Pub Date : 2026-01-21DOI: 10.1038/s42255-025-01439-y
Kang Lei, Xinyu Li, Ting Zhong, Rong Tang, Qiaolin Deng, Paul E. Love, Zhiguang Zhou, Bin Zhao, Xia Li
The innate immune system is increasingly recognized as a contributor to the development of type 1 diabetes (T1D), but the role of natural killer (NK) cells remains largely unclear. Here, we identify an expanded subset of transcriptionally active CD226+CD56dimCD16+ NK cells at the onset of T1D that contracts in remission. Using single-cell RNA sequencing integrated with cross-sectional and longitudinal analyses in patients with T1D, we show that CD226+ NK cell frequency correlates with disease progression. CD226+ NK cells exhibit enhanced cytotoxicity, inflammation and glucose metabolism. Mechanistically, CD161+CD4+ T cells promote pathogenic NK cell generation through interleukin-21 (IL-21) and mTOR signalling. Inhibition of this pathway by CD226 blockade, IL-21 receptor fusion protein, IL-21 knockout or mTOR inhibition attenuates NK cell activation, reduces pancreatic infiltration and delays diabetes onset in female mice. Our data reveal a mechanistic link, bridging adaptive and innate immunity, in the progression and remission of T1D that could potentially be exploited in T1D immunotherapy. A pathogenic subset of NK cells is identified that promotes type 1 diabetes and is generated via T cell-derived IL-21.
{"title":"IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes","authors":"Kang Lei, Xinyu Li, Ting Zhong, Rong Tang, Qiaolin Deng, Paul E. Love, Zhiguang Zhou, Bin Zhao, Xia Li","doi":"10.1038/s42255-025-01439-y","DOIUrl":"10.1038/s42255-025-01439-y","url":null,"abstract":"The innate immune system is increasingly recognized as a contributor to the development of type 1 diabetes (T1D), but the role of natural killer (NK) cells remains largely unclear. Here, we identify an expanded subset of transcriptionally active CD226+CD56dimCD16+ NK cells at the onset of T1D that contracts in remission. Using single-cell RNA sequencing integrated with cross-sectional and longitudinal analyses in patients with T1D, we show that CD226+ NK cell frequency correlates with disease progression. CD226+ NK cells exhibit enhanced cytotoxicity, inflammation and glucose metabolism. Mechanistically, CD161+CD4+ T cells promote pathogenic NK cell generation through interleukin-21 (IL-21) and mTOR signalling. Inhibition of this pathway by CD226 blockade, IL-21 receptor fusion protein, IL-21 knockout or mTOR inhibition attenuates NK cell activation, reduces pancreatic infiltration and delays diabetes onset in female mice. Our data reveal a mechanistic link, bridging adaptive and innate immunity, in the progression and remission of T1D that could potentially be exploited in T1D immunotherapy. A pathogenic subset of NK cells is identified that promotes type 1 diabetes and is generated via T cell-derived IL-21.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"177-195"},"PeriodicalIF":20.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006252","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}
Pub Date : 2026-01-20DOI: 10.1038/s42255-025-01429-0
Daniele Neri,Seoeun Lee,Alexis M Fohn,Xinhong Chen,Dominique Bozec,Alexandre J Lafond,Natalie R Lopatinsky,Lucas Castro E Souza,Gawri Mohanan Nair,Angela M Ramos-Lobo,Markus Heine,Anna Worthmann,Joerg Heeren,Vidhu V Thaker,Viviana Gradinaru,Lori M Zeltser
Brown adipose tissue (BAT) contributes to thermoregulation and glucose metabolism, but how these functions are coordinated remains unclear. While thermogenesis in the activated BAT typically coincides with increased blood flow and glucose uptake1-5, several pathophysiological and nutritional states dissociate these processes6,7, suggesting they are governed by distinct sympathetic circuits. Here we identify subpopulations of sympathetic neurons in the stellate ganglion that mediate distinct functions of intrascapular BAT (iBAT) in mice. Two main types of sympathetic neurons project to iBAT: those that innervate the organ parenchyma and those that innervate the large blood vessels feeding the depot8-12. Here we develop a toolkit to parse the functions of these neuronal subclasses through targeted chemogenetic activation of projections to iBAT, while sparing other organs, and single-cell transcriptomics coupled to retrograde tracing from iBAT to the stellate ganglion. We find that stimulation of the parenchymal projections increases blood flow and thermogenesis in iBAT, without affecting circulating glucose levels. Conversely, stimulation of the vascular projections improves glucose tolerance but does not alter blood flow or thermogenesis in iBAT. These data provide a mechanistic explanation for the dissociation between the thermogenic and glycaemic effects of BAT activation13-16.
