Pub Date : 2025-12-02DOI: 10.1016/j.cmet.2025.11.004
Salvatore Fabbiano, Mari-Carmen Fernández-Agüera, Beste Mutlu, Patrick Schaefer, Yongmei Sun
{"title":"Toward the next 20 years of Cell Metabolism","authors":"Salvatore Fabbiano, Mari-Carmen Fernández-Agüera, Beste Mutlu, Patrick Schaefer, Yongmei Sun","doi":"10.1016/j.cmet.2025.11.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.004","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"159 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657120","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 : 2025-12-01DOI: 10.1016/j.cmet.2025.10.022
Baharan Meghdadi, Wajd N. Al-Holou, Andrew J. Scott, Anjali Mittal, Ningning Liang, Palavalasa Sravya, Abhinav Achreja, Alexandra O’Brien, Kathy Do, Zhe Wu, Jiane Feng, Nathan R. Qi, Vijay Tarnal, Sriram Venneti, C. Ryan Miller, Jann N. Sarkaria, Weihua Zhou, Theodore S. Lawrence, Costas A. Lyssiotis, Daniel R. Wahl, Deepak Nagrath
Recent advancements in metabolic flux estimations in vivo are limited to preclinical models, primarily due to challenges in tissue sampling, tumor microenvironment (TME) heterogeneity, and non-steady-state conditions. To address these limitations and enable flux estimation in human patients, we developed two machine learning-based frameworks. First, the digital twin framework (DTF) integrates first-principles stoichiometric and isotopic simulations with convolutional neural networks to estimate fluxes in patient bulk samples. Second, the single-cell metabolic flux analysis (13C-scMFA) framework combines patient single-cell RNA sequencing (scRNA-seq) data with 13C-isotope tracing, allowing single-cell-level flux quantification. These studies allow quantification of metabolic activity in neoplastic glioma cells, revealing frequently elevated purine synthesis and serine uptake, compared with non-malignant cells. Our models also identify metabolic heterogeneity among patients and mice with brain cancer, in turn predicting treatment responses to metabolic inhibitors. Our frameworks advance in vivo metabolic flux analysis, may lead to novel metabolic therapies, and identify biomarkers for metabolism-directed therapies in patients.
{"title":"Digital twins for in vivo metabolic flux estimations in patients with brain cancer","authors":"Baharan Meghdadi, Wajd N. Al-Holou, Andrew J. Scott, Anjali Mittal, Ningning Liang, Palavalasa Sravya, Abhinav Achreja, Alexandra O’Brien, Kathy Do, Zhe Wu, Jiane Feng, Nathan R. Qi, Vijay Tarnal, Sriram Venneti, C. Ryan Miller, Jann N. Sarkaria, Weihua Zhou, Theodore S. Lawrence, Costas A. Lyssiotis, Daniel R. Wahl, Deepak Nagrath","doi":"10.1016/j.cmet.2025.10.022","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.022","url":null,"abstract":"Recent advancements in metabolic flux estimations <em>in vivo</em> are limited to preclinical models, primarily due to challenges in tissue sampling, tumor microenvironment (TME) heterogeneity, and non-steady-state conditions. To address these limitations and enable flux estimation in human patients, we developed two machine learning-based frameworks. First, the digital twin framework (DTF) integrates first-principles stoichiometric and isotopic simulations with convolutional neural networks to estimate fluxes in patient bulk samples. Second, the single-cell metabolic flux analysis (<sup>13</sup>C-scMFA) framework combines patient single-cell RNA sequencing (scRNA-seq) data with <sup>13</sup>C-isotope tracing, allowing single-cell-level flux quantification. These studies allow quantification of metabolic activity in neoplastic glioma cells, revealing frequently elevated purine synthesis and serine uptake, compared with non-malignant cells. Our models also identify metabolic heterogeneity among patients and mice with brain cancer, in turn predicting treatment responses to metabolic inhibitors. Our frameworks advance <em>in vivo</em> metabolic flux analysis, may lead to novel metabolic therapies, and identify biomarkers for metabolism-directed therapies in patients.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"123 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651402","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 : 2025-12-01DOI: 10.1016/j.cmet.2025.10.021
