Nature metabolism最新文献

{"title":"A data-driven framework reconstructs the molecular continuum of human MASLD progression","authors":"Ioannis Kamzolas, Thodoris Koutsandreas, Charlie George Barker, Anna Vathrakokoili Pournara, Harry Weston, Naoto Fujiwara, Yujin Hoshida, Quentin M. Anstee, Michele Vacca, Irene Papatheodorou, Antonio Vidal-Puig, Evangelia Petsalaki","doi":"10.1038/s42255-026-01543-7","DOIUrl":"10.1038/s42255-026-01543-7","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses along a continuum from simple steatosis to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. However, current clinical and research frameworks rely primarily on static, histology-defined stages that fail to capture the continuous nature of disease progression. Here, we present a data-driven framework that reconstructs MASLD progression as a continuous molecular trajectory from cross-sectional liver transcriptomic profiles. By positioning patients along this trajectory, we move beyond conventional stage-based classifications and resolve the ordered activation of regulatory programmes, signalling pathways and cellular remodelling processes underlying disease progression. To enable non-invasive patient stratification, we integrate the inferred molecular trajectory with paired liver-plasma proteomics data and identify a 57-gene plasma-accessible biomarker panel that accurately predicts advanced fibrosis and continuously positions patients along the disease trajectory across independent cohorts, outperforming established non-invasive clinical scores. Together, this work establishes a generalizable trajectory-based framework for understanding MASLD pathophysiology and provides a foundation for mechanistically informed biomarker discovery, precision staging and stage-aware therapeutic prioritization. A trajectory-based molecular framework reveals coordinated temporal shifts in metabolic, inflammatory and fibrogenic mechanisms across the human MASLD spectrum.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1545-1562"},"PeriodicalIF":27.5,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01543-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432007","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":"Itaconate as a paracrine brake on thermogenesis","authors":"Lei-Lei Chen, Dan Ye","doi":"10.1038/s42255-026-01573-1","DOIUrl":"10.1038/s42255-026-01573-1","url":null,"abstract":"Thermogenesis must be precisely controlled to avoid wasting energy. In this issue of Nature Metabolism, Tang et al. reveal that macrophage-derived itaconate acts as a paracrine metabolic brake that blocks MCT1-dependent succinate uptake and restrains brown adipose tissue thermogenesis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1629-1630"},"PeriodicalIF":27.5,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432448","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":"Decoding MASLD progression beyond histological stages","authors":"","doi":"10.1038/s42255-026-01548-2","DOIUrl":"10.1038/s42255-026-01548-2","url":null,"abstract":"We reconstruct metabolic dysfunction-associated steatotic liver disease (MASLD) as a continuous molecular trajectory, revealing dynamic regulatory programmes underlying disease progression. By integrating transcriptomics, network analysis and plasma proteomics, we identify a mechanistically grounded biomarker panel that enables non-invasive, stage-aware patient stratification beyond conventional histological staging.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1460-1461"},"PeriodicalIF":27.5,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432005","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":"Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis","authors":"Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E. Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A. Ryback, Carl D. Novina, Karine Auclair, Haopeng Xiao, Evanna L. Mills","doi":"10.1038/s42255-026-01572-2","DOIUrl":"10.1038/s42255-026-01572-2","url":null,"abstract":"Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3–14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance. Tang et al. reveal that macrophage-derived itaconate acts as a paracrine inhibitor of adipose tissue thermogenesis by blocking succinate uptake into brown adipose tissue.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1694-1712"},"PeriodicalIF":27.5,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01572-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432003","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":"Author Correction: SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.","authors":"Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li","doi":"10.1038/s42255-026-01585-x","DOIUrl":"https://doi.org/10.1038/s42255-026-01585-x","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148448164","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 perineurium integrates leptin with its sympathetic outflow to protect against obesity","authors":"Gitalee Sarker, Emma Haberman, Anandhakumar Chandran, Thomas Monfeuga, Cyrielle Maroteau, Sofia Lundh, David S. Oliveira, Andrea Raimondi, Karin Ziegler, Tiago Gomes, Tiago N. Cordeiro, Karishma Parekh, Emilia Schmid, Paola Fernández-Sanmartín, Alina Griebel, Noelia Martinez-Sanchez, Bernardo A. Arús, Samson W. Cheung, Yitao Zhu, Michal Shaked, Sarah C. L. Knowles, Stefan Hanns Engelhardt, Matteo Iannacone, Philipp E. Scherer, Miguel López, Enrique M. Toledo, Ana Domingos","doi":"10.1038/s42255-026-01555-3","DOIUrl":"10.1038/s42255-026-01555-3","url":null,"abstract":"The regulatory mechanism of leptin’s afferent action in the brain is contingent upon the efferent sympathetic innervation of white and brown adipose tissues. Nonetheless, the peripheral regulation governing the afferent–efferent balance remains ambiguous. Here we show the enriched expression of both leptin receptor (Lepr) and β2-adrenergic receptor (Adrb2) in perineurial cells that form a barrier around sympathetic ganglia and nerve bundles in