Pub Date : 2026-02-03DOI: 10.1038/s42255-026-01461-8
Reduced mitochondrial activity during development triggers a specific superoxide signal that downregulates the biosynthesis of unsaturated fatty acids. This metabolic shift limits lipid peroxidation, preserving nuclear envelope integrity and delaying ageing in Caenorhabditis elegans and in mammalian cells.
{"title":"Mitochondrial superoxide signals shield the nucleus to delay ageing","authors":"","doi":"10.1038/s42255-026-01461-8","DOIUrl":"10.1038/s42255-026-01461-8","url":null,"abstract":"Reduced mitochondrial activity during development triggers a specific superoxide signal that downregulates the biosynthesis of unsaturated fatty acids. This metabolic shift limits lipid peroxidation, preserving nuclear envelope integrity and delaying ageing in Caenorhabditis elegans and in mammalian cells.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 2","pages":"297-298"},"PeriodicalIF":20.8,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113661","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 : 2026-01-30DOI: 10.1038/s42255-025-01437-0
Fedra Luciano-Mateo, Joaquim Moreno-Caceres, Miguel Hernández-Madrigal, Franziska Püschel, Lidia Collado-Rodriguez, Francesca Favaro, Sara Hijazo-Pechero, Mabel Cruz-Rodríguez, Felipe Jiménez-Hernández, Verónica Villagrasa-Araya, Nil Figueras-Duch, Jaime Redondo-Pedraza, Didac Palau-Gallinat, Silvia Plans-Marin, Agnés Figueras, Pedro Fuentes Varela, Lidia de Benito-Gómez, Antonio Gentilella, José Carlos Perales, Xavier Solé, Andrés Méndez-Lucas, Francesc Viñals, Ernest Nadal, Cristina Muñoz-Pinedo
Glucose deficiency promotes the secretion of cytokines and inflammatory factors to rewire the immune compartment and restore blood flow. Here we show that cancer cells subjected to glucose deprivation or hypoxia, but not to other metabolic stressors, secrete LIF, an interleukin-6 family cytokine implicated in the development of solid tumours. We find that mannose supplementation prevents LIF release by sustaining multiple metabolic pathways in the absence of glucose. Mechanistically, LIF release is associated with impairment of N-glycosylation and activation of PERK and MEK MAP kinases. In mouse models of non-small-cell lung cancer, reduction of LIF impairs angiogenesis and tumour growth, rewires the immune system toward an antitumour phenotype and inhibits tumour implantation in the lung. In individuals with non-small-cell lung cancer, LIF levels correlate with markers of hypoxia, glucose deprivation and angiogenesis. Overall, these findings identify LIF as a metabolic stress-induced cytokine that could be targeted to disrupt adaptive responses in cancer. Glucose deprivation triggers the secretion of the cytokine LIF, which promotes angiogenesis and immune suppression in lung cancer models.