Claire H. Feetham, Sam Groom, Linu M. John, Berit Ostergaard Christoffersen, Valeria Collabolletta, David Lyons, Antony Adamson, Sofia Lundh, Marina Kjærgaard Gerstenberg, Mads Tang-Christensen, Kilian W. Conde-Frieboes, Anna Secher, Ann Maria Kruse Hansen, Simon M. Luckman
Prolactin-releasing peptide and its cognate receptor, G protein-coupled receptor (GPR)10, are important in the physiological regulation of body weight in both rodents and humans. Here, we describe a modified peptide, NN501, with agonist properties at both GPR10 and neuropeptide FF receptor 2 (NPFFR2), which reduces body weight when administered systemically without causing obvious aversive responses. Weight reduction is similar to that of glucagon-like peptide 1 (GLP-1) receptor agonists, but with only a modest effect on food intake, suggesting a different weight-lowering mechanism. Moreover, when treatment is discontinued, mice receiving NN501 display a more gradual weight regain and no compensatory hyperphagic response (as is observed with caloric restriction and GLP-1 receptor agonism). Instead, NN501 increases energy expenditure on treatment and has a sustained effect on fatty-acid oxidation. These results indicate that GPR10/NPFFR2 agonism produces weight loss by alternative mechanisms to GLP-1 receptor agonism, suggesting it could be a viable alternative or complementary therapy for obesity.
{"title":"Analog of prolactin-releasing peptide reduces body weight primarily through sustained fatty acid oxidation rather than hypophagia","authors":"Claire H. Feetham, Sam Groom, Linu M. John, Berit Ostergaard Christoffersen, Valeria Collabolletta, David Lyons, Antony Adamson, Sofia Lundh, Marina Kjærgaard Gerstenberg, Mads Tang-Christensen, Kilian W. Conde-Frieboes, Anna Secher, Ann Maria Kruse Hansen, Simon M. Luckman","doi":"10.1016/j.cmet.2025.10.021","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.021","url":null,"abstract":"Prolactin-releasing peptide and its cognate receptor, G protein-coupled receptor (GPR)10, are important in the physiological regulation of body weight in both rodents and humans. Here, we describe a modified peptide, NN501, with agonist properties at both GPR10 and neuropeptide FF receptor 2 (NPFFR2), which reduces body weight when administered systemically without causing obvious aversive responses. Weight reduction is similar to that of glucagon-like peptide 1 (GLP-1) receptor agonists, but with only a modest effect on food intake, suggesting a different weight-lowering mechanism. Moreover, when treatment is discontinued, mice receiving NN501 display a more gradual weight regain and no compensatory hyperphagic response (as is observed with caloric restriction and GLP-1 receptor agonism). Instead, NN501 increases energy expenditure on treatment and has a sustained effect on fatty-acid oxidation. These results indicate that GPR10/NPFFR2 agonism produces weight loss by alternative mechanisms to GLP-1 receptor agonism, suggesting it could be a viable alternative or complementary therapy for obesity.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"57 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657114","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 : 2025-11-25DOI: 10.1016/j.cmet.2025.10.016
Steven E. Pilley, Dominik Awad, Djakim Latumalea, Connie New, Edgar Esparza, Shuo Wang, Xuanyi Shi, Li Zhang, Maximilian Unfried, Jasinda H. Lee, Ernst Schmid, Ipsita Mohanty, Jenna L.E. Blum, Shivaanishaa Raventhiran, Esther Wong, Preeti R. Iyengar, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Peter J. Mullen
Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.
