Nature metabolism最新文献

{"title":"Multi-omics profiling of cachexia-targeted tissues reveals a spatio-temporally coordinated response to cancer","authors":"Pauline Morigny, Michaela Vondrackova, Honglei Ji, Kristyna Brejchova, Monika Krakovkova, Konstantinos Makris, Radka Trubacova, Tuna F. Samanci, Doris Kaltenecker, Su-Ping Ng, Vignesh Karthikaisamy, Sophia E. Chrysostomou, Anna Bidovec, Mariana Ponce-de-Leon, Tanja Krauss, Claudine Seeliger, Olga Prokopchuk, Marc E. Martignoni, Melina Claussnitzer, Hans Hauner, Martina Schweiger, Laure B. Bindels, Mauricio Berriel Diaz, Stephan Herzig, Dominik Lutter, Ondrej Kuda, Maria Rohm","doi":"10.1038/s42255-025-01434-3","DOIUrl":"10.1038/s42255-025-01434-3","url":null,"abstract":"Cachexia is a wasting disorder associated with high morbidity and mortality in patients with cancer. Tumour–host interaction and maladaptive metabolic reprogramming are substantial, yet poorly understood, contributors to cachexia. Here we present a comprehensive overview of the spatio-temporal metabolic reprogramming during cachexia, using integrated metabolomics, RNA sequencing and 13C-glucose tracing data from multiple tissues and tumours of C26 tumour-bearing male mice at different disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice and patients and linked to inflammation, glucose hypermetabolism and atrophy in muscle. The same metabolic rewiring also occurred in five additional mouse models, namely Panc02, 8025, ApcMin, LLC and KPP, and a humanised cachexia mouse model. Together, our study provides a molecular framework for understanding metabolic reprogramming and the multi-tissue metabolite-coordinated response during cancer cachexia progression, with one-carbon metabolism as a tissue-overarching mechanism linked to wasting. Multi-omics profiling of diverse cancer cachexia models uncovers a multi-tissue metabolite-coordinated response associated with disease progression and links multi-tissue one-carbon metabolism to wasting.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"237-259"},"PeriodicalIF":20.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01434-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968780","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":"The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans","authors":"Stefan Christen, Karine Redeuil, Laurence Goulet, Maria-Pilar Giner, Isabelle Breton, Riccardo Rota, Adrien Frézal, Atiye Nazari, Pieter Van den Abbeele, Jean-Philippe Godin, Sophie Nutten, Bernard Cuenoud","doi":"10.1038/s42255-025-01421-8","DOIUrl":"10.1038/s42255-025-01421-8","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD(H)) and its phosphorylated form NADP(H) are vitamin B3-derived redox cofactors essential for numerous metabolic reactions and protein modifications. Various health conditions are associated with disturbances in NAD+ homeostasis. To restore NAD+ levels, the main biosynthetic pathways have been targeted, with nicotinamide (Nam), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) being the most prominent boosters. However, while many preclinical studies have examined the effects of these precursors, a direct comparison in humans is lacking, and recent rodent research suggests that the NAD+-boosting effects of NR and NMN may depend on their microbial conversion to nicotinic acid (NA), a mechanism not yet confirmed in humans. Here we show in a randomized, open-label, placebo-controlled study in 65 healthy participants that 14 days of supplementation with NR and NMN, but not Nam, comparably increases circulatory NAD+ concentrations in healthy adults. Unlike the chronic effect, only Nam acutely and transiently affects the whole-blood NAD+ metabolome. Using ex vivo fermentation with human microbiota, we identify that NR and NMN give rise to NA and specifically enhance microbial growth and metabolism. We further demonstrate ex vivo in whole blood that NA is a potent NAD+ booster, while NMN, NR and Nam are not. Ultimately, we propose a gut-dependent model for the modes of action of the three NAD+ precursors with NR and NMN elevating circulatory NAD+ via the Preiss–Handler pathway, while rapidly absorbed Nam acutely affects NAD+ levels via the salvage pathway. Overall, these results indicate a dual effect of NR and NMN and their microbially produced metabolite NA: a sustained increase in systemic NAD+ levels and a potent modulator of gut health. ClinicalTrials.gov identifier: NCT05517122 . A comparison of the effects of different NAD+ boosters is lacking. This clinical study compares the efficacy of the NAD+ boosters NR, NMN and Nam in increasing circulating NAD+ levels and analyses their effects on gut microbial metabolism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"62-73"},"PeriodicalIF":20.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01421-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968775","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":"The microbiome at the centre of NAD+ supplementation","authors":"Youngjae Jo, Narendra R. Joshi, Karthikeyani Chellappa","doi":"10.1038/s42255-025-01438-z","DOIUrl":"10.1038/s42255-025-01438-z","url":null,"abstract":"Christen et al. present the first comparisons between vitamin B3 and two derivatives that are widely used in humans, showing that the vitamin B3 derivatives rely on microbiome-generated nicotinic acid to synthesize NAD+ and stimulate gut microbial activity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"4-5"},"PeriodicalIF":20.