Nature metabolism最新文献

{"title":"A futile Na⁺ K⁺ transport cycle augments energy expenditure in beige adipocytes.","authors":"Qing Liu, Ying Cheng, Dandan Yan, Wenjie Wu, Zhenchuan Lei, Qiaoyun Long, Ziyu Zhao, Yuan Gao, Baile Wang, Tianshi Feng, Jihoon Shin, Jiayu Zhao, Shiting Zhao, Kang Chen, Kingyip Cheng, Xiaoqiang Yao, Ping Gu, Xuefei Gao, Ching-Lung Cheung, Shingo Kajimura, Pengtao Liu, Donghai Wu, Wei Sun, Jinfeng Xiao, Zexin Lin, Yi Wang, Maxwell Kwok, Ngar Yun Ellen Poon, Cheng Hu, Aimin Xu, Hannah Xiaoyan Hui","doi":"10.1038/s42255-026-01630-9","DOIUrl":"https://doi.org/10.1038/s42255-026-01630-9","url":null,"abstract":"<p><p>Uncoupling protein 1 (UCP1)-independent energy dissipation has been proven to serve physiological functions in beige adipocytes. Here we show that a futile sodium/potassium (Na⁺/K⁺) transport cycle is preferentially amplified in mouse and human beige adipocytes and contributes to UCP1-independent energy expenditure. In mice, cold exposure activates a sympathetic-thyroid hormone signaling axis that coordinatedly induces the Na⁺/K⁺-ATPase subunit ATP1A2 together with Na⁺ and K⁺ channels, increasing bidirectional ion flux across the plasma membrane while maintaining ionic balance. Atp1a2⁺Kcnk3⁺ adipocytes are detected in mouse inguinal white adipose tissue after cold exposure. Acute inhibition of Na⁺/K⁺-ATPase reduces energy expenditure in mouse and human beige adipocytes, whereas overexpressing Atp1a2 in murine adipocytes potentiates energy expenditure, independent of UCP1. Adipocyte-specific Atp1a2 deletion impairs thermogenic capacity and exacerbates diet-induced obesity in mice. Expression of a human ATP1A2 missense variant reduces ATP1A2-dependent respiration in mouse adipocytes. Together, these identify ion transport as a tunable ATP-consuming mechanism that expands the thermogenic repertoire of beige adipocytes.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149239013","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":"NNMT enhances hyperandrogenism in polyendocrine metabolic ovarian syndrome through epigenetic remodelling.","authors":"Weiwei Huang, Chuanjin Yu, Yishu Wang, Ningxia Sun, Liang Wang, Jun Ren, Yue Xu, Xinghui Guo, Xinyuan Li, Yiting Mao, Jiexue Pan, Tingting Liu, Hongbo Yang, Hefeng Huang","doi":"10.1038/s42255-026-01625-6","DOIUrl":"https://doi.org/10.1038/s42255-026-01625-6","url":null,"abstract":"<p><p>Polyendocrine metabolic ovarian syndrome (PMOS) features intertwined reproductive, endocrine and metabolic defects, yet its initiating mechanisms remain incompletely understood. Here we show that an epigenetic mechanism driven by nicotinamide N-methyltransferase (NNMT) in granulosa cells contributes to disease progression in PMOS. We observe that Nnmt overexpression in mouse granulosa cells reduces histone H3 lysine 27 trimethylation (H3K27me3), leading to increased retinoic acid receptor beta (RARB) expression. RARB, in turn, amplifies ovarian androgen synthesis. The resulting androgen excess further suppresses H3K27me3, locking cells into a feedforward loop that sustains hyperandrogenism and disrupts follicle development. Pharmacological inhibition of NNMT restores H3K27me3, disrupts the RARB-androgen feedback circuit, and ameliorates both metabolic and hormonal phenotypes in PMOS models. Our findings suggest NNMT as a regulator of PMOS through metabolic and epigenetic reprogramming. The NNMT-H3K27me3-RARB-androgen axis emerges as a mechanistic nexus linking methionine and epigenetic dysregulation to PMOS pathogenesis and represents a tractable therapeutic target.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207482","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":"IRF7 signalling in tanycytes controls brain-body-immune response across the ovarian cycle.","authors":"Sreekala Nampoothiri, Daniela Fernandois, Nathalie Journiac, Fabien Delahaye, Yvon Mbouamboua, Florent Sauve, Marie Couralet, Sarah Gallet, Naziha Mroueh, Maria Laura Serradas Aponte, Nathalie Jouy, Rachel Spenle, Ruth Schmidt-Ullrich, Ines Martinez Corral, Virginie Mattot, Carmen Ruiz de Almodovar, Andreas Schlitzer, Philippe Froguel, Claude-Alain Maurage, Pascal Barbry, Paolo Giacobini, Lennart T Mars, Amelie Bonnefond, Ruben Nogueiras, Markus Schwaninger, Vincent Prevot","doi":"10.1038/s42255-026-01635-4","DOIUrl":"https://doi.org/10.1038/s42255-026-01635-4","url":null,"abstract":"<p><p>Sex-specific differences in metabolic and immune function are shaped by endocrine-immune interactions, yet the complexity of this relationship remains poorly understood. Here, we identify an immune cell-like state of