{"title":"Glucose deprivation drives LIF-dependent lung cancer","authors":"Fedra Luciano-Mateo, Joaquim Moreno-Caceres, Miguel Hernández-Madrigal, Franziska Püschel, Lidia Collado-Rodriguez, Francesca Favaro, Sara Hijazo-Pechero, Mabel Cruz-Rodríguez, Felipe Jiménez-Hernández, Verónica Villagrasa-Araya, Nil Figueras-Duch, Jaime Redondo-Pedraza, Didac Palau-Gallinat, Silvia Plans-Marin, Agnés Figueras, Pedro Fuentes Varela, Lidia de Benito-Gómez, Antonio Gentilella, José Carlos Perales, Xavier Solé, Andrés Méndez-Lucas, Francesc Viñals, Ernest Nadal, Cristina Muñoz-Pinedo","doi":"10.1038/s42255-025-01437-0","DOIUrl":"10.1038/s42255-025-01437-0","url":null,"abstract":"Glucose deficiency promotes the secretion of cytokines and inflammatory factors to rewire the immune compartment and restore blood flow. Here we show that cancer cells subjected to glucose deprivation or hypoxia, but not to other metabolic stressors, secrete LIF, an interleukin-6 family cytokine implicated in the development of solid tumours. We find that mannose supplementation prevents LIF release by sustaining multiple metabolic pathways in the absence of glucose. Mechanistically, LIF release is associated with impairment of N-glycosylation and activation of PERK and MEK MAP kinases. In mouse models of non-small-cell lung cancer, reduction of LIF impairs angiogenesis and tumour growth, rewires the immune system toward an antitumour phenotype and inhibits tumour implantation in the lung. In individuals with non-small-cell lung cancer, LIF levels correlate with markers of hypoxia, glucose deprivation and angiogenesis. Overall, these findings identify LIF as a metabolic stress-induced cytokine that could be targeted to disrupt adaptive responses in cancer. Glucose deprivation triggers the secretion of the cytokine LIF, which promotes angiogenesis and immune suppression in lung cancer models.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 2","pages":"410-430"},"PeriodicalIF":20.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088910","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 : 2026-01-29DOI: 10.1038/s42255-025-01441-4
Theresia H. Mina, Pritesh R. Jain, Nita G. Forouhi, John C. Chambers
Obesity, diabetes and cardiovascular disease are rising rapidly in Asia. Population-based data consistently show that Asians are at higher risk for these non-communicable diseases than their European counterparts, especially when living in urban and migrant settings. Contrary to initial hypotheses, genetic susceptibility factors only partially explain globally divergent health outcomes. In this Perspective, we discuss potential additional mechanisms to explain this divergence. We review the global disparities in the cardiometabolic disease burden and the role of genetic variation. We then summarize potential pathways linking prenatal and postnatal adversity with unfavourable nutrition, increased adiposity and altered metabolic well-being in Asian populations. In parallel, molecular epidemiological studies are providing insights into how life-course exposures and environmental adversity intersect with adverse nutrition to establish the functional genomic changes that may drive cardiometabolic risk in global Asian populations. We highlight opportunities in precision health studies to advance Asian health through the identification of underlying aetiology critical to the development of effective interventions to promote and maintain metabolic health in current and future generations of Asian individuals worldwide. In this Perspective, the authors discuss reasons for the increased cardiometabolic disease risk observed in Asian populations, including nutrition, genetic factors and environmental adversity.
{"title":"Adversity, adiposity, nutrition and metabolic well-being in multi-ethnic Asia","authors":"Theresia H. Mina, Pritesh R. Jain, Nita G. Forouhi, John C. Chambers","doi":"10.1038/s42255-025-01441-4","DOIUrl":"10.1038/s42255-025-01441-4","url":null,"abstract":"Obesity, diabetes and cardiovascular disease are rising rapidly in Asia. Population-based data consistently show that Asians are at higher risk for these non-communicable diseases than their European counterparts, especially when living in urban and migrant settings. Contrary to initial hypotheses, genetic susceptibility factors only partially explain globally divergent health outcomes. In this Perspective, we discuss potential additional mechanisms to explain this divergence. We review the global disparities in the cardiometabolic disease burden and the role of genetic variation. We then summarize potential pathways linking prenatal and postnatal adversity with unfavourable nutrition, increased adiposity and altered metabolic well-being in Asian populations. In parallel, molecular epidemiological studies are providing insights into how life-course exposures and environmental adversity intersect with adverse nutrition to establish the functional genomic changes that may drive cardiometabolic risk in global Asian populations. We highlight opportunities in precision health studies to advance Asian health through the identification of underlying aetiology critical to the development of effective interventions to promote and maintain metabolic health in current and future generations of Asian individuals worldwide. In this Perspective, the authors discuss reasons for the increased cardiometabolic disease risk observed in Asian populations, including nutrition, genetic factors and environmental adversity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"16-26"},"PeriodicalIF":20.8,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071399","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 : 2026-01-28DOI: 10.1038/s42255-025-01449-w
Dan Huang, Ziwei Dai
Metabolism regulates cell fates through the epigenome. Wang, Shi et al. demonstrate that the cell fates of pluripotency, differentiation and ageing emerge from how a nuclear protein channels metabolic fluxes into distinct epigenetic marks by regulating expression of metabolic genes.
