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}
Pub Date : 2026-01-15DOI: 10.1038/s42255-025-01438-z
Youngjae Jo, Narendra R. Joshi, Karthikeyani Chellappa
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.
{"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}
Pub Date : 2026-01-15DOI: 10.1038/s42255-025-01440-5
Hui Ming, Miao Yin, Qun-Ying Lei
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.
{"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}
Pub Date : 2026-01-13DOI: 10.1038/s42255-025-01423-6
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.
{"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}
Pub Date : 2026-01-13DOI: 10.1038/s42255-025-01422-7
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
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.
{"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}
Pub Date : 2026-01-12DOI: 10.1038/s42255-025-01433-4
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
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.
{"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}
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