{"title":"A metabolic atlas of mouse aging","authors":"Steven E. Pilley, Dominik Awad, Djakim Latumalea, Connie New, Edgar Esparza, Shuo Wang, Xuanyi Shi, Li Zhang, Maximilian Unfried, Jasinda H. Lee, Ernst Schmid, Ipsita Mohanty, Jenna L.E. Blum, Shivaanishaa Raventhiran, Esther Wong, Preeti R. Iyengar, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Peter J. Mullen","doi":"10.1016/j.cmet.2025.10.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.016","url":null,"abstract":"Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"57 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593511","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}
Our randomized, placebo-controlled trial showed resistant starch (RS), a type of prebiotic, has therapeutic effects in metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we observed its heterogeneous efficacy, where 30% of participants exhibited limited benefits, which was replicated in a multi-center trial (ChiCTR2300074588). Multi-omics analysis and fecal microbiota transplantation identified baseline microbiota as a dominant contributor of response. Further population stratification and network analysis combined with in vitro and in vivo experiments revealed Prevotella as the key cause of low response by inhibiting RS-degrading bacteria, thereby impairing RS utilization. Conversely, Bifidobacterium pseudocatenulatum RRP01, a strain isolated from our cohort, restored RS degradation and improved Prevotella-attenuated RS response. Furthermore, we developed a predictive model integrating baseline microbial and clinical features (area under the curve [AUC] = 0.74–0.87), enabling stratification for personalized interventions. Our study indicates that gut microbiota determines the heterogeneity in RS efficacy and offers possibilities for novel microbiota-oriented precision therapeutics for MASLD.
{"title":"Interindividual variability in gut microbiome mediates the efficacy of resistant starch on MASLD","authors":"Xiaoxue Long, Hui Wang, Yuwei Lu, Xiaojing Gao, Yuanyuan Xiao, Mingliang Zhang, Jingyi Guo, Jingyi Yang, Ruiqi Zhang, Qian Li, Guiyun Zhou, Ruibao Yang, Feng Chen, Qingqing Wu, Liming Sun, Chengshuang Chu, Xuexue Zhu, Zhengjun Wu, Quanlu Ren, Chunping You, Huating Li","doi":"10.1016/j.cmet.2025.10.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.017","url":null,"abstract":"Our randomized, placebo-controlled trial showed resistant starch (RS), a type of prebiotic, has therapeutic effects in metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we observed its heterogeneous efficacy, where 30% of participants exhibited limited benefits, which was replicated in a multi-center trial (ChiCTR2300074588). Multi-omics analysis and fecal microbiota transplantation identified baseline microbiota as a dominant contributor of response. Further population stratification and network analysis combined with <em>in vitro</em> and <em>in vivo</em> experiments revealed <em>Prevotella</em> as the key cause of low response by inhibiting RS-degrading bacteria, thereby impairing RS utilization. Conversely, <em>Bifidobacterium pseudocatenulatum RRP01</em>, a strain isolated from our cohort, restored RS degradation and improved <em>Prevotella</em>-attenuated RS response. Furthermore, we developed a predictive model integrating baseline microbial and clinical features (area under the curve [AUC] = 0.74–0.87), enabling stratification for personalized interventions. Our study indicates that gut microbiota determines the heterogeneity in RS efficacy and offers possibilities for novel microbiota-oriented precision therapeutics for MASLD.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"11 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554810","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 : 2025-11-20DOI: 10.1016/j.cmet.2025.10.009
Masayoshi Suda, Selim Chaib, Larissa G.P. Langhi Prata, Yi Zhu, Utkarsh Tripathi, Karl H. Paul, Allyson K. Palmer, Tamar Pirtskhalava, Vagisha Kulshreshtha, Christina L. Inman, Kurt O. Johnson, Nino Giorgadze, Runqing Huang, Carolyn M. Roos, Luisa F. Leon-Sanchez, Jordan D. Miller, Thomas White, Linshan Laux, Laura J. Niedernhofer, Paul D. Robbins, James L. Kirkland
Accumulation of senescent cells is a key contributor to multiple diseases across the lifespan, including metabolic dysfunction. We previously demonstrated that elimination of senescent cells using senolytic drugs alleviates obesity-induced metabolic dysfunction. However, the contribution of senescent endothelial cells to metabolic disorders remains elusive. Hence, we crossed mice that allow selective elimination of senescent cells (p16Ink4a-LOX-ATTAC mice) with Tie2-Cre mice (Tie2-Cre;p16Ink4a-LOX-ATTAC) to enable identification and inducible, selective elimination of p16Ink4a+ senescent endothelial cells. Targeted removal of senescent endothelial cells from obese Tie2-Cre;p16Ink4a-LOX-ATTAC mice attenuated the pro-inflammatory senescence-associated secretory phenotype and alleviated metabolic dysfunction. Conversely, transplanting senescent endothelial cells into lean mice caused adipose tissue inflammation and metabolic dysfunction. Consistent with these findings, the senolytic, fisetin, which targets senescent endothelial cells among other senescent cell types, reduced adipose tissue senescent endothelial cell abundance and improved glucose metabolism in obese mice or mice transplanted with senescent mouse endothelial cells. Our results indicate that specifically eliminating p16Ink4a+ senescent endothelial cells is a potential therapeutic strategy for metabolic disease.
