Pub Date : 2025-08-06DOI: 10.1016/j.cmet.2025.07.007
Edgar Bernardo, Matías Gonzalo De Vas, Diego Balboa, Mirabai Cuenca-Ardura, Sílvia Bonàs-Guarch, Mercè Planas-Fèlix, Fanny Mollandin, Miquel Torrens-Dinarès, Miguel Angel Maestro, Javier García-Hurtado, Sonia Moratinos, Philippe Ravassard, Haiqiang Dou, Holger Heyn, Alexander van Oudenaarden, Nathalie Groen, Eelco de Koning, Christian Conrad, Roland Eils, Santiago Vernia, Jorge Ferrer
Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic β cell dysfunction and insulin resistance, whose pathophysiology remains poorly understood. HNF1A, which encodes transcription factor hepatocyte nuclear factor-1 alpha, is the most commonly mutated gene in Mendelian diabetes. HNF1A also carries loss- or gain-of-function coding variants that respectively predispose to or protect against polygenic T2D. The mechanisms underlying HNF1A-deficient diabetes, however, are still unclear. We now demonstrate that diabetes arises from β cell-autonomous defects and identify direct β cell genomic targets of HNF1A. This uncovered a regulatory axis where HNF1A controls transcription of A1CF, which orchestrates an RNA splicing program encompassing genes that regulate β cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in β cells from T2D individuals, while genetic variants reducing pancreatic islet A1CF are associated with increased glycemia and T2D susceptibility. Our findings, therefore, identify a linear hierarchy that coordinates β cell-specific transcription and splicing programs and link this pathway to T2D pathogenesis.
{"title":"HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes","authors":"Edgar Bernardo, Matías Gonzalo De Vas, Diego Balboa, Mirabai Cuenca-Ardura, Sílvia Bonàs-Guarch, Mercè Planas-Fèlix, Fanny Mollandin, Miquel Torrens-Dinarès, Miguel Angel Maestro, Javier García-Hurtado, Sonia Moratinos, Philippe Ravassard, Haiqiang Dou, Holger Heyn, Alexander van Oudenaarden, Nathalie Groen, Eelco de Koning, Christian Conrad, Roland Eils, Santiago Vernia, Jorge Ferrer","doi":"10.1016/j.cmet.2025.07.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.007","url":null,"abstract":"Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic β cell dysfunction and insulin resistance, whose pathophysiology remains poorly understood. <em>HNF1A</em>, which encodes transcription factor hepatocyte nuclear factor-1 alpha, is the most commonly mutated gene in Mendelian diabetes. <em>HNF1A</em> also carries loss- or gain-of-function coding variants that respectively predispose to or protect against polygenic T2D. The mechanisms underlying HNF1A-deficient diabetes, however, are still unclear. We now demonstrate that diabetes arises from β cell-autonomous defects and identify direct β cell genomic targets of HNF1A. This uncovered a regulatory axis where HNF1A controls transcription of <em>A1CF</em>, which orchestrates an RNA splicing program encompassing genes that regulate β cell function. This <em>HNF1A</em>-<em>A1CF</em> transcription-splicing axis is suppressed in β cells from T2D individuals, while genetic variants reducing pancreatic islet <em>A1CF</em> are associated with increased glycemia and T2D susceptibility. Our findings, therefore, identify a linear hierarchy that coordinates β cell-specific transcription and splicing programs and link this pathway to T2D pathogenesis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.06.005
Eugenio Barone, D. Allan Butterfield
Insulin resistance is a risk factor for Alzheimer’s disease (AD). Chen et al.1 show that microglial insulin signaling is essential for metabolic homeostasis and immune regulation, while insulin resistance impairs Aβ clearance and promotes neuroinflammation in AD. Their findings reframe AD pathogenesis through a cell-type-specific lens.
