Nature metabolism最新文献

{"title":"Artificial intelligence in metabolic research.","authors":"Jens Juul Holst, Camilla Schéele, Philipp E Scherer, Weiping Jia, Eran Segal, Nikolai Slavov, Ruth J F Loos, Golnaz Vahedi, Lei Sun, M Madan Babu, Melissa D McCradden, Peter G Jacobs","doi":"10.1038/s42255-025-01395-7","DOIUrl":"https://doi.org/10.1038/s42255-025-01395-7","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213199","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":"DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.","authors":"Saber H Saber,Nyakuoy Yak,Xuan Ling Hilary Yong,Yih Tyng Bong,Hannah Leeson,Chuan-Yang Dai,Tobias Binder,Siyuan Lu,Reshinthine Purushothaman,An-Sofie Lenaerts,Leonardo Almeida-Souza,Lidiia Koludarova,Safak Er,Irena Hlushchuk,Arnaud Gaudin,Sachin Singh,Tuula A Nyman,Jeffrey R Harmer,Steven Zuryn,Ernst Wolvetang,Gert Hoy Talbo,Mikko Airavaara,Brendan J Battersby,Ashley J van Waardenberg,Victor Anggono,Giuseppe Balistreri,Merja Joensuu","doi":"10.1038/s42255-025-01367-x","DOIUrl":"https://doi.org/10.1038/s42255-025-01367-x","url":null,"abstract":"Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production in Ddhd2 knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused by DDHD2 mutations.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"24 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194932","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":"Shooting for the stars: caspase-8-meteorin in MASH and fibrosis.","authors":"Suchira Gallage,Tabea Bieler,Mathias Heikenwalder","doi":"10.1038/s42255-025-01361-3","DOIUrl":"https://doi.org/10.1038/s42255-025-01361-3","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"42 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153409","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-apoptotic caspase-8-meteorin pathway in hepatocytes promotes MASH fibrosis.","authors":"Xiaobo Wang,Mary P Moore,Hongxue Shi,Yang Xiao,Jiayu Zhang,Lanuza A P Faccioli,Zhiping Hu,Shareef Khalid,Danish Saleheen,Dwayne G Stupack,Tatiana Kisseleva,Alejandro Soto Gutierrez,Mitchell A Lazar,Ira Tabas","doi":"10.1038/s42255-025-01355-1","DOIUrl":"https://doi.org/10.1038/s42255-025-01355-1","url":null,"abstract":"Metabolic-dysfunction-associated steatohepatitis (MASH) is the leading cause of chronic liver disease, but an incomplete understanding of MASH-induced liver fibrosis has limited therapeutic options. Here we show that hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism. Hepatic caspase-8 expression correlates with liver fibrosis in both human and experimental MASH, and hepatocyte-specific caspase-8 deletion in male mice with MASH suppressed liver fibrosis and hepatic stellate cell (HSC) activation without affecting hepatocyte apoptosis. Mechanistic studies showed that a caspase-8-YY1 pathway in hepatocytes induces secretory meteorin (Metrn), which activates HSCs via a c-Kit-STAT3 pathway. Meteorin expression was increased in human and male mouse MASH livers and decreased by deletion of hepatocyte caspase-8 in MASH mice and human and mouse primary hepatocytes. Genetic restoration of hepatocyte meteorin in hepatocyte-caspase-8-deleted MASH mice restored HSC activation and liver fibrosis while silencing hepatocyte meteorin lowered liver fibrosis. These findings reveal a therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"1 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153410","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 salute to innovation: exenatide in diabetes and obesity drug development at Amylin Pharmaceuticals.","authors":"James L Trevaskis,David G Parkes,Andrew A Young","doi":"10.1038/s42255-025-01383-x","DOIUrl":"https://doi.org/10.1038/s42255-025-01383-x","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"23 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140440","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 consensus guide to preclinical indirect calorimetry experiments","authors":"Alexander S. Banks, David B. Allison, Thierry Alquier,  Ansarullah, Steven N. Austad, Johan Auwerx, Julio E. Ayala, Joseph A. Baur, Stefania Carobbio, Gary A. Churchill, Morten Dall, Rafael de Cabo, Jose Donato Jr., Nathalia R. V. Dragano, Carol F. Elias, Anthony W. Ferrante Jr., Brian N. Finck, Jose E. Galgani, Zachary Gerhart-Hines, Laurie J. Goodyear, Justin L. Grobe, Rana K. Gupta, Kirk M. Habegger, Sean M. Hartig, Andrea L. Hevener, Steven B. Heymsfield, Corey D. Holman, Martin Hrabě de Angelis, David E. James, Lawrence Kazak, Jae Bum Kim, Martin Klingenspor, Xingxing Kong, Sander Kooijman, Louise Lantier, K. C. Kent Lloyd, James C. Lo, Irfan J. Lodhi, Paul S. MacLean, Owen P. McGuinness, Gema Medina-Gómez, Raghavendra G. Mirmira, Christopher D. Morrison, Gregory J. Morton, Timo D. Müller, Yoshihiro Ogawa, David Pajuelo-Reguera, Matthew J. Potthoff, Nathan Qi, Marc L. Reitman, Patrick C. N. Rensen, Jan Rozman, Jennifer M. Rutkowsky, Kei Sakamoto, Philipp E. Scherer, Gary J. Schwartz, Radislav Sedlacek, Mohammed