{"title":"Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance.","authors":"Daniele Neri,Seoeun Lee,Alexis M Fohn,Xinhong Chen,Dominique Bozec,Alexandre J Lafond,Natalie R Lopatinsky,Lucas Castro E Souza,Gawri Mohanan Nair,Angela M Ramos-Lobo,Markus Heine,Anna Worthmann,Joerg Heeren,Vidhu V Thaker,Viviana Gradinaru,Lori M Zeltser","doi":"10.1038/s42255-025-01429-0","DOIUrl":"https://doi.org/10.1038/s42255-025-01429-0","url":null,"abstract":"Brown adipose tissue (BAT) contributes to thermoregulation and glucose metabolism, but how these functions are coordinated remains unclear. While thermogenesis in the activated BAT typically coincides with increased blood flow and glucose uptake1-5, several pathophysiological and nutritional states dissociate these processes6,7, suggesting they are governed by distinct sympathetic circuits. Here we identify subpopulations of sympathetic neurons in the stellate ganglion that mediate distinct functions of intrascapular BAT (iBAT) in mice. Two main types of sympathetic neurons project to iBAT: those that innervate the organ parenchyma and those that innervate the large blood vessels feeding the depot8-12. Here we develop a toolkit to parse the functions of these neuronal subclasses through targeted chemogenetic activation of projections to iBAT, while sparing other organs, and single-cell transcriptomics coupled to retrograde tracing from iBAT to the stellate ganglion. We find that stimulation of the parenchymal projections increases blood flow and thermogenesis in iBAT, without affecting circulating glucose levels. Conversely, stimulation of the vascular projections improves glucose tolerance but does not alter blood flow or thermogenesis in iBAT. These data provide a mechanistic explanation for the dissociation between the thermogenic and glycaemic effects of BAT activation13-16.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"30 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005100","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}
Pub Date : 2026-01-20DOI: 10.1038/s42255-025-01435-2
Xun Huang,Li Ye
{"title":"Heterogeneous sympathetic control of brown adipose tissue.","authors":"Xun Huang,Li Ye","doi":"10.1038/s42255-025-01435-2","DOIUrl":"https://doi.org/10.1038/s42255-025-01435-2","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"39 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005099","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}
Psychological stress is increasingly linked to liver disease, but the underlying mechanisms remain unclear. Here we show that chronic stress disrupts a brain–liver circuit that impairs hepatic CD8+ T cell immunity and accelerates liver cancer progression. Using both oncogene-driven and carcinogen-driven liver cancer models in male mice, we find that psychological stress disrupts catecholamine/β2-adrenergic receptor (ADRB2) signalling, which suppresses the expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme of the kynurenine pathway, in hepatocytes. QPRT loss diverts kynurenine metabolism away from nicotinamide adenine dinucleotide (NAD+) synthesis towards kynurenic acid (KA) accumulation. This shift results in mitochondrial impairment and reduced effector function of liver CD8+ T cells. We confirm that ADRB2/QPRT expression correlates with hepatic NAD+ and KA levels and with CD8+ T cell frequency and function in human liver tissues. Importantly, ADRB2/QPRT overexpression in hepatocytes, or nicotinamide administration, recovers CD8+ T cell function in stressed mice and reduces liver cancer progression. These findings identify a stress-responsive metabolic checkpoint in the liver that links the nervous system to immune surveillance and may be therapeutically targeted in liver cancers. Psychological stress-mediated dysregulation of catecholamine signalling rewires the hepatic kynurenine pathway, which in turn impairs liver CD8+ T cell function and promotes liver cancer progression.