{"title":"Endothelial senescent-cell-specific clearance alleviates metabolic dysfunction in obese mice","authors":"Masayoshi Suda, Selim Chaib, Larissa G.P. Langhi Prata, Yi Zhu, Utkarsh Tripathi, Karl H. Paul, Allyson K. Palmer, Tamar Pirtskhalava, Vagisha Kulshreshtha, Christina L. Inman, Kurt O. Johnson, Nino Giorgadze, Runqing Huang, Carolyn M. Roos, Luisa F. Leon-Sanchez, Jordan D. Miller, Thomas White, Linshan Laux, Laura J. Niedernhofer, Paul D. Robbins, James L. Kirkland","doi":"10.1016/j.cmet.2025.10.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.009","url":null,"abstract":"Accumulation of senescent cells is a key contributor to multiple diseases across the lifespan, including metabolic dysfunction. We previously demonstrated that elimination of senescent cells using senolytic drugs alleviates obesity-induced metabolic dysfunction. However, the contribution of senescent endothelial cells to metabolic disorders remains elusive. Hence, we crossed mice that allow selective elimination of senescent cells (<em>p16</em><sup><em>Ink4a</em></sup><em>-LOX-ATTAC</em> mice) with <em>Tie2-Cre</em> mice (<em>Tie2-Cre</em>;<em>p16</em><sup><em>Ink4a</em></sup><em>-LOX-ATTAC</em>) to enable identification and inducible, selective elimination of p16<sup>Ink4a+</sup> senescent endothelial cells. Targeted removal of senescent endothelial cells from obese <em>Tie2-Cre</em>;<em>p16</em><sup><em>Ink4a</em></sup><em>-LOX-ATTAC</em> mice attenuated the pro-inflammatory senescence-associated secretory phenotype and alleviated metabolic dysfunction. Conversely, transplanting senescent endothelial cells into lean mice caused adipose tissue inflammation and metabolic dysfunction. Consistent with these findings, the senolytic, fisetin, which targets senescent endothelial cells among other senescent cell types, reduced adipose tissue senescent endothelial cell abundance and improved glucose metabolism in obese mice or mice transplanted with senescent mouse endothelial cells. Our results indicate that specifically eliminating p16<sup>Ink4a+</sup> senescent endothelial cells is a potential therapeutic strategy for metabolic disease.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554824","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 : 2025-11-19DOI: 10.1016/j.cmet.2025.10.014
Junzhe Huang, Andrew J. Kwok, Jason Chak Yan Li, Clement Lek Hin Chiu, Bonaventure Y. Ip, Lok Yi Tung, Roy C.H. Chan, Danny C.W. Chan, Ziyu Wang, Xianyi Zheng, Hoi Tung Chow, Michelle P.S. Lo, Zhongqi Li, Nenghan Lin, Manyu Wang, Leo Y.C. Yan, William K.K. Wu, Kim Hei-Man Chow, Wei-Jye Lin, Yamei Tang, Ho Ko
Identifying practical ways to counteract aging and associated degenerative disorders is urgently needed. We performed deep molecular profiling and functional assessments in aging male mice to show that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment broadly counteracts age-related changes. In mice treated with a GLP-1RA from 11 months for 30 weeks, we observed strong body-wide multi-omic age-counteracting effects and improved selected physical functions. Importantly, the effects were specific to aged mice, not young adults, and were attained with a relatively low dose that minimally affected food intake or body weight. With GLP-1RA treatment beginning at 18 months for 13 weeks, the molecular age-counteracting effects were even stronger and largely dependent on hypothalamic GLP-1R, pointing to a brain-body axis of aging modulation. Comparison with mammalian target of rapamycin (mTOR) inhibition, a proven anti-aging strategy, revealed strong multi-omic similarities. Our findings have broad implications for the mechanisms behind GLP-1RAs’ pleiotropic benefits, guiding clinical trials, and informing development of anti-aging-based therapeutics.