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986413","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":"Spatio-temporal metabolic alterations in cachexia","authors":"Hui Ming, Miao Yin, Qun-Ying Lei","doi":"10.1038/s42255-025-01440-5","DOIUrl":"10.1038/s42255-025-01440-5","url":null,"abstract":"Cachexia is a wasting disorder characterized by progressive metabolic dysregulation. A new study demonstrates using systematic multi-omics analyses that activation of one-carbon metabolism potentially contributes to energy wasting in cachexia, providing in-depth understanding of cachexia in terms of metabolic rewiring.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"12-13"},"PeriodicalIF":20.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990064","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":"Enhanced crosstalk between α- and δ-cells promotes recurrent hypoglycaemia","authors":"","doi":"10.1038/s42255-025-01423-6","DOIUrl":"10.1038/s42255-025-01423-6","url":null,"abstract":"In pancreatic islets, α-cells secrete glucagon in response to hypoglycaemia. We report that neighbouring δ-cells regulate this process via a negative feedback loop. Hypoglycaemia enhances this intercellular crosstalk, resulting in impaired glucagon response and systemic counter-regulation. Targeting this feedback circuit between α- and δ-cells may help to prevent recurrent iatrogenic hypoglycaemia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"14-15"},"PeriodicalIF":20.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961373","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":"Publisher Correction: Gut mucosal mycobiome profiling in Crohn’s disease uncovers an AMP-mediated anti-inflammatory effect of Cladosporium sphaerospermum","authors":"Ziyu Huang, Yunyun Liu, Yushan Wu, Feng Zhang, Leyi Yu, Shanshan Gao, Weijie Wen, Guannan Wang, Runping Su, Pei Xia, Qiming Zhou, Yiran Bie, Peishan Hu, Elke Burgermeister, Ping Lan, Xiaojian Wu, Hu Zhang, Fen Zhang, Emad M. El-Omar, Tao Zuo","doi":"10.1038/s42255-026-01460-9","DOIUrl":"10.1038/s42255-026-01460-9","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 2","pages":"521-521"},"PeriodicalIF":20.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01460-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966739","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":"Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control","authors":"Rui Gao, Samuel Acreman, Haiqiang Dou, Jinfang Ma, Caroline Miranda, Ruiling Zhao, Matthew T. Dickerson, Andrei Tarasov, Qi Zou, Marta Gironella-Torrent, Johan Tolö, Anne Clark, Rui Gao, Yang De Marinis, David A. Jacobson, Joan Camunas-Soler, Tao Yang, Patrik Rorsman, Quan Zhang","doi":"10.1038/s42255-025-01422-7","DOIUrl":"10.1038/s42255-025-01422-7","url":null,"abstract":"Somatostatin, produced by pancreatic islet δ cells, is a key intra-islet paracrine factor that regulates the secretion of the glucoregulatory hormones insulin and glucagon from β cells and α cells, respectively. Here, we show that glutamate and glucagon released by α cells cooperatively activate neighbouring δ cells through AMPA and glucagon receptors, thereby enabling spatiotemporal feedback control of glucagon secretion. Crucially, prior hypoglycaemia enhances this mechanism by sensitizing δ cells to α cell-derived factors and inducing long-lasting structural and functional changes that facilitate δ cell and α cell paracrine interaction. This culminates in somatostatin hypersecretion that impairs counter-regulatory glucagon release. These hypoglycaemia-driven effects were emulated by chemogenetic activation of α cells or high concentrations of exogenous glucagon but prevented by inhibitors of glucagon receptors or the transcription factor CREB. This plasticity represents a key component of the islet’s ‘metabolic memory’, which, through impaired counter-regulatory glucagon secretion, increases the occurrence of recurrent hypoglycaemia that complicates the management of insulin-dependent diabetes. Prior hypoglycemia alters the paracrine interaction between islet α and δ cells, leading to impaired counter-regulatory glucagon secretion through somatostatin hypersecretion, increasing the risk of recurrent hypoglycemia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"159-176"},"PeriodicalIF":20.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956273","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":"Single-cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss","authors":"Anne Loft, Rasmus Rydbirk, Ellen Gammelmark Klinggaard, Elvira Laila Van Hauwaert, Charlotte Wilhelmina Wernberg, Andreas Fønss Møller, Trine Vestergaard Dam, Mohamed Nabil Hassan, Babukrishna Maniyadath, Ronni Nielsen, Aleksander Krag, Joanna Kalucka, Søren Fisker Schmidt, Mette Enok Munk Lauridsen, Jesper Grud Skat Madsen, Susanne Mandrup","doi":"10.1038/s42255-025-01433-4","DOIUrl":"10.1038/s42255-025-01433-4","url":null,"abstract":"Human white adipose tissue undergoes major remodelling during sustained weight gain that may compromise tissue function and drive cardiometabolic comorbidities. Although weight loss reverses many of these