tanycytes, an ependymoglial cell type lining the third ventricle that mediates brain-body communication^1,2 in both mice and humans. Using single-cell transcriptomics, we provide a high-resolution cellular map of the mouse and human mediobasal hypothalamus with cross-species comparison of tanycytes. We capture dynamic sex-, oestrous cycle- and high-fat diet-dependent transcriptomic changes in tanycytes, including a cyclic interferon response in tanycytes during the physiological oestrous cycle in female mice. We found that the oestrous cycle, with its changing hormonal milieu, especially oestradiol, affected the brain's immune responses, characterized by the temporal and cyclic expression of interferon regulatory factor 7 (Irf7) gene, as well as downstream interferon-stimulated genes such as Cxcl10 in tanycytes of female mice, which are associated with increased infiltration of leukocytes and cytokine responses. Irf7 expression in tanycytes of physiological males remained stable and markedly lower, suggesting a distinct immune activation pattern in the brains of cycling females. By targeting oestrogen and interferon signaling in tanycytes, we show that balanced, cyclic leukocyte infiltration into the median eminence may have a role in oestrous cycle maintenance, whereas Irf7 in tanycytes modulates circulating monocyte proportions, revealing brain-immune system communication through tanycytes. Our findings reveal an immune-associated role for tanycytes, with potential implications for understanding the endocrine and immunological mechanisms underlying sex-biased diseases.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195291","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 homeostasis and women's reproductive health.","authors":"Xiao Liu, Lili Yang, Jingjing Jiang, Hsun-Ming Chang, Liangshan Mu","doi":"10.1038/s42255-026-01646-1","DOIUrl":"https://doi.org/10.1038/s42255-026-01646-1","url":null,"abstract":"<p><p>Metabolic homeostasis and female reproductive health are governed by tightly coupled regulatory systems, yet their reciprocal interactions have often been investigated in isolation. In this Review, we synthesize current epidemiological, mechanistic and clinical evidence to propose an integrated framework in which dynamic, bidirectional crosstalk between key metabolic organs and endocrine mediators constitutes a central determinant of female reproductive function across the life course. We delineate how disruption of this integrated network underpins a broad spectrum of reproductive dysfunction, particularly in polyendocrine metabolic ovarian syndrome and reproductive ageing, as well as cardiometabolic risk, highlighting the bidirectional nature of these associations. Finally, we critically evaluate current metabolism-targeted strategies, including lifestyle interventions, metabolic surgery and pharmacological therapies, and discuss emerging opportunities for precision approaches. By integrating mechanistic insights with clinical evidence, this Review reframes female reproductive disorders from a systemic metabolic perspective and outlines future directions for metabolism-focused strategies to improve reproductive health outcomes.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195331","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":"Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.","authors":"Xingxiu Pan, Austin L Zuckerman, Karl N Miller, Marcos G Teneche, Subrata Munan, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Roya AminiTabrizi, Adarsh Rajesh, Sara Violante, Jiwu Wang, Justin R Cross, Peter D Adams, Hardik Shah, Valentin Cracan","doi":"10.1038/s42255-026-01640-7","DOIUrl":"https://doi.org/10.1038/s42255-026-01640-7","url":null,"abstract":"<p><p>An elevated NADH/NAD⁺ ratio (NADH-reductive stress) is a hallmark of mitochondrial dysfunction, yet how it drives pathologies ranging from primary mitochondrial disorders to ageing remains poorly understood^1,2. Here, we show that mitochondrial respiratory chain inhibition in primary human fibroblasts induces NADH-reductive stress that coexists with profound NADPH depletion. Using the Escherichia coli soluble transhydrogenase (EcSTH)³ to model this redox coupling in cells with intact mitochondria, we demonstrate that perturbation of both NAD(H) and NADP(H) redox pairs elicits metabolomic and transcriptomic reprogramming, culminating in proliferation arrest with senescence features. Notably, normalizing the NADH/NAD⁺ ratio alone while NADPH depletion persists fails to rescue proliferation in EcSTH-expressing primary human cells, unlike in transformed HeLa