{"title":"Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer’s disease","authors":"Eugenio Barone, D. Allan Butterfield","doi":"10.1016/j.cmet.2025.06.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.005","url":null,"abstract":"Insulin resistance is a risk factor for Alzheimer’s disease (AD). Chen et al.<span><span><sup>1</sup></span></span> show that microglial insulin signaling is essential for metabolic homeostasis and immune regulation, while insulin resistance impairs Aβ clearance and promotes neuroinflammation in AD. Their findings reframe AD pathogenesis through a cell-type-specific lens.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"27 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.07.003
Sharmili Edwin Thanarajah, Sita Arjune, Ruth Hanssen
Despite advances in elucidating obesity pathophysiology, predicting individual responses to weight loss interventions remains challenging. Cifuentes et al.1 developed a predictive model integrating genetic risk scores and anthropometric parameters to estimate caloric intake to satiation, demonstrating potential in forecasting weight loss trajectories with phentermine-topiramate and liraglutide therapies.
{"title":"Calories to satiation—A new predictor of anti-obesity therapy outcome?","authors":"Sharmili Edwin Thanarajah, Sita Arjune, Ruth Hanssen","doi":"10.1016/j.cmet.2025.07.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.003","url":null,"abstract":"Despite advances in elucidating obesity pathophysiology, predicting individual responses to weight loss interventions remains challenging. Cifuentes et al.<span><span><sup>1</sup></span></span> developed a predictive model integrating genetic risk scores and anthropometric parameters to estimate caloric intake to satiation, demonstrating potential in forecasting weight loss trajectories with phentermine-topiramate and liraglutide therapies.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"20 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.06.007
Nicole M. Avena, Mark S. Gold, Ashley N. Gearhardt
Section snippets
Main text
This letter responds to the study by Darcey et al.1 The authors conclude that there was “no significant post-ingestive striatal dopamine response to an ultra-processed milkshake” and argue that this challenges the idea that ultra-processed foods (UPFs) drive overeating by triggering dopamine surges similar to those seen with drugs of abuse.1While we appreciate research aimed at understanding how UPFs affect the brain and their role in obesity and metabolic syndrome, we believe key
{"title":"Missed signals: How PET imaging may fail to capture the addictive potential of ultra-processed foods","authors":"Nicole M. Avena, Mark S. Gold, Ashley N. Gearhardt","doi":"10.1016/j.cmet.2025.06.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.007","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>This letter responds to the study by Darcey et al.<sup>1</sup> The authors conclude that there was “no significant post-ingestive striatal dopamine response to an ultra-processed milkshake” and argue that this challenges the idea that ultra-processed foods (UPFs) drive overeating by triggering dopamine surges similar to those seen with drugs of abuse.<sup>1</sup>While we appreciate research aimed at understanding how UPFs affect the brain and their role in obesity and metabolic syndrome, we believe key</section></section><section><section><h2>Declaration of interests</h2>The authors declare no competing interests.</section></section>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.07.002
Lin Wang, Kaili Ma, Lianjun Zhang, Ping-Chih Ho
In a recent Molecular Cell study,1 Zhou et al. elucidated how glycogenolysis-derived glucose-1-phosphate mediates source-specific routing of glucose-6-phosphate into the pentose phosphate pathway through allosteric activation of glucose-6-phosphate dehydrogenase and liquid-liquid phase separation-mediated metabolic compartments. This compartmentalized distribution enables efficient reduced nicotinamide adenine dinucleotide phosphate (NADPH) generation from glycogenolytic flux, promoting Tm cell persistence by maintaining redox homeostasis.
