Nature metabolismPub Date : 2025-09-24DOI: 10.1038/s42255-025-01360-4
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)
{"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":"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. Persistent microglial activation upon ischaemic injury leads to the formation of stroke-associated foamy microglia, perpetuating long-term inflammation, white matter damage and functional impairments. These effects can be ameliorated by reducing microglial cholesterol overload through activation of CYP46A1.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2099-2116"},"PeriodicalIF":20.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01379-7.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature metabolismPub Date : 2025-09-23DOI: 10.1038/s42255-025-01362-2
Stefano Pluchino, Cory M. Willis
{"title":"Cholesterol fuels microglia in chronic stroke","authors":"Stefano Pluchino, Cory M. Willis","doi":"10.1038/s42255-025-01362-2","DOIUrl":"10.1038/s42255-025-01362-2","url":null,"abstract":"Cholesterol accumulation in microglia drives persistent inflammation after stroke. In this issue of Nature Metabolism, Zhao et al. suggest that enhancing microglial cholesterol catabolism may offer a promising strategy to reduce brain damage and improve recovery.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1970-1971"},"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}
Nature metabolismPub Date : 2025-09-22DOI: 10.1038/s42255-025-01354-2
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
{"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}
Nature metabolismPub Date : 2025-09-22DOI: 10.1038/s42255-025-01365-z
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
{"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":"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. The authors introduce the Neurolipid Atlas, a dynamic resource for the community to gain insight into lipid alterations in neurodegenerative disease, and they leverage the platform to show how cholesterol alterations in astrocytes can dysregulate neuroinflammatory pathways in Alzheimer disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2142-2164"},"PeriodicalIF":20.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01365-z.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature metabolismPub Date : 2025-09-19DOI: 10.1038/s42255-025-01368-w
Tianshi Feng, Qin Luo, Yanlin Liu, Zeyu Jin, David Skwarchuk, Rumi Lee, Miso Nam, John M. Asara, Daya R. Adye, Philip L. Lorenzi, Lin Tan, Guangsheng Pei, Zhongming Zhao, Neda Zarrin-Khameh, Adriana Paulucci-Holthauzen, Brian W. Simons, Ju-Seog Lee, Scott Kopetz, Jihye Yun
{"title":"Fructose and glucose from sugary drinks enhance colorectal cancer metastasis via SORD","authors":"Tianshi Feng, Qin Luo, Yanlin Liu, Zeyu Jin, David Skwarchuk, Rumi Lee, Miso Nam, John M. Asara, Daya R. Adye, Philip L. Lorenzi, Lin Tan, Guangsheng Pei, Zhongming Zhao, Neda Zarrin-Khameh, Adriana Paulucci-Holthauzen, Brian W. Simons, Ju-Seog Lee, Scott Kopetz, Jihye Yun","doi":"10.1038/s42255-025-01368-w","DOIUrl":"10.1038/s42255-025-01368-w","url":null,"abstract":"The consumption of sugar-sweetened beverages (SSBs), which contain high levels of fructose and glucose, has been causally and mechanistically linked to an increased risk of colorectal cancer (CRC). However, the effects of SSB consumption on advanced stages of disease progression, including metastasis, remain poorly understood. Here we show that exposure of CRC cells to a glucose and fructose formulation—reflecting the composition of both high-fructose corn syrup and sucrose found in SSBs—enhances cellular motility and metastatic potential compared to glucose alone. Given that CRC cells grow poorly in fructose alone, and cells in vivo are not physiologically exposed to fructose without glucose, we excluded the fructose-only condition from our studies unless needed as a control. Mechanistically, the combination of glucose and fructose elevates the NAD⁺/NADH ratio by activation of the reverse reaction of sorbitol dehydrogenase in the polyol pathway. This redox shift relieves NAD⁺ limitations and accelerates glycolytic activity, which in turn fuels activation of the mevalonate pathway, ultimately promoting CRC cell motility and metastasis. Our findings highlight the detrimental impact of SSBs on CRC progression and suggest potential dietary and therapeutic strategies to mitigate metastasis in patients with CRC. Feng, Luo and colleagues show that the combination of glucose and fructose, as found in sugar-sweetened beverages, promotes colorectal cancer metastasis through a mechanism involving sorbitol dehydrogenase (SORD).","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2018-2032"},"PeriodicalIF":20.