{"title":"Methylation, acetylation and cell fate","authors":"Dan Huang, Ziwei Dai","doi":"10.1038/s42255-025-01449-w","DOIUrl":"10.1038/s42255-025-01449-w","url":null,"abstract":"Metabolism regulates cell fates through the epigenome. Wang, Shi et al. demonstrate that the cell fates of pluripotency, differentiation and ageing emerge from how a nuclear protein channels metabolic fluxes into distinct epigenetic marks by regulating expression of metabolic genes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 2","pages":"287-289"},"PeriodicalIF":20.8,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089393","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 : 2026-01-28DOI: 10.1038/s42255-025-01447-y
Using tissue- and ancestry-aware causal inference analyses, we identified 923 genes and 46 proteins whose expression levels causally influence type 2 diabetes risk. Tissue-related heterogeneity was high, whereas ancestry-related heterogeneity was low, although some effects were observed only in non-European populations. These results underscore the need to investigate disease-relevant tissues and diverse populations.
{"title":"Identifying genes and proteins with causal effects on type 2 diabetes risk across tissues and populations","authors":"","doi":"10.1038/s42255-025-01447-y","DOIUrl":"10.1038/s42255-025-01447-y","url":null,"abstract":"Using tissue- and ancestry-aware causal inference analyses, we identified 923 genes and 46 proteins whose expression levels causally influence type 2 diabetes risk. Tissue-related heterogeneity was high, whereas ancestry-related heterogeneity was low, although some effects were observed only in non-European populations. These results underscore the need to investigate disease-relevant tissues and diverse populations.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 2","pages":"295-296"},"PeriodicalIF":20.8,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069972","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 : 2026-01-28DOI: 10.1038/s42255-025-01443-2
Yinuo Wang, Haojie Shi, Janina Wittig, Yonggang Ren, Julio Cordero, Matthias Dewenter, Jessica Mella, Abigail Buchwalter, Johannes Backs, Thomas Wieland, Joerg Heineke, Ingrid Fleming, Sofia-Iris Bibli, Gergana Dobreva
Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases. Lamin A/C in the nuclear lamina is identified as a regulator of cysteine catabolic flux, necessary for cell fate decisions and function.
{"title":"Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming","authors":"Yinuo Wang, Haojie Shi, Janina Wittig, Yonggang Ren, Julio Cordero, Matthias Dewenter, Jessica Mella, Abigail Buchwalter, Johannes Backs, Thomas Wieland, Joerg Heineke, Ingrid Fleming, Sofia-Iris Bibli, Gergana Dobreva","doi":"10.1038/s42255-025-01443-2","DOIUrl":"10.1038/s42255-025-01443-2","url":null,"abstract":"Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases. Lamin A/C in the nuclear lamina is identified as a regulator of cysteine catabolic flux, necessary for cell fate decisions and function.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 2","pages":"431-453"},"PeriodicalIF":20.8,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01443-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057204","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 : 2026-01-27DOI: 10.1038/s42255-025-01444-1
Ozvan Bocher, Ana Luiza Arruda, Satoshi Yoshiji, Chi Zhao, Alicia Huerta-Chagoya, Chen-Yang Su, Xianyong Yin, Davis Cammann, Henry J. Taylor, Jingchun Chen, Ken Suzuki, Ravi Mandla, Ta-Yu Yang, Fumihiko Matsuda, Josep M. Mercader, Jason Flannick, James B. Meigs, Alexis C. Wood, Marijana Vujkovic, Benjamin F. Voight, Cassandra N. Spracklen, Jerome I. Rotter, Andrew P. Morris, Eleftheria Zeggini
