Pub Date : 2025-10-16DOI: 10.1016/j.cmet.2025.09.009
Connor S.R. Jankowski, Laith Z. Samarah, Michael R. MacArthur, Sarah J. Mitchell, Daniel R. Weilandt, Craig J. Hunter, Xianfeng Zeng, Melanie R. McReynolds, Joshua D. Rabinowitz
Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20–30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.
{"title":"Aged mice exhibit widespread metabolic changes but preserved major fluxes","authors":"Connor S.R. Jankowski, Laith Z. Samarah, Michael R. MacArthur, Sarah J. Mitchell, Daniel R. Weilandt, Craig J. Hunter, Xianfeng Zeng, Melanie R. McReynolds, Joshua D. Rabinowitz","doi":"10.1016/j.cmet.2025.09.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.009","url":null,"abstract":"Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20–30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"24 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295524","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 : 2025-10-15DOI: 10.1016/j.cmet.2025.09.008
Joseph Longo, McLane J. Watson, Kelsey S. Williams, Ryan D. Sheldon, Russell G. Jones
T cell activation and function are intricately linked to metabolic reprogramming. The classic view of T cell metabolic reprogramming centers on glucose as the dominant bioenergetic fuel, where T cell receptor (TCR) stimulation promotes a metabolic switch from relying primarily on oxidative phosphorylation (OXPHOS) for energy production to aerobic glycolysis (i.e., the Warburg effect). More recently, studies have revealed this classic model to be overly simplistic. Activated T cells run both glycolysis and OXPHOS programs concurrently, allocating diverse nutrient sources toward distinct biosynthetic and bioenergetic fates. Moreover, studies of T cell metabolism in vivo and ex vivo highlight that physiologic nutrient availability influences how glucose is allocated by T cells to fuel both optimal proliferation and effector function. Here, we summarize recent advancements that support a revised model of effector T cell metabolism, where strategic nutrient allocation fuels optimal T cell-mediated immunity.
{"title":"Nutrient allocation fuels T cell-mediated immunity","authors":"Joseph Longo, McLane J. Watson, Kelsey S. Williams, Ryan D. Sheldon, Russell G. Jones","doi":"10.1016/j.cmet.2025.09.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.008","url":null,"abstract":"T cell activation and function are intricately linked to metabolic reprogramming. The classic view of T cell metabolic reprogramming centers on glucose as the dominant bioenergetic fuel, where T cell receptor (TCR) stimulation promotes a metabolic switch from relying primarily on oxidative phosphorylation (OXPHOS) for energy production to aerobic glycolysis (i.e., the Warburg effect). More recently, studies have revealed this classic model to be overly simplistic. Activated T cells run both glycolysis and OXPHOS programs concurrently, allocating diverse nutrient sources toward distinct biosynthetic and bioenergetic fates. Moreover, studies of T cell metabolism <em>in vivo</em> and <em>ex vivo</em> highlight that physiologic nutrient availability influences how glucose is allocated by T cells to fuel both optimal proliferation and effector function. Here, we summarize recent advancements that support a revised model of effector T cell metabolism, where strategic nutrient allocation fuels optimal T cell-mediated immunity.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"71 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145289269","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 brain relies heavily on glucose for energy resources, and thus prompt counterregulatory responses to hypoglycemia in connection with glucose production are fundamental. We identified a biphasic pattern in blood and hypothalamic glucose dynamics during prolonged fasting, revealing an additional threshold-dependent mechanism for counterregulation. This mechanism is mediated by a ventromedial hypothalamus (VMH)→paraventricular hypothalamic nucleus (PVH)→lateral paragigantocellular nucleus (LPGi)→liver neurocircuit that detects neuroglycopenia and transmits neural signals to drive hepatic glucose production via intrahepatic sympathetic activation. Using viral tracing, single-nucleus RNA sequencing, and various unbiased methods, we identified Galnt2 as both a genetic marker and molecular brake of VMH glucose-inhibited neurons, modulating the glycemic threshold for hypoglycemia perception and metabolic homeostasis. Our results highlight a VMHGalnt2-originated brain-liver neurocircuit that perceives and counterregulates hypoglycemia and may pave the way to innovative therapeutic strategies against metabolic disorders characterized by glucose dysregulation.