{"title":"Body-wide multi-omic counteraction of aging with GLP-1R agonism","authors":"Junzhe Huang, Andrew J. Kwok, Jason Chak Yan Li, Clement Lek Hin Chiu, Bonaventure Y. Ip, Lok Yi Tung, Roy C.H. Chan, Danny C.W. Chan, Ziyu Wang, Xianyi Zheng, Hoi Tung Chow, Michelle P.S. Lo, Zhongqi Li, Nenghan Lin, Manyu Wang, Leo Y.C. Yan, William K.K. Wu, Kim Hei-Man Chow, Wei-Jye Lin, Yamei Tang, Ho Ko","doi":"10.1016/j.cmet.2025.10.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.014","url":null,"abstract":"Identifying practical ways to counteract aging and associated degenerative disorders is urgently needed. We performed deep molecular profiling and functional assessments in aging male mice to show that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment broadly counteracts age-related changes. In mice treated with a GLP-1RA from 11 months for 30 weeks, we observed strong body-wide multi-omic age-counteracting effects and improved selected physical functions. Importantly, the effects were specific to aged mice, not young adults, and were attained with a relatively low dose that minimally affected food intake or body weight. With GLP-1RA treatment beginning at 18 months for 13 weeks, the molecular age-counteracting effects were even stronger and largely dependent on hypothalamic GLP-1R, pointing to a brain-body axis of aging modulation. Comparison with mammalian target of rapamycin (mTOR) inhibition, a proven anti-aging strategy, revealed strong multi-omic similarities. Our findings have broad implications for the mechanisms behind GLP-1RAs’ pleiotropic benefits, guiding clinical trials, and informing development of anti-aging-based therapeutics.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545861","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 : 2025-11-18DOI: 10.1016/j.cmet.2025.10.013
Yao Wang, Jiaming Wu, Jianyu Yao, Jiarui Chen, Kenneth K.Y. Cheng, Melody Yuen-man Ho, Chi Ho Lee, Karen Siu-Ling Lam, Michael Andrew Tse, Gianni Panagiotou, Aimin Xu
Exercise is an effective intervention for the prevention and management of diabetes, but the high interpersonal variability in response to exercise impedes its widespread implementation. Herein, we identify adipocyte-derived soluble interleukin-6 receptor (sIL-6R) as a key exerkine determining exercise efficacy in improving metabolic health. In individuals with obesity who underwent a 12-week exercise intervention, circulating sIL-6R level exhibits dichotomous changes between exercise responders (Rs) and non-responders (NRs), in close association with exercise-mediated alterations in insulin sensitivity and glycemic control. Mechanistically, elevated gut microbiome-mediated leucine in NR acts on white adipocytes to promote disintegrin and metalloproteinase 17 (ADAM17)-mediated sIL-6R production via the mammalian target of rapamycin (mTOR)-hypoxia-inducible factor 1α (HIF1α) pathway, which in turn impairs the metabolic benefits of exercise through interleukin (IL)-6 trans-signaling-induced adipose inflammation. Adipocyte-selective ablation of ADAM17 prevents the effects of fecal microbiota transplantation from NR on elevation of sIL-6R, thereby restoring the efficacy of exercise-shaped gut microbiome in counteracting glucose intolerance and insulin resistance in obese mice. Thus, therapeutic interventions targeting adipocyte-derived sIL-6R represent a promising strategy for maximizing exercise efficacy in personalized diabetes prevention.