Type 2 diabetes (T2D) is a prevalent disease arising from complex molecular mechanisms. Here we leverage T2D genetic associations to identify causal molecular mechanisms in an ancestry-aware and tissue-aware manner. Using two-sample Mendelian randomization corroborated by colocalization across four global ancestries, we analyse 20,307 gene and 1,630 protein expression levels using blood-derived cis-quantitative trait loci (QTLs). We detect causal effects of genetically predicted levels of 335 genes and 46 proteins on T2D risk, with 16.4% and 50% replication in independent cohorts, respectively. Using gene expression cis-QTLs derived from seven T2D-relevant tissues, we identify causal links between the expression of 676 genes and T2D risk, refining known associations such as BAK1 and describing additional ones like CPXM1. Causal effects are mostly shared across ancestries but are highly heterogeneous across tissues. Our findings provide insights into cross-ancestry and tissue-informed multi-omics causal inference approaches and demonstrate their power in uncovering molecular processes driving T2D. Analysing the causal links of gene expression and protein abundance on type 2 diabetes risk in blood and seven tissues related to the disease from individuals of four ancestries, the authors advance our understanding of the genetic architecture of type 2 diabetes
{"title":"Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues","authors":"Ozvan Bocher, Ana Luiza Arruda, Satoshi Yoshiji, Chi Zhao, Alicia Huerta-Chagoya, Chen-Yang Su, Xianyong Yin, Davis Cammann, Henry J. Taylor, Jingchun Chen, Ken Suzuki, Ravi Mandla, Ta-Yu Yang, Fumihiko Matsuda, Josep M. Mercader, Jason Flannick, James B. Meigs, Alexis C. Wood, Marijana Vujkovic, Benjamin F. Voight, Cassandra N. Spracklen, Jerome I. Rotter, Andrew P. Morris, Eleftheria Zeggini","doi":"10.1038/s42255-025-01444-1","DOIUrl":"10.1038/s42255-025-01444-1","url":null,"abstract":"Type 2 diabetes (T2D) is a prevalent disease arising from complex molecular mechanisms. Here we leverage T2D genetic associations to identify causal molecular mechanisms in an ancestry-aware and tissue-aware manner. Using two-sample Mendelian randomization corroborated by colocalization across four global ancestries, we analyse 20,307 gene and 1,630 protein expression levels using blood-derived cis-quantitative trait loci (QTLs). We detect causal effects of genetically predicted levels of 335 genes and 46 proteins on T2D risk, with 16.4% and 50% replication in independent cohorts, respectively. Using gene expression cis-QTLs derived from seven T2D-relevant tissues, we identify causal links between the expression of 676 genes and T2D risk, refining known associations such as BAK1 and describing additional ones like CPXM1. Causal effects are mostly shared across ancestries but are highly heterogeneous across tissues. Our findings provide insights into cross-ancestry and tissue-informed multi-omics causal inference approaches and demonstrate their power in uncovering molecular processes driving T2D. Analysing the causal links of gene expression and protein abundance on type 2 diabetes risk in blood and seven tissues related to the disease from individuals of four ancestries, the authors advance our understanding of the genetic architecture of type 2 diabetes","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 2","pages":"506-520"},"PeriodicalIF":20.8,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01444-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057217","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 : 2026-01-21DOI: 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. Neri et al. develop elegant tools to understand how the sympathetic nervous system regulates intrascapular brown adipose tissue (iBAT) function. Using these tools, they find that sympathetic nerves targeting the iBAT parenchyma control local blood flow and heat production, while those innervating the iBAT vasculature regulate systemic glucose metabolism.
{"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":"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. Neri et al. develop elegant tools to understand how the sympathetic nervous system regulates intrascapular brown adipose tissue (iBAT) function. Using these tools, they find that sympathetic nerves targeting the iBAT parenchyma control local blood flow and heat production, while those innervating the iBAT vasculature regulate systemic glucose metabolism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 2","pages":"313-326"},"PeriodicalIF":20.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01429-0.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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