Pub Date : 2024-12-17DOI: 10.1016/j.cmet.2024.11.004
Francesca Ligorio, Andrea Vingiani, Tommaso Torelli, Caterina Sposetti, Lorenzo Drufuca, Fabio Iannelli, Lucrezia Zanenga, Catherine Depretto, Secondo Folli, Gianfranco Scaperrotta, Giuseppe Capri, Giulia V. Bianchi, Cristina Ferraris, Gabriele Martelli, Ilaria Maugeri, Leonardo Provenzano, Federico Nichetti, Luca Agnelli, Riccardo Lobefaro, Giovanni Fucà, Claudio Vernieri
In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998).
{"title":"Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients","authors":"Francesca Ligorio, Andrea Vingiani, Tommaso Torelli, Caterina Sposetti, Lorenzo Drufuca, Fabio Iannelli, Lucrezia Zanenga, Catherine Depretto, Secondo Folli, Gianfranco Scaperrotta, Giuseppe Capri, Giulia V. Bianchi, Cristina Ferraris, Gabriele Martelli, Ilaria Maugeri, Leonardo Provenzano, Federico Nichetti, Luca Agnelli, Riccardo Lobefaro, Giovanni Fucà, Claudio Vernieri","doi":"10.1016/j.cmet.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.004","url":null,"abstract":"In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at <span><span>Clinicaltrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span> (NCT04248998).","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"49 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832847","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 : 2024-12-17DOI: 10.1016/j.cmet.2024.11.006
Isabel Reinisch, Adhideb Ghosh, Falko Noé, Wenfei Sun, Hua Dong, Peter Leary, Arne Dietrich, Anne Hoffmann, Matthias Blüher, Christian Wolfrum
Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints.
{"title":"Unveiling adipose populations linked to metabolic health in obesity","authors":"Isabel Reinisch, Adhideb Ghosh, Falko Noé, Wenfei Sun, Hua Dong, Peter Leary, Arne Dietrich, Anne Hoffmann, Matthias Blüher, Christian Wolfrum","doi":"10.1016/j.cmet.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.006","url":null,"abstract":"Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"87 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832849","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 : 2024-12-13DOI: 10.1016/j.cmet.2024.11.001
Lexiang Yu, Yong Xiao Yang, Zhen Gong, Qianfen Wan, Yifei Du, Qiuzhong Zhou, Yang Xiao, Tarik Zahr, Zhaobin Wang, Zhewei Yu, Kangkang Yang, Jinyang Geng, Susan K. Fried, Jing Li, Rebecca A. Haeusler, Kam W. Leong, Lin Bai, Yingjie Wu, Lei Sun, Pan Wang, Li Qiang
Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with in vivo and in vitro experimental models, we unexpectedly uncovered an interaction between IgG’s Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.
{"title":"FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology","authors":"Lexiang Yu, Yong Xiao Yang, Zhen Gong, Qianfen Wan, Yifei Du, Qiuzhong Zhou, Yang Xiao, Tarik Zahr, Zhaobin Wang, Zhewei Yu, Kangkang Yang, Jinyang Geng, Susan K. Fried, Jing Li, Rebecca A. Haeusler, Kam W. Leong, Lin Bai, Yingjie Wu, Lei Sun, Pan Wang, Li Qiang","doi":"10.1016/j.cmet.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.001","url":null,"abstract":"Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with <em>in vivo</em> and <em>in vitro</em> experimental models, we unexpectedly uncovered an interaction between IgG’s Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"21 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816150","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 : 2024-12-09DOI: 10.1016/j.cmet.2024.11.007
Honghao Huang, Yifan Chen, Wei Xu, Linlin Cao, Kun Qian, Evelyne Bischof, Brian K. Kennedy, Jun Pu
Chronological age is a crucial risk factor for diseases and disabilities among older adults. However, individuals of the same chronological age often exhibit divergent biological aging states, resulting in distinct individual risk profiles. Chronological age estimators based on omics data and machine learning techniques, known as aging clocks, provide a valuable framework for interpreting molecular-level biological aging. Metabolomics is an intriguing and rapidly growing field of study, involving the comprehensive profiling of small molecules within the body and providing the ultimate genome-environment interaction readout. Consequently, leveraging metabolomics to characterize biological aging holds immense potential. The aim of this review was to provide an overview of metabolomics approaches, highlighting the establishment and interpretation of metabolomic aging clocks while emphasizing their strengths, limitations, and applications, and to discuss their underlying biological significance, which has the potential to drive innovation in longevity research and development.