complications, the cellular and molecular adaptations of adipose tissue to different weight loss interventions are poorly understood. Here we show how abdominal subcutaneous adipose tissue (SAT) in men and women with severe obesity adapts to modest lifestyle-induced (8–10%) weight loss followed by substantial bariatric surgery-induced (20–45%) weight loss, using single-nucleus RNA sequencing (snRNA-seq) combined with bulk RNA-seq, and three-dimensional light-sheet fluorescence microscopy. To enable interactive exploration, all snRNA-seq data are available in a browsable format on the Single Cell Portal ( SCP2849 ). Lifestyle-induced weight loss activated proadipogenic gene programmes in progenitor cells, indicating early beneficial effects on SAT. Subsequent surgery-induced weight loss drove profound compositional and transcriptional remodelling of SAT, including increased vascularization and marked reduction of myeloid cell populations. Collectively, our study indicates that following major and sustained weight loss, SAT from individuals with severe obesity has the capacity to return to a state comparable to that observed in lean individuals. This resource highlights the compositional and transcriptional remodelling of abdominal subcutaneous adipose tissue (SAT) in humans undergoing initial lifestyle-induced weight loss followed by bariatric surgery, with implications for modulating tissue function, systemic metabolism and inflammation.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"260-278"},"PeriodicalIF":20.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956284","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":"AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis","authors":"Tyler K. T. Smith, Logan K. Townsend, William J. Smiles, Jonathan S. Oakhill, Morgan D. Fullerton, Gregory R. Steinberg","doi":"10.1038/s42255-025-01442-3","DOIUrl":"10.1038/s42255-025-01442-3","url":null,"abstract":"The orchestration of cellular metabolism requires the integration of signals related to energy stores and nutrient availability through multiple overlapping mechanisms. AMP-activated protein kinase (AMPK) is a pivotal energy sensor that responds to reductions in adenylate charge; however, studies over the past decade have also positioned AMPK as a key integrator of nutrient-derived signals that coordinate metabolic function. This Review highlights recent advances in our understanding of how AMPK senses nutrients and regulates metabolic activity across tissues, timescales and cell types. These effects are mediated through the phosphorylation of substrates involved in metabolite trafficking, mitochondrial function, autophagy, transcription, ubiquitination, proliferation and cell survival pathways, including ferroptosis. Particular attention is given to the role of AMPK in the pathophysiology of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular and renal diseases, neurodegenerative disorders and cancer. Collectively, these findings reinforce AMPK as a central metabolic node that aligns cellular behaviour with energetic demand. Continued investigation into its nutrient-sensing mechanisms holds promise for identifying new strategies to restore metabolic balance in disease. In this Review, Smith et al. summarize the most recent findings on AMPK and emphasize its role as a nutrient sensor and in regulating metabolic homeostasis, as well as how AMPK dysregulation contributes to various diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"27-51"},"PeriodicalIF":20.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956125","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 Messengers: testosterone","authors":"Franck Mauvais-Jarvis, Shalender Bhasin","doi":"10.1038/s42255-025-01431-6","DOIUrl":"10.1038/s42255-025-01431-6","url":null,"abstract":"Testosterone, discovered during the endocrine gold rush of the 1930s, was the first hormone chemically synthesized for replacement therapy. In both men and women, testosterone functions directly through the androgen receptor (AR) and indirectly as a prohormone, converted by aromatase into 17β-oestradiol (oestradiol), which activates the oestrogen receptors ERα and ERβ. Testosterone is also metabolized to dihydrotestosterone—a potent, non-aromatizable AR agonist—through steroid 5α-reductases. Testosterone and its metabolites signal through AR- and ER-mediated genomic and rapid non-genomic actions. Long recognized for its role as a sex hormone, mounting evidence underscores the importance of testosterone in the regulation of systemic metabolism in both male and female organisms. Here, we highlight key milestones in the history of testosterone’s discovery and therapeutic applications. Additionally, we synthesize the current understanding of testosterone as a key messenger promoting metabolic homeostasis in preclinical models and humans. Mauvais-Jarvis and Bhasin provide an in-depth review of testosterone’s role in maintaining cardiometabolic health, musculoskeletal integrity and energy balance, drawing on evidence from testosterone replacement therapy in humans and mechanistic research in rodent models.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"52-61"},"PeriodicalIF":20.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145938300","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}