adipose tissues, using single-cell RNA sequencing on mouse sympathetic ganglia. Lepr+ sympathetic perineurial cells (SPCs) are molecularly similar to endothelial cells. Conditional knockout of Adrb2 in Lepr+ cells, including SPCs, predisposes male mice to obesity by lowering energy expenditure and thermogenesis without affecting food intake. Notably, obesity-associated hyperleptinaemia causes apoptosis in SPCs, disrupting the perineurial barrier and concomitant adipose sympathetic neuropathy. This deleterious effect can be reversed by partial reduction of leptin or sympathomimetic β2-adrenergic receptor agonism. Clinically, we observed a male-specific synergistic effect of LEPR and ADRB2 polymorphisms on increased body mass index risk in a large European population. We propose that SPCs coordinate the afferent and efferent arms of the neuroendocrine loop of leptin action to regulate energy expenditure and body weight. Lepr+Adrb2+ sympathetic perineurial cells coordinate leptin signalling and sympathetic output to modulate energy expenditure, thermogenesis and body weight in male mice, independent of changes to food intake.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1563-1582"},"PeriodicalIF":27.5,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01555-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432068","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":"Association of GLP-1RA discontinuation and risk of depressive and anxiety disorders in people with type 2 diabetes: a cohort study","authors":"Tingyu Zhang, Ping He, Yunxi Ji, Juan Shi, Zizheng Zhang, Kan Wang, Haolei Pan, Huayan Yao, Yanbin Xue, Ruizhi Zheng, Qingxia Wu, Bin Cui, Yifei Zhang, Weiqing Wang, Guang Ning","doi":"10.1038/s42255-026-01567-z","DOIUrl":"10.1038/s42255-026-01567-z","url":null,"abstract":"The psychiatric safety profile of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is characterized by inconsistent findings during active treatment and remains largely unexplored after cessation. Here we show that GLP-1RA discontinuation is associated with an increased risk of psychiatric events. Using large-scale electronic health records from the Shanghai Hospital Link Database, we investigate incident depressive and anxiety disorders during GLP-1RA treatment and after its discontinuation in people with type 2 diabetes, compared with dipeptidyl peptidase-4 inhibitors (DPP4is) or sodium–glucose cotransporter-2 inhibitors (SGLT2is). During treatment, GLP-1RAs show a neutral risk compared with DPP4is and a lower risk compared with SGLT2is. In contrast, after cessation, prior use of GLP-1RAs is associated with a higher risk than prior use of DPP4is or SGLT2is. This increase is modestly mediated by elevated triglyceride levels. These findings highlight the need for clinical vigilance regarding anxiety following GLP-1RA discontinuation. Discontinuation of GLP-1 receptor agonists is associated with an increased risk of anxiety disorders in people with type 2 diabetes compared with discontinuation of DPP4 or SGLT2 inhibitors.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1489-1494"},"PeriodicalIF":27.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148416032","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":"Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction","authors":"Anthony S. Grillo","doi":"10.1038/s42255-026-01569-x","DOIUrl":"10.1038/s42255-026-01569-x","url":null,"abstract":"Hypoxia has emerged as an unexpected therapy for some mitochondrial diseases. Garg et al. now extend this concept beyond primary respiratory chain mutations, showing that reducing oxygen tension can rescue a disease of mitochondrial protein quality control linked to the HTRA2–CLPB axis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1633-1635"},"PeriodicalIF":27.5,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408297","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":"Hypoxia rescues complex 1-associated disease caused by proteostatic defects","authors":"Ankur Garg, Brandon R. Desousa, Raju Roy, Amy Flis, Skyler Y. Blume, Yohei Abe, Arthur A. Melo, Ryan R. Cupo, Gabriela Grigorean, Daniel R. Southworth, James Shorter, Isha H. Jain","doi":"10.1038/s42255-026-01566-0","DOIUrl":"10.1038/s42255-026-01566-0","url":null,"abstract":"Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy. Using an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, we find that continuous hypoxia rescues striatal degeneration and extends lifespan. Mechanistically, we demonstrate that HTRA2 forms a functional complex with the disaggregase CLPB. Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction. These changes impair tissue oxygen consumption and probably cause pathological hyperoxia, which is corrected by hypoxia. Together, these findings define a proteostasis pathway linking intermembrane space quality control to complex I function and expand the potential of hypoxia therapy to secondary complex I disease. The HTRA2–CLPB proteostasis system is a mitochondrial quality control module whose dysfunction drives local oxygen toxicity, which can be mitigated by lowering ambient oxygen levels.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 8","pages":"1791-1804"},"PeriodicalIF":27.5,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01566-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408424","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":"Pyruvate leaves its mark on chromatin","authors":"Xin Li, Xiang David Li","doi":"10.1038/s42255-026-01561-5","DOIUrl":"10.1038/s42255-026-01561-5","url":null,"abstract":"Lysine pyruvylation, a newly discovered histone modification installed by HAT1 and p300 and removed by SIRT3, connects the glycolytic metabolite pyruvate to transcriptional regulation, shedding light on metabolism–epigenetics crosstalk.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 7","pages":"1452-1454"},"PeriodicalIF":27.5,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379642","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}