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.06.006
Kevin D. Hall, Valerie L. Darcey
Section snippets
Main text
We had not anticipated that our recent paper in Cell Metabolism reporting surprisingly null results for one of its primary outcomes1 would cause so much consternation. Our empirical evidence ran against preconceived narratives (including our own) and caused a cascade of previously unimaginable events.Despite our paper emphasizing that our study’s “results do not imply that ultra-processed foods high in fat and sugar are not addictive,” it seems that several readers believe we suggested
{"title":"The peril of preconceived narratives","authors":"Kevin D. Hall, Valerie L. Darcey","doi":"10.1016/j.cmet.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.006","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>We had not anticipated that our recent paper in <em>Cell Metabolism</em> reporting surprisingly null results for one of its primary outcomes<sup>1</sup> would cause so much consternation. Our empirical evidence ran against preconceived narratives (including our own) and caused a cascade of previously unimaginable events.Despite our paper emphasizing that our study’s “results do not imply that ultra-processed foods high in fat and sugar are not addictive,” it seems that several readers believe we suggested</section></section><section><section><h2>Declaration of interests</h2>The authors declare no competing interests.</section></section>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"730 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.06.008
Natasha Kim de Oliveira da Fonseca, Elisa Brietzke
Section snippets
Main text
The recent study by Darcey et al.1 offers a thought-provoking contribution to our understanding of how the human brain responds to ultra-processed foods, particularly in relation to striatal dopamine signaling and adiposity. Using a rigorous positron emission tomography (PET) imaging protocol, the authors report high interindividual variability and an absence of significant association between dopaminergic response and body fat. These findings challenge reductionist views of food addiction as a
{"title":"Ultra-processed foods and dopamine: Parsing complexity beyond observed variability","authors":"Natasha Kim de Oliveira da Fonseca, Elisa Brietzke","doi":"10.1016/j.cmet.2025.06.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.008","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>The recent study by Darcey et al.<sup>1</sup> offers a thought-provoking contribution to our understanding of how the human brain responds to ultra-processed foods, particularly in relation to striatal dopamine signaling and adiposity. Using a rigorous positron emission tomography (PET) imaging protocol, the authors report high interindividual variability and an absence of significant association between dopaminergic response and body fat. These findings challenge reductionist views of food addiction as a</section></section><section><section><h2>Declaration of interests</h2>The authors declare no competing interests.</section></section>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"29 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.07.004
Takuya Karasawa, Ran Hee Choi, Cesar A. Meza, Subhasmita Rout, Micah J. Drummond, Amandine Chaix, Katsuhiko Funai
Section snippets
Main text
Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as semaglutide, represent a significant breakthrough in pharmacological interventions to treat obesity. Meanwhile, there have been recent concerns that GLP-1R agonist treatment leads to a loss of lean mass, potentially compromising physical functions and quality of life, particularly in those susceptible to sarcopenia. In the STEP-1 trial of semaglutide, lean mass was reduced by 6.92 kg with a weight reduction of 15.3 kg, indicating that
Acknowledgments
This work was supported by NIH grants DK107397, DK127979, GM144613, and AG074535 to K.F.; CA286584 and AG065993 to A.C.; and AG076075 and AG086328 to M.J.D. and the grant-in-aid for Japan Society for Promotion of Science (JSPS) Fellows 24KJ2039 to T.K.
Author contributions
T.K., R.H.C., M.J.D., A.C., and K.F. conceived the project and designed the experiments. T.K., R.H.C., and C.A.M. conducted the majority of experiments for this manuscript. S.R. assisted with tissue histological analyses. T.K. and K.F. wrote the manuscript. This manuscript was reviewed, revised, and given approval by all authors for publication. K.F. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity and the