{"title":"Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance","authors":"Renhui Sun, Deyan Jiao, Wenjing Yuan, Hao Wang, Lingtong Ren, Zhendong Fu, Jiaxuan Zhang, Xuetian Yue, Zhuanchang Wu, Chunyang Li, Huili Hu, Jianping Wang, Lifen Gao, Chunhong Ma, Xiaohong Liang","doi":"10.1038/s42255-025-01430-7","DOIUrl":"10.1038/s42255-025-01430-7","url":null,"abstract":"Psychological stress is increasingly linked to liver disease, but the underlying mechanisms remain unclear. Here we show that chronic stress disrupts a brain–liver circuit that impairs hepatic CD8+ T cell immunity and accelerates liver cancer progression. Using both oncogene-driven and carcinogen-driven liver cancer models in male mice, we find that psychological stress disrupts catecholamine/β2-adrenergic receptor (ADRB2) signalling, which suppresses the expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme of the kynurenine pathway, in hepatocytes. QPRT loss diverts kynurenine metabolism away from nicotinamide adenine dinucleotide (NAD+) synthesis towards kynurenic acid (KA) accumulation. This shift results in mitochondrial impairment and reduced effector function of liver CD8+ T cells. We confirm that ADRB2/QPRT expression correlates with hepatic NAD+ and KA levels and with CD8+ T cell frequency and function in human liver tissues. Importantly, ADRB2/QPRT overexpression in hepatocytes, or nicotinamide administration, recovers CD8+ T cell function in stressed mice and reduces liver cancer progression. These findings identify a stress-responsive metabolic checkpoint in the liver that links the nervous system to immune surveillance and may be therapeutically targeted in liver cancers. Psychological stress-mediated dysregulation of catecholamine signalling rewires the hepatic kynurenine pathway, which in turn impairs liver CD8+ T cell function and promotes liver cancer progression.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"196-214"},"PeriodicalIF":20.8,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003854","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}
Pub Date : 2026-01-19DOI: 10.1038/s42255-025-01446-z
Gerard Clarke, Lily Keane, John F. Cryan
In this issue of Nature Metabolism, Sun et al. show that the kynurenine pathway of tryptophan metabolism links stress-induced impairment of immune surveillance to liver cancer progression.
{"title":"Hepatic tryptophan metabolism links chronic stress to liver cancer","authors":"Gerard Clarke, Lily Keane, John F. Cryan","doi":"10.1038/s42255-025-01446-z","DOIUrl":"10.1038/s42255-025-01446-z","url":null,"abstract":"In this issue of Nature Metabolism, Sun et al. show that the kynurenine pathway of tryptophan metabolism links stress-induced impairment of immune surveillance to liver cancer progression.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"10-11"},"PeriodicalIF":20.8,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003887","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}
Pub Date : 2026-01-16DOI: 10.1038/s42255-025-01428-1
Kimberly S. Huggler, Kyle M. Flickinger, Matthew H. Forsberg, Carlos A. Mellado Fritz, Gavin R. Chang, Meghan F. McGuire, Christian M. Capitini, Jason R. Cantor
Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis. Hexokinase detachment from the outer mitochondrial membrane is shown to support aerobic glycolysis in cancer cells. Differential localization of the HK1 isoform to the outer mitochondrial membrane, compared to the HK2 isoform, explains the conditional essentiality of HK2 in cancer cells cultured in physiologic media.
{"title":"Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production","authors":"Kimberly S. Huggler, Kyle M. Flickinger, Matthew H. Forsberg, Carlos A. Mellado Fritz, Gavin R. Chang, Meghan F. McGuire, Christian M. Capitini, Jason R. Cantor","doi":"10.1038/s42255-025-01428-1","DOIUrl":"10.1038/s42255-025-01428-1","url":null,"abstract":"Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis. Hexokinase detachment from the outer mitochondrial membrane is shown to support aerobic glycolysis in cancer cells. Differential localization of the HK1 isoform to the outer mitochondrial membrane, compared to the HK2 isoform, explains the conditional essentiality of HK2 in cancer cells cultured in physiologic media.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"215-236"},"PeriodicalIF":20.8,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990090","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}
Pub Date : 2026-01-16DOI: 10.1038/s42255-025-01445-0
Rodrigo Fernández-Verdejo,Kaja Falkenhain,José E Galgani,Eric Ravussin
{"title":"Standardizing the analysis and visualization of human energy expenditure data.","authors":"Rodrigo Fernández-Verdejo,Kaja Falkenhain,José E Galgani,Eric Ravussin","doi":"10.1038/s42255-025-01445-0","DOIUrl":"https://doi.org/10.1038/s42255-025-01445-0","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"221 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986412","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}
Pub Date : 2026-01-15DOI: 10.1038/s42255-025-01434-3
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
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.
{"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}
Pub Date : 2026-01-15DOI: 10.1038/s42255-025-01421-8
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
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.
{"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}
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