these histone marks in physiology and disease, with a focus on the intestine and associated tissues. Understanding the mechanistic link between the microbiota and the host epigenome, particularly emerging histone marks, provides new avenues of how microbial metabolites influence host physiology. This Perspective describes the emerging roles of microbiota-derived metabolites in influencing host chromatin and thereby gene regulation and host physiology.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1638-1651"},"PeriodicalIF":27.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549704","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":"Endocrine-like regulation through brown fat-secreted microRNAs","authors":"","doi":"10.1038/s42255-026-01570-4","DOIUrl":"10.1038/s42255-026-01570-4","url":null,"abstract":"In vivo, 4-thiouracil-based, tissue-specific microRNA labelling highlights the endocrine role of brown adipose tissue-derived microRNAs that are taken up by and regulate metabolic function in peripheral tissues such as muscle, liver and hypothalamus.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1462-1463"},"PeriodicalIF":27.5,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148459522","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":"Brown fat-specific RNA labelling reveals a network of inter-organ communication by secreted microRNAs","authors":"Marsel Lino, Gabriel Palermo-Ruiz, Vissarion Efthymiou, Alice Rodrigues, Shraddha Bhonsle, Allah Nawaz, Anindya Ghosh, Bruna Brasil Brandão, Yoshiyuki Watanabe, Rafael Barrera Salgueiro, Yingying Yu, C. Ronald Kahn","doi":"10.1038/s42255-026-01558-0","DOIUrl":"10.1038/s42255-026-01558-0","url":null,"abstract":"Extracellular microRNAs (miRNAs) are emerging as key regulators of organismal homeostasis. Here, using tissue-specific RNA labelling based on uracil phosphoribosyltransferase-mediated incorporation of 4-thiouracil in male mice, we develop a roadmap of miRNA transfer from brown adipose tissue (BAT) to other tissues, where they can act to regulate energy metabolism. We show that BAT secretes miRNAs in both small extracellular vesicles and is associated with plasma proteins, and that miRNAs in both compartments exhibit tissue-selective uptake in the liver, muscle and hypothalamus. Disruption of Dicer in BAT leads to a significant depletion of multiple miRNAs in both BAT and distal tissues, including 80–90% decreases in the most abundant miRNAs in muscle. Target analyses, in vitro modelling and PAR-CLIP analysis in muscle in vivo confirm that these BAT-secreted miRNAs directly interact with target mRNAs and alter mitochondrial function in recipient tissues. These findings provide a framework for understanding the role of BAT-secreted miRNAs in inter-organ communication. This study uses in vivo, 4TU-based, tissue-specific miRNA labelling to highlight the endocrine role of BAT-derived miRNAs that are taken up by tissues like the muscle, liver and hypothalamus, and demonstrates their role in regulating metabolic function in tissues such as muscle.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1583-1602"},"PeriodicalIF":27.5,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01558-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148459751","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}