{"title":"Galnt2 neurons in the ventromedial hypothalamus counterregulate hypoglycemia via a brain-liver neurocircuit","authors":"Junjie Wang, Xinyuan Sun, Xiangfei Gong, Wenling Dai, Hao Hong, Li Jiang, Zhonglong Wang, Zhiyuan Tang, Xiaobo Wu, Peng Sun, Yongjie Zhang, Kun Hao, Fang Zhou, Ying Cui, Tianyu Tang, Xiao Zheng, Lanqun Mao, Guangji Wang, Haiping Hao, Hao Xie","doi":"10.1016/j.cmet.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.006","url":null,"abstract":"The brain relies heavily on glucose for energy resources, and thus prompt counterregulatory responses to hypoglycemia in connection with glucose production are fundamental. We identified a biphasic pattern in blood and hypothalamic glucose dynamics during prolonged fasting, revealing an additional threshold-dependent mechanism for counterregulation. This mechanism is mediated by a ventromedial hypothalamus (VMH)→paraventricular hypothalamic nucleus (PVH)→lateral paragigantocellular nucleus (LPGi)→liver neurocircuit that detects neuroglycopenia and transmits neural signals to drive hepatic glucose production via intrahepatic sympathetic activation. Using viral tracing, single-nucleus RNA sequencing, and various unbiased methods, we identified Galnt2 as both a genetic marker and molecular brake of VMH glucose-inhibited neurons, modulating the glycemic threshold for hypoglycemia perception and metabolic homeostasis. Our results highlight a VMH<sup>Galnt2</sup>-originated brain-liver neurocircuit that perceives and counterregulates hypoglycemia and may pave the way to innovative therapeutic strategies against metabolic disorders characterized by glucose dysregulation.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283559","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 : 2025-10-10DOI: 10.1016/j.cmet.2025.09.015
Artem Khan, Frederick S. Yen, Gokhan Unlu, Nicole L. DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R. Gamazon, Gary J. Patti, Kıvanç Birsoy
Solute carriers (SLCs) regulate cellular and organismal metabolism by transporting small molecules and ions across membranes, yet the physiological substrates of ∼20% remain elusive. To address this, we developed a machine-learning platform to predict gene-metabolite associations. This approach identifies UNC93A and SLC45A4 as candidate plasma membrane transporters for acetylglucosamine and polyamines, respectively. Additionally, we uncover SLC25A45 as a mitochondrial transporter linked to serum levels of methylated basic amino acids, products of protein catabolism. Mechanistically, SLC25A45 is necessary for the mitochondrial import of methylated basic amino acids, including ADMA and TML, the latter serving as a precursor for carnitine synthesis. In line with this observation, SLC25A45 loss impairs carnitine synthesis and blunts upregulation of carnitine-containing metabolites under fasted conditions. By facilitating mitochondrial TML import, SLC25A45 connects protein catabolism to carnitine production, sustaining β-oxidation during fasting. Altogether, our study identifies putative substrates for three SLCs and provides a resource for transporter deorphanization.
{"title":"Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis","authors":"Artem Khan, Frederick S. Yen, Gokhan Unlu, Nicole L. DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R. Gamazon, Gary J. Patti, Kıvanç Birsoy","doi":"10.1016/j.cmet.2025.09.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.015","url":null,"abstract":"Solute carriers (SLCs) regulate cellular and organismal metabolism by transporting small molecules and ions across membranes, yet the physiological substrates of ∼20% remain elusive. To address this, we developed a machine-learning platform to predict gene-metabolite associations. This approach identifies UNC93A and SLC45A4 as candidate plasma membrane transporters for acetylglucosamine and polyamines, respectively. Additionally, we uncover SLC25A45 as a mitochondrial transporter linked to serum levels of methylated basic amino acids, products of protein catabolism. Mechanistically, SLC25A45 is necessary for the mitochondrial import of methylated basic amino acids, including ADMA and TML, the latter serving as a precursor for carnitine synthesis. In line with this observation, SLC25A45 loss impairs carnitine synthesis and blunts upregulation of carnitine-containing metabolites under fasted conditions. By facilitating mitochondrial TML import, SLC25A45 connects protein catabolism to carnitine production, sustaining β-oxidation during fasting. Altogether, our study identifies putative substrates for three SLCs and provides a resource for transporter deorphanization.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"37 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254946","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 : 2025-10-07DOI: 10.1016/j.cmet.2025.09.005
Joanne F. Garbincius, John W. Elrod
The mechanisms mediating calcium transport into and out of the mitochondrial matrix have critical implications for signaling, bioenergetics, and cell death. Zhang et al.1 propose that the protein TMEM65, recently identified as a key component of the mitochondrial calcium efflux machinery, functions as the mitochondrial sodium/calcium exchanger. Their report encourages critical re-examination of the components required for mitochondrial calcium handling.