Selloum, Saame Raza Shaikh, Shuai Chen, Gerald I. Shulman, Vojtěch Škop, Alexander A. Soukas, John R. Speakman, Bruce M. Spiegelman, Gregory R. Steinberg, Katrin J. Svensson, John P. Thyfault, Tony Tiganis, Paul M. Titchenell, Nigel Turner, Licio A. Velloso, Antonio Vidal-Puig, Christopher S. Ward, Ashley S. Williams, Christian Wolfrum, Allison W. Xu, Ying Xu, Juleen R. Zierath, on behalf of The International Indirect Calorimetry Consensus Committee (IICCC)","doi":"10.1038/s42255-025-01360-4","DOIUrl":"10.1038/s42255-025-01360-4","url":null,"abstract":"Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations. The authors highlight inconsistencies and divergencies in the literature reporting data on indirect calorimetry for studies on whole-body energy homeostasis, and propose harmonization of standards to facilitate data comparison and interpretation across different datasets.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1765-1780"},"PeriodicalIF":20.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129493","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":"Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.","authors":"Qiang Zhao,Jiajian Li,Jingjing Feng,Xin Wang,Yueting Liu,Fei Wang,Liang Liu,Bingxue Jin,Ming Lin,Ya-Chao Wang,Xiuhua Guo,Jieli Chen,Junwei Hao","doi":"10.1038/s42255-025-01379-7","DOIUrl":"https://doi.org/10.1038/s42255-025-01379-7","url":null,"abstract":"Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"338 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127101","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":"Cholesterol fuels microglia in chronic stroke.","authors":"Stefano Pluchino,Cory M Willis","doi":"10.1038/s42255-025-01362-2","DOIUrl":"https://doi.org/10.1038/s42255-025-01362-2","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"35 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127099","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":"Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis","authors":"Saloua Benhmammouch, Coraline Borowczyk, Clara Pierrot-Blanchet, Thibault Barouillet, Florent Murcy, Sébastien Dussaud, Marina Blanc, Camille Blériot, Tiit Örd, Lama Habbouche, Nathalie Vaillant, Yohan Gerber, Clément Cochain, Emmanuel L. Gautier, Florent Ginhoux, Edward B. Thorp, Erik A. L. Biessen, Judith C. Sluimer, Susanna Bodoy, Manuel Palacin, Béatrice Bailly-Maitre, Minna U. Kaikkonen, Laurent Yvan-Charvet","doi":"10.1038/s42255-025-01354-2","DOIUrl":"10.1038/s42255-025-01354-2","url":null,"abstract":"Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages: Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion of Slc7a7 accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability. The authors provide a comprehensive characterization of how glutamine uptake and utilization regulate macrophage function in atherosclerosis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1924-1938"},"PeriodicalIF":20.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117040","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 Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.","authors":"Femke M Feringa,Sascha J Koppes-den Hertog,Lian Y Wang,Rico J E Derks,Iris Kruijff,Lena Erlebach,Jorin Heijneman,Ricardo Miramontes,Nadine Pömpner,Niek Blomberg,Damien Olivier-Jimenez,Lill Eva Johansen,Alexander J Cammack,Ashling Giblin,Christina E Toomey,Indigo V L Rose,Hebao Yuan,Michael E Ward,Adrian M Isaacs,Martin Kampmann,Deborah Kronenberg-Versteeg,Tammaryn Lashley,Leslie M Thompson,Alessandro Ori,Yassene Mohammed,Martin Giera,Rik van der Kant","doi":"10.1038/s42255-025-01365-z","DOIUrl":"https://doi.org/10.1038/s42255-025-01365-z","url":null,"abstract":"Lipid alterations in the brain have been implicated in many neurodegenerative diseases. To facilitate comparative lipidomic research across brain diseases, we establish a data common named the Neurolipid Atlas that we prepopulated with isogenic induced pluripotent stem cell (iPS cell)-derived lipidomics data for different brain diseases. Additionally, the resource contains lipidomics data of human and mouse brain tissue. Leveraging multiple datasets, we demonstrate that iPS cell-derived neurons, microglia and astrocytes exhibit distinct lipid profiles that recapitulate in vivo lipotypes. Notably, the Alzheimer disease (AD) risk gene ApoE4 drives cholesterol ester (CE) accumulation specifically in human astrocytes and we also observe CE accumulation in whole-brain lipidomics from persons with AD. Multiomics interrogation of iPS cell-derived astrocytes revealed that altered cholesterol metabolism has a major role in astrocyte immune pathways such as the immunoproteasome and major histocompatibility complex class I antigen presentation. Our data commons, available online ( https://neurolipidatlas.com/ ), allows for data deposition by the community and provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"40 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117039","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}