Nature metabolism最新文献

{"title":"Polygenic determinants of monogenic diabetes","authors":"Rashmi B. Prasad, Tiinamaija Tuomi","doi":"10.1038/s42255-025-01380-0","DOIUrl":"10.1038/s42255-025-01380-0","url":null,"abstract":"In a new study, the polygenic background of type 2 diabetes (T2D) is found to determine the risk of diabetes associated with so-called monogenic forms of β-cell diabetes, as well as the age at onset and severity of diabetes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1723-1724"},"PeriodicalIF":20.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018066","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":"An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells","authors":"Faith C. Kaluba, Thomas J. Rogers, Yu-Jin Jeong, Rachel ‘Rae’ J. House, Althea Waldhart, Kelly H. Sokol, Samuel R. Daniels, Cameron J. Lee, Joseph Longo, Amy Johnson, Vincent J. Sartori, Ryan D. Sheldon, Russell G. Jones, Evan C. Lien","doi":"10.1038/s42255-025-01366-y","DOIUrl":"10.1038/s42255-025-01366-y","url":null,"abstract":"Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows β-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouse KrasG12D; Trp53−/− pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use β-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth. Kaluba, Rogers et al. show that in cancer cells that can metabolize ketones, they may reroute them to produce cytosolic acetyl-CoA and support tumour growth.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2033-2044"},"PeriodicalIF":20.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01366-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009292","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":"ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation","authors":"Olivia I. Coleman, Adam Sorbie, Alessandra Riva, Miriam von Stern, Stephanie Kuhls, Denise M. Selegato, Luisa Siegert, Isabel Keidel, Nikolai Köhler, Jakob Wirbel, Tim Kacprowski, Andreas Dunkel, Josch K. Pauling, Johannes Plagge, Diego Mediel-Cuadra, Sophia J. Wagner, Ines Chadly, Sandra Bierwith, Tingying Peng, Thomas Metzler, Xin Li, Mathias Heikenwälder, Clemens Schafmayer, Sebastian Hinz, Christian Röder, Christoph Röcken, Michael Zimmermann, Philip Rosenstiel, Katja Steiger, Moritz Jesinghaus, Gerhard Liebisch, Josef Ecker, Christina Schmidt, Georg Zeller, Klaus-Peter Janssen, Dirk Haller","doi":"10.1038/s42255-025-01350-6","DOIUrl":"10.1038/s42255-025-01350-6","url":null,"abstract":"Endoplasmic reticulum unfolded protein responses contribute to cancer development, with activating transcription factor 6 (ATF6) involved in microbiota-dependent tumorigenesis. Here we show the clinical relevance of ATF6 in individuals with early-onset and late colorectal cancer, and link ATF6 signalling to changes in lipid metabolism and intestinal microbiota. Transcriptional analysis in intestinal epithelial cells of ATF6 transgenic mice (nATF6IEC) identifies bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype labelling confirm ATF6-related enrichment of long-chain fatty acids in colonic tissue of humans, mice and organoids. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirm the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumour-relevant microbial taxa, including Desulfovibrio fairfieldensis, is mechanistically linked to long-chain fatty acid exposure using bioorthogonal non-canonical amino acid tagging, and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signalling to select for tumour-promoting microbiota by altering lipid metabolism. The transcription factor ATF6 causes an enrichment in long-chain fatty acids in the colonic epithelium, which leads to changes in the gut microbiota and contributes to the development of colorectal cancer in humans and mice, thereby linking endoplasmic reticulum stress responses to lipid metabolism and tumorigenesis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1830-1850"},"PeriodicalIF":20.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01350-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144924214","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":"Mitochondria transfer","authors":"Navdeep S. Chandel, Marni J. Falk, Janine H. Santos, Jonathan R. Brestoff, Ana V. Lechuga-Vieco, Yasemin S. Sancak, Quan Chen, Alvaro A. Elorza, Rubén Quintana-Cabrera","doi":"10.1038/s42255-025-01364-0","DOIUrl":"10.1038/s42255-025-01364-0","url":null,"abstract":"Intercellular mitochondria transfer has recently attracted substantial attention, both from a fundamental and therapeutic point of view. At the same time, the topic continues to be met with scepticism. In this Viewpoint, different experts in mitochondrial biology share their personal view on the topic.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1716-1719"},"PeriodicalIF":20.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905910","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":"Dual gains from targeting MondoA in T cells","authors":"Ermei Xie, Guideng Li","doi":"10.1038/s42255-025-01329-3","DOIUrl":"10.1038/s42255-025-01329-3","url":null,"abstract":"Lactic acid activates the MondoA–TXNIP pathway, dampening CD8⁺ T cell responses and boosting regulatory T cell function. Inhibiting MondoA revives antitumour immunity and amplifies the effects of anti-PD-1 treatment.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1725-1727"},"PeriodicalIF":20.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900204","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":"Targeting MondoA–TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment","authors":"Nannan Xu, Yemin Zhu, Yichao Han, Qi Liu, Lingfeng Tong, Yakui Li, Zhangbing Chen, Sijia Shao, Wenrui He, Mingrui Li, Yi Wang, Siyuan Qiang, Peiwei Chai, Peng Du, Wenyi Zhao, Lifang Wu, Ping Zhang, Jianli He, Hecheng Li, Jinke Cheng, Renbing Jia, Bin Li, Ying Lu, Xuemei Tong","doi":"10.1038/s42255-025-01347-1","DOIUrl":"10.1038/s42255-025-01347-1","url":null,"abstract":"In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg cells, loss of MondoA enhanced CD8+ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA–TXNIP axis, which impaired TCR/CD28-signal-induced CD8+ T cell activation. Importantly, targeting the MondoA–TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA–TXNIP axis is a promising therapeutic target for improving cancer immunotherapy. Xu et al. identify the MondoA–TXNIP signalling axis as a regulator of antitumour immune surveillance in response to lactic acid in the tumour microenvironment.