Nature metabolism最新文献

{"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":"https://doi.org/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.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"18 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"9 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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}

{"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}

{"title":"BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states","authors":"Francesca Rizzollo, Abril Escamilla-Ayala, Nicola Fattorelli, Natalia Barbara Lysiak, Sanket More, Pablo Hernández Varas, Lucia Barazzuol, Chris Van den Haute, Joris Van Asselberghs, David Nittner, Jonathan Coene, Vivek Venkataramani, Bernhard Michalke, Christine Gaillet, Tatiana Cañeque, Irwin Davidson, Steven H. L. Verhelst, Peter Vangheluwe, Tito Calì, Jean-Christophe Marine, Raphaël Rodriguez, Julie Bonnereau, Patrizia Agostinis","doi":"10.1038/s42255-025-01352-4","DOIUrl":"10.1038/s42255-025-01352-4","url":null,"abstract":"Iron sustains cancer cell plasticity, yet it also sensitizes the mesenchymal, drug-tolerant phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe(II) compartmentalization remains elusive. Here, we show that BDH2 is a key effector of inter-organelle Fe(II) redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In MEL cells, BDH2 localizes at the mitochondria–lysosome contacts (MLCs) to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA), which ferries iron into the mitochondria. Fe(II) transfer by BDH2 supports mitochondrial bioenergetics, which is required to maintain lysosomal acidification and MLC formation. Loss of BDH2 alters lysosomal pH and MLC tethering dynamics, causing lysosomal iron sequestration, which primes MES cells for ferroptosis. Rescuing BDH2 expression, or supplementing 2,5-DHBA, rectifies lysosomal pH and MLCs, protecting MES cells from ferroptosis and enhancing their ability to metastasize. Thus, we unveil a BDH2-dependent mechanism that orchestrates inter-organelle Fe(II) transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the mesenchymal, drug-tolerant cancer cells. Rizzollo et al. show that BDH2 participates in iron distribution between cellular compartments, which sets the threshold for the ferroptosis vulnerability of the melanoma cell phenotypes, ultimately affecting their metastatic capacity","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1851-1870"},"PeriodicalIF":20.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01352-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067695","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":"Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice","authors":"Hailan Liu, Veronica L. Li, Qingzhuo Liu, Yao Liu, Cunjin Su, Hueyxian Wong, Na Yin, Hesong Liu, Xing Fang, Kristine M. McDermott, Hueyzhong Wong, Meng Yu, Longlong Tu, Jonathan C. Bean, Yongxiang Li, Mengjie Wang, Yue Deng, Yuhan Shi, Olivia Z. Ginnard, Yuxue Yang, Junying Han, Megan E. Burt, Sanika V. Jossy, Chunmei Wang, Yongjie Yang, Benjamin R. Arenkiel, Dong Kong, Yang He, Jonathan Z. Long, Yong Xu","doi":"10.1038/s42255-025-01377-9","DOIUrl":"https://doi.org/10.1038/s42255-025-01377-9","url":null,"abstract":"<p><i>N</i>-Lactoyl-phenylalanine (Lac-Phe) is a lactate-derived circulating metabolite that reduces feeding and obesity, but the molecular mechanisms that underlie the metabolic benefits of Lac-Phe remain unknown. Here we show that Lac-Phe directly inhibits hypothalamic neurons that express Agouti-related protein (AgRP), resulting in an indirect activation of anorexigenic neurons in the paraventricular nucleus of the hypothalamus (PVH). Both AgRP inhibition and PVH activation are required to mediate Lac-Phe-induced hypophagia. Lac-Phe-mediated inhibition of AgRP neurons occurs through activation of the ATP-sensitive potassium (K_ATP) channel, whereas inhibition of the K_ATP channel blunts the effects of Lac-Phe to suppress feeding. Together, these results reveal the molecular and neurobiological mechanisms by which Lac-Phe mediates metabolic improvements and suggest this exercise-induced metabolite might have therapeutic benefits in various human diseases.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"16 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067694","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":"Small but mighty: inulin promotes small intestinal bacterial fructose feeding","authors":"Hallie R. Wachsmuth,&nbsp;Frank A. Duca","doi":"10.1038/s42255-025-01374-y","DOIUrl":"10.1038/s42255-025-01374-y","url":null,"abstract":"Although the gut microbiome contributes to the development of metabolic disease, beneficially altering the gut microbiome via increased fibre intake improves metabolic outcomes in rodents and humans. A new study by Jung et al. describes a novel mechanism by which the prebiotic fibre, inulin, can prevent and reverse hepatic steatosis via adaptations in the small intestinal microbiome.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1720-1722"},"PeriodicalIF":20.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059252","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":"Dietary fibre-adapted gut microbiome clears dietary fructose and reverses hepatic steatosis","authors":"Sunhee Jung,&nbsp;Hosung Bae,&nbsp;Won-Suk Song,&nbsp;Yujin Chun,&nbsp;Johnny Le,&nbsp;Yasmine Alam,&nbsp;Amandine Verlande,&nbsp;Sung Kook Chun,&nbsp;Joohwan Kim,&nbsp;Miranda E. Kelly,&nbsp;Miranda L. Lopez,&nbsp;Sang Hee Park,&nbsp;Daniel Onofre,&nbsp;Jongwon Baek,&nbsp;Ki-Hong Jang,&nbsp;Varvara I. Rubtsova,&nbsp;Alexis Anica,&nbsp;Selma Masri,&nbsp;Gina Lee,&nbsp;Cholsoon Jang","doi":"10.1038/s42255-025-01356-0","DOIUrl":"10.1038/s42255-025-01356-0","url":null,"abstract":"Excessive consumption of the simple sugar fructose, which induces excessive hepatic lipogenesis and gut dysbiosis, is a risk factor for cardiometabolic diseases. Here we show in male mice that the gut microbiome, when adapted to dietary fibre inulin, catabolizes dietary fructose and mitigates or reverses insulin resistance, hepatic steatosis and fibrosis. Specifically, inulin supplementation, without affecting the host’s small intestinal fructose catabolism, promotes the small intestinal microbiome to break down incoming fructose, thereby decreasing hepatic lipogenesis and fructose spillover to the colonic microbiome. Inulin also activates hepatic de novo serine synthesis and cystine uptake, augmenting glutathione production and protecting the liver from fructose-induced lipid peroxidation. These multi-modal effects of inulin are transmittable by the gut microbiome, where Bacteroides acidifaciens acts as a key player. Thus, the gut microbiome, adapted to use inulin (a fructose polymer), efficiently catabolizes dietary monomeric fructose, thereby protecting the host. These findings provide a mechanism for how fibre can facilitate the gut microbiome to mitigate the host’s exposure to harmful nutrients and disease progression. The dietary fibre inulin is shown to promote fructose catabolism by the small intestinal microbiome, thereby mitigating fructose-induced hepatic lipogenesis and steatosis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1801-1818"},"PeriodicalIF":20.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01356-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059253","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":"Nutritional advice on social media: clicks over credibility","authors":"","doi":"10.1038/s42255-025-01385-9","DOIUrl":"10.1038/s42255-025-01385-9","url":null,"abstract":"Social media has become a go-to source for nutritional advice, and a space in which influencers compete with, and often drown out, evidence-based guidance. The scientific community should counter this viral spread of misinformation by making trustworthy information more accessible.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1715-1715"},"PeriodicalIF":20.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01385-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035108","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}