{"title":"Decoding aging clocks: New insights from metabolomics","authors":"Honghao Huang, Yifan Chen, Wei Xu, Linlin Cao, Kun Qian, Evelyne Bischof, Brian K. Kennedy, Jun Pu","doi":"10.1016/j.cmet.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.007","url":null,"abstract":"Chronological age is a crucial risk factor for diseases and disabilities among older adults. However, individuals of the same chronological age often exhibit divergent biological aging states, resulting in distinct individual risk profiles. Chronological age estimators based on omics data and machine learning techniques, known as aging clocks, provide a valuable framework for interpreting molecular-level biological aging. Metabolomics is an intriguing and rapidly growing field of study, involving the comprehensive profiling of small molecules within the body and providing the ultimate genome-environment interaction readout. Consequently, leveraging metabolomics to characterize biological aging holds immense potential. The aim of this review was to provide an overview of metabolomics approaches, highlighting the establishment and interpretation of metabolomic aging clocks while emphasizing their strengths, limitations, and applications, and to discuss their underlying biological significance, which has the potential to drive innovation in longevity research and development.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"93 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793549","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 : 2024-12-06DOI: 10.1016/j.cmet.2024.11.002
Aaron M. Cypess, Barbara Cannon, Jan Nedergaard, Lawrence Kazak, Douglas C. Chang, Jonathan Krakoff, Yu-Hua Tseng, Camilla Schéele, Jeremie Boucher, Natasa Petrovic, Denis P. Blondin, André C. Carpentier, Kirsi A. Virtanen, Sander Kooijman, Patrick C.N. Rensen, Cheryl Cero, Shingo Kajimura
Until two decades ago, brown adipose tissue (BAT) was studied primarily as a thermogenic organ of small rodents in the context of cold adaptation. The discovery of functional human BAT has opened new opportunities to understand its physiological role in energy balance and therapeutic applications for metabolic disorders. Significantly, the role of BAT extends far beyond thermogenesis, including glucose and lipid homeostasis, by releasing mediators that communicate with other cells and organs. The field has made major advances by using new model systems, ranging from subcellular studies to clinical trials, which have also led to debates. In this perspective, we identify six fundamental issues that are currently controversial and comprise dichotomous models. Each side presents supporting evidence and, critically, the necessary methods and falsifiable experiments that would resolve the dispute. With this collaborative approach, the field will continue to productively advance the understanding of BAT physiology, appreciate the importance of thermogenic adipocytes as a central area of ongoing research, and realize the therapeutic potential.
{"title":"Emerging debates and resolutions in brown adipose tissue research","authors":"Aaron M. Cypess, Barbara Cannon, Jan Nedergaard, Lawrence Kazak, Douglas C. Chang, Jonathan Krakoff, Yu-Hua Tseng, Camilla Schéele, Jeremie Boucher, Natasa Petrovic, Denis P. Blondin, André C. Carpentier, Kirsi A. Virtanen, Sander Kooijman, Patrick C.N. Rensen, Cheryl Cero, Shingo Kajimura","doi":"10.1016/j.cmet.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.002","url":null,"abstract":"Until two decades ago, brown adipose tissue (BAT) was studied primarily as a thermogenic organ of small rodents in the context of cold adaptation. The discovery of functional human BAT has opened new opportunities to understand its physiological role in energy balance and therapeutic applications for metabolic disorders. Significantly, the role of BAT extends far beyond thermogenesis, including glucose and lipid homeostasis, by releasing mediators that communicate with other cells and organs. The field has made major advances by using new model systems, ranging from subcellular studies to clinical trials, which have also led to debates. In this perspective, we identify six fundamental issues that are currently controversial and comprise dichotomous models. Each side presents supporting evidence and, critically, the necessary methods and falsifiable experiments that would resolve the dispute. With this collaborative approach, the field will continue to productively advance the understanding of BAT physiology, appreciate the importance of thermogenic adipocytes as a central area of ongoing research, and realize the therapeutic potential.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"27 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782651","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 : 2024-12-05DOI: 10.1016/j.cmet.2024.11.003
Xinxin Yu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G. Straub, Valentina Pirro, Margo P. Emont, Brian A. Droz, Kyla AI. Collins, Chanmin Joung, Mackenzie J. Pearson, Corey M. James, Gopal J. Babu, Vissarion Efthymiou, Ashley Vernon, Mary Elizabeth Patti, Yu A. An, Evan D. Rosen, Matthew P. Coghlan, Ricardo J. Samms, Philipp E. Scherer, Christine M. Kusminski
Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (∼35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis, and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance.
{"title":"The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice","authors":"Xinxin Yu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G. Straub, Valentina Pirro, Margo P. Emont, Brian A. Droz, Kyla AI. Collins, Chanmin Joung, Mackenzie J. Pearson, Corey M. James, Gopal J. Babu, Vissarion Efthymiou, Ashley Vernon, Mary Elizabeth Patti, Yu A. An, Evan D. Rosen, Matthew P. Coghlan, Ricardo J. Samms, Philipp E. Scherer, Christine M. Kusminski","doi":"10.1016/j.cmet.2024.11.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.003","url":null,"abstract":"Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (∼35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis, and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776744","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 : 2024-12-05DOI: 10.1016/j.cmet.2024.11.005
Ruilong Liu, Xuelian Ren, Yae Eun Park, Huixu Feng, Xinlei Sheng, Xiaohan Song, Roya AminiTabrizi, Hardik Shah, Lingting Li, Yu Zhang, Kalil G. Abdullah, Sarah Dubois-Coyne, Hening Lin, Philip A. Cole, Ralph J. DeBerardinis, Samuel K. McBrayer, He Huang, Yingming Zhao
Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.