{"title":"Unexpected effects of semaglutide on skeletal muscle mass and force-generating capacity in mice","authors":"Takuya Karasawa, Ran Hee Choi, Cesar A. Meza, Subhasmita Rout, Micah J. Drummond, Amandine Chaix, Katsuhiko Funai","doi":"10.1016/j.cmet.2025.07.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.004","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as semaglutide, represent a significant breakthrough in pharmacological interventions to treat obesity. Meanwhile, there have been recent concerns that GLP-1R agonist treatment leads to a loss of lean mass, potentially compromising physical functions and quality of life, particularly in those susceptible to sarcopenia. In the STEP-1 trial of semaglutide, lean mass was reduced by 6.92 kg with a weight reduction of 15.3 kg, indicating that</section></section><section><section><h2>Acknowledgments</h2>This work was supported by <span>NIH</span> grants <!-- -->DK107397<!-- -->, <!-- -->DK127979<!-- -->, <!-- -->GM144613<!-- -->, and <!-- -->AG074535<!-- --> to K.F.; <!-- -->CA286584<!-- --> and <!-- -->AG065993<!-- --> to A.C.; and <!-- -->AG076075<!-- --> and <!-- -->AG086328<!-- --> to M.J.D. and the grant-in-aid for <span>Japan Society for Promotion of Science</span> (<span>JSPS</span>) Fellows <!-- -->24KJ2039<!-- --> to T.K.</section></section><section><section><h2>Author contributions</h2>T.K., R.H.C., M.J.D., A.C., and K.F. conceived the project and designed the experiments. T.K., R.H.C., and C.A.M. conducted the majority of experiments for this manuscript. S.R. assisted with tissue histological analyses. T.K. and K.F. wrote the manuscript. This manuscript was reviewed, revised, and given approval by all authors for publication. K.F. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity and the</section></section><section><section><h2>Declaration of interests</h2>The authors declare no competing interests.</section></section>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"46 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.07.005
Yan Yue, Shiping Li, Dezhi Mu
Atherosclerosis (AS) is an independent risk factor for vascular cognitive impairment (VCI). Zhang et al.1 revealed that foam cell-derived exosomes transmit redox imbalance and metabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis, causing microglial dysfunction and exacerbating VCI, uncovering a peripheral-brain link and potential therapeutic targets for AS-induced VCI.
{"title":"Foam cell-derived exosomes: Messengers between atherosclerosis and microglia","authors":"Yan Yue, Shiping Li, Dezhi Mu","doi":"10.1016/j.cmet.2025.07.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.005","url":null,"abstract":"Atherosclerosis (AS) is an independent risk factor for vascular cognitive impairment (VCI). Zhang et al.<span><span><sup>1</sup></span></span> revealed that foam cell-derived exosomes transmit redox imbalance and metabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis, causing microglial dysfunction and exacerbating VCI, uncovering a peripheral-brain link and potential therapeutic targets for AS-induced VCI.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"29 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.cmet.2025.07.006
Joseph Longo, Lisa M. DeCamp, Brandon M. Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S. Dahabieh, Abigail E. Ellis, Michael P. Vincent, Hannah Damico, Kristin L. Gallik, Nicole M. Foy, Shelby E. Compton, Colt D. Capan, Kelsey S. Williams, Corinne R. Esquibel, Zachary B. Madaj, Hyoungjoo Lee, Dominic G. Roy, Connie M. Krawczyk, Brian B. Haab, Russell G. Jones
Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2), UDP-Gal-4-epimerase (GALE), or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8+ T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression, cytolytic activity, and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose—beyond energy production—that is required for CD8+ T cell responses in vivo.
{"title":"Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control","authors":"Joseph Longo, Lisa M. DeCamp, Brandon M. Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S. Dahabieh, Abigail E. Ellis, Michael P. Vincent, Hannah Damico, Kristin L. Gallik, Nicole M. Foy, Shelby E. Compton, Colt D. Capan, Kelsey S. Williams, Corinne R. Esquibel, Zachary B. Madaj, Hyoungjoo Lee, Dominic G. Roy, Connie M. Krawczyk, Brian B. Haab, Russell G. Jones","doi":"10.1016/j.cmet.2025.07.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.006","url":null,"abstract":"Glucose is essential for T cell proliferation and function, yet its specific metabolic roles <em>in vivo</em> remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8<sup>+</sup> T cell expansion and cytotoxic function <em>in vivo</em>. Using <sup>13</sup>C-based stable isotope tracing, we demonstrate that CD8<sup>+</sup> effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2), UDP-Gal-4-epimerase (GALE), or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8<sup>+</sup> T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8<sup>+</sup> T cells display reduced granzyme expression, cytolytic activity, and tumor control <em>in vivo</em>. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose—beyond energy production—that is required for CD8<sup>+</sup> T cell responses <em>in vivo</em>.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"95 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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