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1889-1904"},"PeriodicalIF":20.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900203","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":"Investigating metabolic changes in single embryos during early development in Drosophila","authors":"","doi":"10.1038/s42255-025-01375-x","DOIUrl":"10.1038/s42255-025-01375-x","url":null,"abstract":"Metabolism is dynamic during early development in animals. To study this process, we developed a single-embryo metabolomics and transcriptomics method that captures rapid, small-scale changes in metabolism and how they coordinate with gene expression. Our work showcasing this method in Drosophila embryos provides a valuable resource for understanding developmental systems biology.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1972-1973"},"PeriodicalIF":20.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900305","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":"Lighting up targets of dual agonist therapies for diabetes and obesity","authors":"","doi":"10.1038/s42255-025-01346-2","DOIUrl":"10.1038/s42255-025-01346-2","url":null,"abstract":"Dual incretin agonists, such as tirzepatide (a GLP1R–GIPR agonist), show excellent efficacy for type 2 diabetes and obesity therapy. Research identifies the cells and neurons in the pancreas and brain that are targeted by dual agonists, providing further details on their modes of action.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1507-1508"},"PeriodicalIF":20.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883259","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":"Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain","authors":"Anne de Bray, Anna G. Roberts, Sarah Armour, Jason Tong, Christiane Huhn, Blaise Gatin-Fraudet, Kilian Roßmann, Ali H. Shilleh, Wanqing Jiang, Natalie S. Figueredo Burgos, James P. P. Trott, Katrina Viloria, Daniela Nasteska, Abigail Pearce, Satsuki Miyazaki, Jeremy W. Tomlinson, Dylan M. Owen, Daniel J. Nieves, Julia Ast, Malgorzata Cyranka, Alexey Epanchintsev, Carina Ämmälä, Frank Reimann, Tolga Soykan, Graham Ladds, Alice E. Adriaenssens, Stefan Trapp, Ben Jones, Johannes Broichhagen, David J. Hodson","doi":"10.1038/s42255-025-01342-6","DOIUrl":"10.1038/s42255-025-01342-6","url":null,"abstract":"Dual agonists targeting glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are breakthrough treatments for patients with type 2 diabetes and obesity. Compared to GLP1R agonists, dual agonists show superior efficacy for glucose lowering and weight reduction. However, delineation of dual agonist cell targets remains challenging. Here, we develop and test daLUXendin and daLUXendin+, non-lipidated and lipidated fluorescent GLP1R/GIPR dual agonist probes, and use them to visualize cellular targets. daLUXendins are potent GLP1R/GIPR dual agonists that advantageously show less functional selectivity for mouse GLP1R over mouse GIPR. daLUXendins label rodent and human pancreatic islet cells, with a signal intensity of β cells > α cells = δ cells. Systemic administration of daLUXendin strongly labels GLP1R+ and GIPR+ neurons in circumventricular organs characterized by an incomplete blood–brain barrier but does not penetrate the brain beyond labelling seen with single (ant)agonists. At the single-molecule level, daLUXendin targets endogenous GLP1R–GIPR nanodomains, which differ in organization and composition from those targeted by a single agonist. daLUXendins reveal dual agonist targets in the pancreas and brain and exclude a role for brain penetration in determining the superior efficacy of dual agonists, shedding new light on different modes of action of dual agonists versus single agonists. A series of fluorescent probes is designed that act as dual agonists on both GLP1 and GIP receptors, and are used to image receptor binding activities in tissues and animals.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1536-1549"},"PeriodicalIF":20.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883258","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":"Metabolic Messenger: growth differentiation factor 15","authors":"Samuel N. Breit, Vicky W. Tsai","doi":"10.1038/s42255-025-01353-3","DOIUrl":"10.1038/s42255-025-01353-3","url":null,"abstract":"Growth differentiation factor 15 (GDF15; also known as macrophage-inhibitory cytokine-1) is a stress-responsive cytokine that is overexpressed under a broad range of conditions. It has a role in regulating appetite and body weight and is an aetiological factor in anorexia–cachexia syndromes, as well as nausea and vomiting during pregnancy. Long after its original cloning, its receptor was identified as GFRAL, a distant member of the GDNF receptor family within the TGFβ superfamily, with RET as its co-receptor. Both of these are highly localized to specific hindbrain regions. Although many of GFRAL’s metabolic changes may be linked to its effect on suppressing appetite, recent findings suggest that GDF15 also independently regulates energy expenditure and insulin sensitivity. Here, we review recent literature and provide updates on the current understanding of GDF15 biology and its therapeutic applications in health and metabolic diseases. Breit and Tsai provide a concise overview of the role of GDF15 as a signalling molecule in the context of metabolic health and disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1732-1744"},"PeriodicalIF":20.8,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874235","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}