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01368-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089906","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":"Mapping the plasma metabolome to human health and disease in 274,241 adults.","authors":"Jia You,Xi-Han Cui,Yi-Lin Chen,Yi-Xuan Wang,Hai-Yun Li,Yi-Xuan Qiang,Ji-Yun Cheng,Yue-Ting Deng,Yu Guo,Peng Ren,Yi Zhang,Yu He,Xiao-Yu He,Shi-Dong Chen,Ya-Ru Zhang,Yu-Yuan Huang,Ying Mao,Jian-Feng Feng,Wei Cheng,Jin-Tai Yu","doi":"10.1038/s42255-025-01371-1","DOIUrl":"https://doi.org/10.1038/s42255-025-01371-1","url":null,"abstract":"A systematic characterization of metabolic profiles in human health and disease enhances precision medicine. Here we present a comprehensive human metabolome-phenome atlas, using data from 274,241 UK Biobank participants with nuclear magnetic resonance metabolic measures. This atlas links 313 plasma metabolites to 1,386 diseases and 3,142 traits, with participants being prospectively followed for a median of 14.9 years. This atlas uncovered 52,836 metabolite-disease and 73,639 metabolite-trait associations, where the ratio of cholesterol to total lipids in large low-density lipoprotein percentage was found as the metabolite associated with the highest number (n = 526) of diseases. In addition, we found that more than half (57.5%) of metabolites showed statistical variations from healthy individuals over a decade before disease onset. Combined with demographics, the machine-learning-based metabolic risk score signified the top 30 (around 10%) metabolites as biomarkers, yielding favourable classification performance (area under the curve > 0.8) for 94 prevalent and 81 incident diseases. Finally, Mendelian randomization analyses provided support for causal relationships of 454 metabolite-disease pairs, among which 402 exhibited shared genetic determinants. Additional insights can be gleaned via an accessible interactive resource ( https://metabolome-phenome-atlas.com/ ).","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"22 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089904","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-dependent liver gluconeogenesis impacts different intensity exercise in mice","authors":"Takahiro Horiuchi, Keizo Kaneko, Shinichiro Hosaka, Kenji Uno, Seitaro Tomiyama, Kei Takahashi, Maya Yamato, Akira Endo, Hiroto Sugawara, Yohei Kawana, Yoichiro Asai, Shinjiro Kodama, Junta Imai, Seiya Mizuno, Satoru Takahashi, Atsushi Takasaki, Hiraku Ono, Koutaro Yokote, Rae Maeda, Yuki Sugiura, Hideki Katagiri","doi":"10.1038/s42255-025-01373-z","DOIUrl":"10.1038/s42255-025-01373-z","url":null,"abstract":"Hepatic gluconeogenesis produces glucose from various substrates to meet energy demands. However, how these substrates are preferentially used under different conditions remains unclear. Here, we show that preferential supplies of lactate and glycerol modulate hepatic gluconeogenesis, thereby impacting high-intensity and low-intensity exercise capacities, respectively. We find that liver-specific knockout of phosphoenolpyruvate carboxykinase 1 (L-Pck1KO), which blocks gluconeogenesis from lactate, decreases high-intensity exercise capacity but increases low-intensity exercise capacity by enhancing gluconeogenesis from glycerol. Conversely, liver-specific knockout of glycerol kinase (L-GykKO), which inhibits glycerol-derived gluconeogenesis, induces the opposite effects by enhancing gluconeogenesis from lactate. Given that these compensatory steps depend on NAD+-mediated oxidation in the cytosol, we hepatically expressed NADH oxidase from Lactobacillus brevis (LbNOX) to decrease the cytosolic [NADH]/[NAD+] ratio. We find that hepatic LbNOX expression enhances gluconeogenesis from