{"title":"Gut microbiome-adipose crosstalk modulates soluble IL-6 receptor influencing exercise responsiveness in glycemic control and insulin sensitivity","authors":"Yao Wang, Jiaming Wu, Jianyu Yao, Jiarui Chen, Kenneth K.Y. Cheng, Melody Yuen-man Ho, Chi Ho Lee, Karen Siu-Ling Lam, Michael Andrew Tse, Gianni Panagiotou, Aimin Xu","doi":"10.1016/j.cmet.2025.10.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.013","url":null,"abstract":"Exercise is an effective intervention for the prevention and management of diabetes, but the high interpersonal variability in response to exercise impedes its widespread implementation. Herein, we identify adipocyte-derived soluble interleukin-6 receptor (sIL-6R) as a key exerkine determining exercise efficacy in improving metabolic health. In individuals with obesity who underwent a 12-week exercise intervention, circulating sIL-6R level exhibits dichotomous changes between exercise responders (Rs) and non-responders (NRs), in close association with exercise-mediated alterations in insulin sensitivity and glycemic control. Mechanistically, elevated gut microbiome-mediated leucine in NR acts on white adipocytes to promote disintegrin and metalloproteinase 17 (ADAM17)-mediated sIL-6R production via the mammalian target of rapamycin (mTOR)-hypoxia-inducible factor 1α (HIF1α) pathway, which in turn impairs the metabolic benefits of exercise through interleukin (IL)-6 <em>trans</em>-signaling-induced adipose inflammation. Adipocyte-selective ablation of ADAM17 prevents the effects of fecal microbiota transplantation from NR on elevation of sIL-6R, thereby restoring the efficacy of exercise-shaped gut microbiome in counteracting glucose intolerance and insulin resistance in obese mice. Thus, therapeutic interventions targeting adipocyte-derived sIL-6R represent a promising strategy for maximizing exercise efficacy in personalized diabetes prevention.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"65 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536148","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 : 2025-11-17DOI: 10.1016/j.cmet.2025.10.012
L.Felipe Barros, Ignacio Fernández-Moncada, Giovanni Marsicano, Iván Ruminot, Aiman S. Saab, Bruno Weber
The research fields of brain intercellular signaling and brain energy metabolism evolved separately. One dealt with neurotransmission and the assembly of neural circuits and networks. The other focused on enzyme reactions and the compartmentation of biochemical processes between neurons and glial cells. High-order brain functions like cognition operate over long distances and can be fast. By contrast, metabolism is slow and, being limited by diffusion, operates over short distances. However, this comfortable division is now being challenged by the realization that lactate, beta-hydroxybutyrate, ATP/adenosine, and other key elements of the universal metabolic core also play the role of intercellular signals, acting via G protein-coupled receptors and other targets to modulate neural network activity, as showcased by exercise, fasting, and sleep. Here, we discuss the possible physiological meaning of such promiscuity. By arguing that it is no longer possible to understand signaling without understanding metabolism, and vice versa, the purpose of this feature is to raise awareness of the ongoing convergence and foster interdisciplinary collaboration.
{"title":"Scale-spanning crosstalk between metabolism and information processing","authors":"L.Felipe Barros, Ignacio Fernández-Moncada, Giovanni Marsicano, Iván Ruminot, Aiman S. Saab, Bruno Weber","doi":"10.1016/j.cmet.2025.10.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.012","url":null,"abstract":"The research fields of brain intercellular signaling and brain energy metabolism evolved separately. One dealt with neurotransmission and the assembly of neural circuits and networks. The other focused on enzyme reactions and the compartmentation of biochemical processes between neurons and glial cells. High-order brain functions like cognition operate over long distances and can be fast. By contrast, metabolism is slow and, being limited by diffusion, operates over short distances. However, this comfortable division is now being challenged by the realization that lactate, beta-hydroxybutyrate, ATP/adenosine, and other key elements of the universal metabolic core also play the role of intercellular signals, acting via G protein-coupled receptors and other targets to modulate neural network activity, as showcased by exercise, fasting, and sleep. Here, we discuss the possible physiological meaning of such promiscuity. By arguing that it is no longer possible to understand signaling without understanding metabolism, and vice versa, the purpose of this feature is to raise awareness of the ongoing convergence and foster interdisciplinary collaboration.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"26 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531554","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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