cells. Stable isotope tracing reveals that primary fibroblasts rely more on NADPH-driven reductive carboxylation than HeLa cells, explaining why NADH/NAD⁺ normalization alone is insufficient for rescue. To test this NADPH dependency, we develop a constitutively active Staphylococcus aureus NAD kinase (SaNADK) that expands the mammalian NADP(H) pool. In fibroblasts, SaNADK restores reductive carboxylation and de novo pyrimidine biosynthesis, and reverses proliferation arrest and senescence features. Furthermore, hepatic SaNADK expression in aged male mice partially alleviates transcriptional signatures of inflammation and metabolic dysregulation. Together, these findings establish EcSTH and SaNADK as xenotopic tools for dissecting NAD(P)H redox coupling and provide a framework for counteracting ageing-associated metabolic decline.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183049","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 multi-fluid exercise proteomic atlas reveals regulators of health and disease","authors":"","doi":"10.1038/s42255-026-01642-5","DOIUrl":"10.1038/s42255-026-01642-5","url":null,"abstract":"A single bout of exercise triggers thousands of coordinated protein changes across blood, saliva and urine. By integrating tissue atlases, human genetics and in vivo functional validation, we present a multi-fluid resource that serves as a starting point for prioritizing robust candidate exercise-regulated proteins that might mediate the cardiometabolic health benefits of long-term exercise.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 10","pages":"2058-2059"},"PeriodicalIF":27.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166499","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":"Systemic proteomic dynamics of acute exercise reveal genetic links to health and disease","authors":"Nigel Kurgan,&nbsp;Jeppe Kjærgaard,&nbsp;Naja Zenius Jespersen,&nbsp;Virginia Díez-Obrero,&nbsp;Victor Svenstrup,&nbsp;Roger Moreno-Justicia,&nbsp;Sarah Elizabeth Heywood,&nbsp;Cecilie Bergmann Lindqvist,&nbsp;Lisa Ottander,&nbsp;Diana Samodova-Sommer,&nbsp;Alina Malita,&nbsp;Olga Kubrak,&nbsp;Nadja Ahrentløv,&nbsp;Nina Sloth Nielsen,&nbsp;Cody Garett Durrer,&nbsp;Michael Texada,&nbsp;Mathias Ried-Larsen,&nbsp;Simon Rasmussen,&nbsp;Kim Rewitz,&nbsp;Ruth J. F. Loos,&nbsp;Roelof Adriaan Johan Smit,&nbsp;Bente Klarlund Pedersen,&nbsp;Atul Shahaji Deshmukh","doi":"10.1038/s42255-026-01621-w","DOIUrl":"10.1038/s42255-026-01621-w","url":null,"abstract":"Physical activity improves metabolic health, but the molecular responses that mediate its benefits are not fully characterized. Here we present a high-resolution, time-resolved proteomics atlas across plasma, saliva and urine from 25 healthy men in response to acute exercise. We find that exercise regulates more than 3,000 proteins through distinct, fluid-specific temporal dynamics. Network analysis uncovers coordinated remodelling of protein secretion, extracellular matrix and immune activation across body fluids. Replication in an independent cohort shows that many exercise-responsive plasma proteins exhibit consistent responses across age, sex and exercise modalities. Integration with human genome-wide association study data links secreted, exercise-responsive proteins to cardiometabolic diseases. Functional validation of genetically prioritized muscle-specific secreted proteins in Drosophila confirms their role in endurance, behaviour and metabolism. Overall, this open-access atlas ( https://cbmr.ku.dk/research/research-groups/deshmukh-group/shiny-apps/ ) provides a multifluid resource that complements existing exercise-omics efforts for defining molecular adaptations to exercise and for prioritizing candidate exerkines. This study provides a comprehensive, systems-level characterization of acute exercise-induced proteomic responses across several body fluids in humans.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 10","pages":"2178-2198"},"PeriodicalIF":27.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01621-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166802","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":"Inhibiting fructose metabolism to treat fatty liver","authors":"Richard J. Johnson,&nbsp;Miguel A. Lanaspa,&nbsp;Dean R. Tolan","doi":"10.1038/s42255-026-01627-4","DOIUrl":"10.1038/s42255-026-01627-4","url":null,"abstract":"In this issue of Nature Metabolism, Koene et al. present evidence that inhibiting fructose metabolism (using a ketohexokinase inhibitor) can improve hepatic steatosis and insulin resistance in individuals who are prediabetic with obesity and metabolic dysfunction-associated steatotic liver disease, supporting further development and testing of fructose inhibitors in metabolic disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 10","pages":"2051-2053"},"PeriodicalIF":27.