{"title":"Mitochondrial sodium-calcium exchange—Can TMEM65 do it alone?","authors":"Joanne F. Garbincius, John W. Elrod","doi":"10.1016/j.cmet.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.005","url":null,"abstract":"The mechanisms mediating calcium transport into and out of the mitochondrial matrix have critical implications for signaling, bioenergetics, and cell death. Zhang et al.<span><span><sup>1</sup></span></span> propose that the protein TMEM65, recently identified as a key component of the mitochondrial calcium efflux machinery, functions as the mitochondrial sodium/calcium exchanger. Their report encourages critical re-examination of the components required for mitochondrial calcium handling.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"83 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241384","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 : 2025-10-07DOI: 10.1016/j.cmet.2025.09.007
Huixian Li, Daniel Mucida
The gut conveys nutritional, mechanical, and microbial signals to the brain to regulate physiology and behavior. Writing in Nature, Liu et al. reveal a colonic neuropod-vagus circuit that senses bacterial flagellin, highlighting microbial input as a rapid driver of feeding control and expanding paradigms of communication between the gut and the brain.
{"title":"An “electric” microbial cue to control food intake behavior","authors":"Huixian Li, Daniel Mucida","doi":"10.1016/j.cmet.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.007","url":null,"abstract":"The gut conveys nutritional, mechanical, and microbial signals to the brain to regulate physiology and behavior. Writing in <em>Nature</em>, Liu et al. reveal a colonic neuropod-vagus circuit that senses bacterial flagellin, highlighting microbial input as a rapid driver of feeding control and expanding paradigms of communication between the gut and the brain.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"5 7 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241312","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 : 2025-10-07DOI: 10.1016/j.cmet.2025.08.006
Xiangqi Chen, Xiaoqiang Tang, Yanping Li, Jinhan He
Atherosclerosis remains the leading type of cardiovascular disease, yet its pathogenesis is not completely understood, hindering the development of effective early diagnostics and therapeutics. Recent work by Mastrangelo et al. in Nature has identified a novel driver of atherosclerosis, the gut microbiota-derived metabolite imidazole propionate, which triggers atherosclerosis via the imidazoline-1 receptor in myeloid cells.
{"title":"Imidazole propionate: Cause and cure in atherosclerosis?","authors":"Xiangqi Chen, Xiaoqiang Tang, Yanping Li, Jinhan He","doi":"10.1016/j.cmet.2025.08.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.006","url":null,"abstract":"Atherosclerosis remains the leading type of cardiovascular disease, yet its pathogenesis is not completely understood, hindering the development of effective early diagnostics and therapeutics. Recent work by Mastrangelo et al. in <em>Nature</em> has identified a novel driver of atherosclerosis, the gut microbiota-derived metabolite imidazole propionate, which triggers atherosclerosis via the imidazoline-1 receptor in myeloid cells.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"59 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241313","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 : 2025-10-07DOI: 10.1016/j.cmet.2025.09.004
Yunzi Mao, Mei Cui, Yanfeng Jiang, Haowen Yu, Meng Wang, Gang Li, Haihui Zhang, Cheng Zhao, Yanxin Shen, Yupeng Hu, Yanpeng An, Yan Lin, Yiyuan Yuan, Pengcheng Lin, Xingdong Chen, Wei Xu, Shi-Min Zhao
The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer’s disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.
