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}
The intestinal clock plays a role in transmitting feeding signals and generating circadian events, but how this clock system may time homeostatic processes related to sleep-wake regulation is unknown. Our functional dissections of the circadian clock in intestinal epithelial cells (IECs) demonstrate that its integrity is required for maintenance of the diurnal sleep-wake cycle. In IECs, BMAL1 generates diurnal rhythmic SLC6A19 expression that promotes intestinal absorption of glutamine during the active phase, which enhances glutamatergic neuron activities in hypothalamic nuclei and contributes to increased wakefulness and decreased sleep. The involvement of glutamine homeostasis in sleep-wake regulation is also pronounced during the rest phase, as an elevation of glutamine in the rest phase caused by IEC deficiency of REV-ERBα is causally linked to sleep abnormalities characterized by reduced sleep. Overall, the intestinal clock shapes the diurnal sleep-wake cycle through temporally gating glutamine homeostasis and serves as a potential target for boosting the sleep rhythm and for managing sleep disorders.
{"title":"Intestinal clock shapes sleep-wake cycle via sustaining glutamine homeostasis","authors":"Lianxia Guo, Yifei Xiao, Zanjin Li, Yuwei Huang, Haobin Cen, Zicong Wu, Hongbo Wang, Xinyu Liu, Zhehan Yang, Caifeng Zhao, Tingying Hao, Hui Chen, Meng Jin, Danyi Lu, Min Chen, Baojian Wu","doi":"10.1016/j.cmet.2025.10.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.010","url":null,"abstract":"The intestinal clock plays a role in transmitting feeding signals and generating circadian events, but how this clock system may time homeostatic processes related to sleep-wake regulation is unknown. Our functional dissections of the circadian clock in intestinal epithelial cells (IECs) demonstrate that its integrity is required for maintenance of the diurnal sleep-wake cycle. In IECs, BMAL1 generates diurnal rhythmic SLC6A19 expression that promotes intestinal absorption of glutamine during the active phase, which enhances glutamatergic neuron activities in hypothalamic nuclei and contributes to increased wakefulness and decreased sleep. The involvement of glutamine homeostasis in sleep-wake regulation is also pronounced during the rest phase, as an elevation of glutamine in the rest phase caused by IEC deficiency of REV-ERBα is causally linked to sleep abnormalities characterized by reduced sleep. Overall, the intestinal clock shapes the diurnal sleep-wake cycle through temporally gating glutamine homeostasis and serves as a potential target for boosting the sleep rhythm and for managing sleep disorders.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"64 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531553","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 : 2025-11-13DOI: 10.1016/j.cmet.2025.10.011
Matthias Van Hul, Patrice D. Cani
The mapping of the human genome sparked high expectations for biomedical breakthroughs, yet attention has since shifted toward the human microbiome as a key player in health and disease. Pioneering studies revealed striking inter-individual variability and numerous associations between gut microbiota and a wide range of conditions (i.e., obesity, diabetes, cardiovascular and inflammatory bowel diseases, autism, allergies, neurodegenerative diseases, and cancers). However, the field has faced a deluge of correlative “dysbiosis” studies with limited causal evidence. Although animal models have provided crucial mechanistic insights, translating these findings to humans has proven challenging. Interventions such as fecal microbiota transplantation, prebiotics, probiotics, and postbiotics often yield inconsistent or modest effects in clinical trials. This gap highlights the need for precision, functional profiling, and integration of multi-omics , for instance, through artificial intelligence. In this perspective, we discuss what microbiome research offers as a transformative shift and how we conceptualize disease, favoring systems biology and personalized interventions over reductionist approaches.
{"title":"From microbiome to metabolism: Bridging a two-decade translational gap","authors":"Matthias Van Hul, Patrice D. Cani","doi":"10.1016/j.cmet.2025.10.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.011","url":null,"abstract":"The mapping of the human genome sparked high expectations for biomedical breakthroughs, yet attention has since shifted toward the human microbiome as a key player in health and disease. Pioneering studies revealed striking inter-individual variability and numerous associations between gut microbiota and a wide range of conditions (i.e., obesity, diabetes, cardiovascular and inflammatory bowel diseases, autism, allergies, neurodegenerative diseases, and cancers). However, the field has faced a deluge of correlative “dysbiosis” studies with limited causal evidence. Although animal models have provided crucial mechanistic insights, translating these findings to humans has proven challenging. Interventions such as fecal microbiota transplantation, prebiotics, probiotics, and postbiotics often yield inconsistent or modest effects in clinical trials. This gap highlights the need for precision, functional profiling, and integration of multi-omics , for instance, through artificial intelligence. In this perspective, we discuss what microbiome research offers as a transformative shift and how we conceptualize disease, favoring systems biology and personalized interventions over reductionist approaches.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"33 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499117","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 : 2025-11-12DOI: 10.1016/j.cmet.2025.10.006
Rebekah J. Nicholson, Luis Cedeño-Rosario, J. Alan Maschek, Trevor Lonergan, Jonathan G. Van Vranken, Angela R.S. Kruse, Chris J. Stubben, Liping Wang, Deborah Stuart, Queren A. Alcantara, Monica P. Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xuanchen Wu, Juwan Kim, Juna Kim, Isaac Hall, Amanda J. Clark, Samir Parikh, Scott A. Summers
Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. Mechanistic studies in primary PTs, which included a thermal proteomic profiling screen for ceramide effectors, revealed that ceramides altered assembly of the mitochondrial contact site and cristae-organizing system (MICOS) and respiratory supercomplexes, leading to acute disruption of cristae architecture, mitochondrial morphology, and respiration. These ceramide actions were dependent on the presence of the 4,5-trans double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion. Moreover, novel DES1 inhibitors that are attractive clinical drug candidates phenocopied the DES1 knockouts. These studies describe a new, therapeutically tractable mechanism underlying PT mitochondrial damage in AKI.
{"title":"Therapeutic remodeling of the ceramide backbone prevents kidney injury","authors":"Rebekah J. Nicholson, Luis Cedeño-Rosario, J. Alan Maschek, Trevor Lonergan, Jonathan G. Van Vranken, Angela R.S. Kruse, Chris J. Stubben, Liping Wang, Deborah Stuart, Queren A. Alcantara, Monica P. Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xuanchen Wu, Juwan Kim, Juna Kim, Isaac Hall, Amanda J. Clark, Samir Parikh, Scott A. Summers","doi":"10.1016/j.cmet.2025.10.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.006","url":null,"abstract":"Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. Mechanistic studies in primary PTs, which included a thermal proteomic profiling screen for ceramide effectors, revealed that ceramides altered assembly of the mitochondrial contact site and cristae-organizing system (MICOS) and respiratory supercomplexes, leading to acute disruption of cristae architecture, mitochondrial morphology, and respiration. These ceramide actions were dependent on the presence of the 4,5-<em>trans</em> double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion. Moreover, novel DES1 inhibitors that are attractive clinical drug candidates phenocopied the DES1 knockouts. These studies describe a new, therapeutically tractable mechanism underlying PT mitochondrial damage in AKI.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"54 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491968","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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