{"title":"Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis","authors":"Ruilong Liu, Xuelian Ren, Yae Eun Park, Huixu Feng, Xinlei Sheng, Xiaohan Song, Roya AminiTabrizi, Hardik Shah, Lingting Li, Yu Zhang, Kalil G. Abdullah, Sarah Dubois-Coyne, Hening Lin, Philip A. Cole, Ralph J. DeBerardinis, Samuel K. McBrayer, He Huang, Yingming Zhao","doi":"10.1016/j.cmet.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.005","url":null,"abstract":"Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"109 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776743","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 : 2024-12-03DOI: 10.1016/j.cmet.2024.10.022
Andreas Carlström, Martin Ott
Mitochondrial energy conversion supplies cellular energy but can also provide heat in brown adipose tissue (BAT). In a recent study, Shin and Latorre-Muro et al.1 show that respiratory supercomplexes in BAT are remodeled during cold to provide a tighter coupling, revealing a novel, physiologically important role for these supramolecular assemblies.
{"title":"Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue","authors":"Andreas Carlström, Martin Ott","doi":"10.1016/j.cmet.2024.10.022","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.022","url":null,"abstract":"Mitochondrial energy conversion supplies cellular energy but can also provide heat in brown adipose tissue (BAT). In a recent study, Shin and Latorre-Muro et al.<span><span><sup>1</sup></span></span> show that respiratory supercomplexes in BAT are remodeled during cold to provide a tighter coupling, revealing a novel, physiologically important role for these supramolecular assemblies.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"41 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760552","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 : 2024-11-26DOI: 10.1016/j.cmet.2024.10.021
Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E. Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M. Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Umberto De Marchi
Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
{"title":"Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance","authors":"Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E. Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M. Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Umberto De Marchi","doi":"10.1016/j.cmet.2024.10.021","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.021","url":null,"abstract":"Mitochondrial calcium (mtCa<sup>2+</sup>) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa<sup>2+</sup> uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa<sup>2+</sup> uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa<sup>2+</sup> uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa<sup>2+</sup> uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"26 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713096","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}
The effect of the serine/glycine-free diet (−SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the −SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the −SG diet, indicating the potential of combining the −SG diet with immunotherapy. We conducted a single-arm, phase I study (ChiCTR2300067929). The primary outcome suggests that the −SG diet is feasible and safe for regulating systemic immunity. Secondary outcomes include patient tolerability and potential antitumor effects. Collectively, our findings highlight the promising therapeutic potential of the −SG diet for treating solid tumors.
无丝氨酸/甘氨酸饮食（-SG 饮食）对结直肠癌（CRC）的影响仍不清楚；同时，程序性死亡-1（PD-1）抑制剂对大多数 CRC 患者的疗效较差。在这里，我们证明了 -SG 饮食能抑制 CRC 的生长，并促进细胞毒性 T 细胞的积累，从而增强抗肿瘤免疫力。此外，我们还发现肿瘤细胞中程序性死亡配体1（PD-L1）的乳化是细胞毒性T细胞介导的抗肿瘤反应中的免疫逃避机制，而阻断PD-1/PD-L1信号通路能够恢复-SG饮食所招募的CD8+ T细胞的功能，这表明-SG饮食与免疫疗法的结合具有潜力。我们进行了一项单臂 I 期研究（ChiCTR2300067929）。主要结果表明，-SG 饮食在调节全身免疫力方面是可行且安全的。次要结果包括患者的耐受性和潜在的抗肿瘤效果。总之，我们的研究结果凸显了 -SG 饮食治疗实体瘤的巨大潜力。
{"title":"Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation","authors":"Huan Tong, Zedong Jiang, Linlin Song, Keqin Tan, Xiaomeng Yin, Chengyuan He, Juan Huang, Xiaoyue Li, Xiaofan Jing, Hong Yun, Guangqi Li, Yunuo Zhao, Qianlong Kang, Yuhao Wei, Renwei Li, Zhiwen Long, Jun Yin, Qiang Luo, Xiao Liang, Yanzhi Wan, Xuelei Ma","doi":"10.1016/j.cmet.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.019","url":null,"abstract":"The effect of the serine/glycine-free diet (−SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the −SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the −SG diet, indicating the potential of combining the −SG diet with immunotherapy. We conducted a single-arm, phase I study (ChiCTR2300067929). The primary outcome suggests that the −SG diet is feasible and safe for regulating systemic immunity. Secondary outcomes include patient tolerability and potential antitumor effects. Collectively, our findings highlight the promising therapeutic potential of the −SG diet for treating solid tumors.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679049","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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