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090081","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 benefits of ketohexokinase inhibition in individuals with MASLD: a randomized placebo-controlled crossover trial","authors":"Evi J. C. Koene,&nbsp;Vera B. Schrauwen-Hinderling,&nbsp;Jeremy Basset-Sagarminaga,&nbsp;Kim Brouwers,&nbsp;Yvonne M. H. Op den Kamp-Bruls,&nbsp;Julian Mevenkamp,&nbsp;Florian Haans,&nbsp;Gert Schaart,&nbsp;Esther Kornips,&nbsp;Johanna A. Jorgensen,&nbsp;Jean L. J. M. Scheijen,&nbsp;Casper G. Schalkwijk,&nbsp;Michel van Weeghel,&nbsp;Frédéric M. Vaz,&nbsp;Riekelt H. Houtkooper,&nbsp;Elva Wong,&nbsp;Sander Kersten,&nbsp;Aditi R. Saxena,&nbsp;William P. Esler,&nbsp;Patrick Schrauwen,&nbsp;Martijn C. G. J. Brouwers","doi":"10.1038/s42255-026-01626-5","DOIUrl":"10.1038/s42255-026-01626-5","url":null,"abstract":"High fructose consumption, particularly from sugar-sweetened beverages, contributes to cardiometabolic disease. Here we study the metabolic effects of 6-week pharmacological inhibition with PF-06835919 of ketohexokinase, the enzyme that catalyses the first committed step of fructose metabolism, in a randomized placebo-controlled crossover trial in 15 participants with metabolic dysfunction-associated steatotic liver disease. The primary outcome was hepatic insulin sensitivity, measured by insulin-stimulated suppression of endogenous glucose production. Secondary outcomes included fat distribution, peripheral and adipose tissue insulin sensitivity, and fat oxidation. While PF-06835919 treatment did not affect body weight, it improved hepatic insulin sensitivity and reduced intrahepatic lipid and saturated fatty acid content. Besides these beneficial hepatic effects, PF-06835919 also improved insulin-stimulated glucose disposal, adipose tissue insulin sensitivity, adipose tissue distribution and nocturnal fat oxidation. These changes are accompanied by changes in very low-density lipoprotein particle size distribution and circulating hepatokines. These results show that inhibition of fructose metabolism has beneficial metabolic effects that extend beyond the organs that metabolize fructose. ClinicalTrials.gov identifier: NCT05463575 . In a randomized placebo-controlled crossover trial, pharmacological inhibition of ketohexokinase improved hepatic and systemic metabolic health in individuals with MASLD, highlighting fructose metabolism as a promising therapeutic target with benefits extending beyond the liver.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 10","pages":"2165-2177"},"PeriodicalIF":27.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090080","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":"L-Arginine inhibits NLRP3 inflammasome activation","authors":"Feng Liu, Wanxin Zhuang, Yuan Yang, Wenting Zhao, Chao Zhang, Siyuan Li, Xudong Liu, Qingyuan Cao, Shunguo Zhu, Bingyu Liu, Xiangyu Ma, Lintai Da, Chengjiang Gao","doi":"10.1038/s42255-026-01636-3","DOIUrl":"https://doi.org/10.1038/s42255-026-01636-3","url":null,"abstract":"Nutritional status and metabolic homeostasis are intricately associated with the inflammatory response. However, the direct mechanistic link between nutrition, metabolism and inflammation remains unclear. Here, we show that the amino acid L-arginine (L-Arg) is a potent endogenous inhibitor of the NLRP3 inflammasome, a central component of the inflammatory signalling pathway. We show that L-Arg binds directly to the Asp31 site of the NLRP3 protein, blocking its interaction with the adaptor ASC and subsequent inflammasome assembly and activation. L-Arg supplementation inhibits the NLRP3 inflammasome activation in macrophages, while deprivation promotes it. Treatment with L-Arg in mice alleviates monosodium urate crystal-induced arthritis and aluminium-induced peritonitis. In addition, L-Arg supplementation alleviates neuroinflammation and motor deficits in mouse models of Parkinson’s disease, whereas L-Arg deprivation exacerbates pathology. In patients with Parkinson’s disease, L-Arg levels are reduced in serum. Our study establishes L-Arg supplementation as a promising therapeutic avenue for managing NLRP3-driven inflammatory pathologies.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"1 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087864","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}