both redox-dependent substrates and increases exercise capacities at both intensities. Importantly, LbNOX-induced enhancement of high-intensity and low-intensity exercise capacities is abolished in L-Pck1KO and L-GykKO mice, respectively. Therefore, supplies of gluconeogenic substrates and cytosolic redox states, rather than altered enzyme expressions, modulate hepatic gluconeogenesis and exercise capacity at different intensities. Globally, this study shows that regulating hepatic gluconeogenesis through cytosolic redox states is a potent strategy for increasing exercise performance. This study shows that the preferential use of gluconeogenic pathways in the liver depends on exercise load.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1991-2003"},"PeriodicalIF":20.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01373-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083351","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}
Nature metabolismPub Date : 2025-09-17DOI: 10.1038/s42255-025-01370-2
{"title":"Tracking dietary exposures with metabolite biomarkers","authors":"","doi":"10.1038/s42255-025-01370-2","DOIUrl":"10.1038/s42255-025-01370-2","url":null,"abstract":"Plasma metabolic variation reflects dietary exposures. We show that biomarker panels are objective and reproducible in assessing dietary intake and quality, and can accurately predict clinical phenotypes such as diabetes and hypertension.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1728-1729"},"PeriodicalIF":20.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078198","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}
Nature metabolismPub Date : 2025-09-17DOI: 10.1038/s42255-025-01359-x
Dorrain Y. Low, Theresia H. Mina, Nilanjana Sadhu, Kari E. Wong, Pritesh Rajesh Jain, Rinkoo Dalan, Hong Kiat Ng, Wubin Xie, Benjamin Lam, Darwin Tay, Xiaoyan Wang, Yik Weng Yew, James D. Best, Rangaprasad Sarangarajan, Paul Elliott, Elio Riboli, Jimmy Lee, Eng Sing Lee, Joanne Ngeow, Patricia A. Sheridan, Xue Li Guan, Gregory A. Michelotti, Marie Loh, John C. Chambers
{"title":"Metabolic variation reflects dietary exposure in a multi-ethnic Asian population","authors":"Dorrain Y. Low, Theresia H. Mina, Nilanjana Sadhu, Kari E. Wong, Pritesh Rajesh Jain, Rinkoo Dalan, Hong Kiat Ng, Wubin Xie, Benjamin Lam, Darwin Tay, Xiaoyan Wang, Yik Weng Yew, James D. Best, Rangaprasad Sarangarajan, Paul Elliott, Elio Riboli, Jimmy Lee, Eng Sing Lee, Joanne Ngeow, Patricia A. Sheridan, Xue Li Guan, Gregory A. Michelotti, Marie Loh, John C. Chambers","doi":"10.1038/s42255-025-01359-x","DOIUrl":"10.1038/s42255-025-01359-x","url":null,"abstract":"Understanding how diet shapes metabolism across diverse populations is essential to improving nutrition and health. Biomarkers reflecting diet are explored largely in European and American populations, but the food metabolome is highly complex and varies across region and culture. We assessed 1,055 plasma metabolites and 169 foods/beverages in 8,391 multi-ethnic Asian individuals and carried out diet–metabolite association analyses. Using machine learning, we developed multi-biomarker panels and composite scores for key foods, beverages and overall diet quality. Here we show these biomarker panels can be used to objectively assess dietary intakes in the Asian multi-ethnic population and can explain variances in intake prediction models better than single biomarkers. The identified diet–metabolite relationships are reproducible over time and improve prediction of clinical outcomes (insulin resistance, diabetes, body mass index, carotid intima-media thickness and hypertension), compared to self-reports. Our findings show insights into multi-ethnic diet-related metabolic variations and an opportunity to link exposure to population health outcomes. In a large multi-ethnic Asian cohort, associations between over 1,000 plasma metabolites and specific foods and beverages are made. These diet–metabolite relationships were used to accurately predict clinical phenotypes such as diabetes and hypertension.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1939-1954"},"PeriodicalIF":20.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081276","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}