{"title":"AMPKα2 signals amino acid insufficiency to inhibit protein synthesis","authors":"Yunzi Mao, Mei Cui, Yanfeng Jiang, Haowen Yu, Meng Wang, Gang Li, Haihui Zhang, Cheng Zhao, Yanxin Shen, Yupeng Hu, Yanpeng An, Yan Lin, Yiyuan Yuan, Pengcheng Lin, Xingdong Chen, Wei Xu, Shi-Min Zhao","doi":"10.1016/j.cmet.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.004","url":null,"abstract":"The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer’s disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of <em>α2</em>, but not <em>α1</em>, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2<em>-</em>p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2<em>-</em>p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"128 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241311","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 : 2025-10-06DOI: 10.1016/j.cmet.2025.09.002
Martin Picard, Nirosha J. Murugan
Living organisms are physical-energetic systems that must obey simple principles guiding energy transformation across physical and temporal scales. The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. Although éR is required to sustain life, excess éR directly causes reductive and oxidative stress, heat, inflammation, molecular damage, and information loss—all hallmarks of disease and aging. We discuss how disease-causing stressors elevate éR and circulating growth differentiation factor 15 (GDF15) levels, whereas sleep, physical activity, and restorative interventions that promote healing minimize éR. The ERP is a testable general framework for discovering the modifiable bioenergetic forces that shape development, aging, and the dynamic health-disease continuum.
{"title":"The energy resistance principle","authors":"Martin Picard, Nirosha J. Murugan","doi":"10.1016/j.cmet.2025.09.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.002","url":null,"abstract":"Living organisms are physical-energetic systems that must obey simple principles guiding energy transformation across physical and temporal scales. The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. Although éR is required to sustain life, excess éR directly causes reductive and oxidative stress, heat, inflammation, molecular damage, and information loss—all hallmarks of disease and aging. We discuss how disease-causing stressors elevate éR and circulating growth differentiation factor 15 (GDF15) levels, whereas sleep, physical activity, and restorative interventions that promote healing minimize éR. The ERP is a testable general framework for discovering the modifiable bioenergetic forces that shape development, aging, and the dynamic health-disease continuum.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"68 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229362","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 : 2025-10-06DOI: 10.1016/j.cmet.2025.09.003
Xin Yin, Azhar Anwar, Linbo Yan, Ranran Yu, Yang Luo, Liang Shi, Botao Li, Jiehao Chen, Gaoli Liang, Yongci Chen, Jie Tang, Jie Liang, Yansheng Kan, Zhihao Zhang, Xiahuan Zhou, Jizheng Ma, Chenbo Ji, Yanbo Wang, Qipeng Zhang, Jing Li, Xi Chen
Paternal exercise influences exercise capacity and metabolic health of offspring, but the underlying mechanisms remain poorly understood. We demonstrate that offspring sired by exercise-trained fathers display intrinsic exercise adaptations and improved metabolic parameters compared with those sired by sedentary fathers. Similarly, offspring born to transgenic mice with muscle-specific overexpression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a booster of mitochondrial function, exhibit improved endurance capacity and metabolic traits, even in the absence of the inherited PGC-1α transgene. Injecting sperm small RNAs from exercised fathers into normal zygotes recapitulates exercise-trained phenotypes in offspring at the behavioral, metabolic, and molecular levels. Mechanistically, exercise training and muscular PGC-1α overexpression remodel sperm microRNAs, which directly suppress nuclear receptor corepressor 1 (NCoR1), a functional antagonist of PGC-1α, in early embryos, thereby reprogramming transcriptional networks to promote mitochondrial biogenesis and oxidative metabolism. Overall, this study underscores a causal role for paternal PGC-1α, sperm microRNAs, and embryonic NCoR1 in transmitting exercise-induced phenotypes and metabolic adaptations to offspring.
{"title":"Paternal exercise confers endurance capacity to offspring through sperm microRNAs","authors":"Xin Yin, Azhar Anwar, Linbo Yan, Ranran Yu, Yang Luo, Liang Shi, Botao Li, Jiehao Chen, Gaoli Liang, Yongci Chen, Jie Tang, Jie Liang, Yansheng Kan, Zhihao Zhang, Xiahuan Zhou, Jizheng Ma, Chenbo Ji, Yanbo Wang, Qipeng Zhang, Jing Li, Xi Chen","doi":"10.1016/j.cmet.2025.09.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.003","url":null,"abstract":"Paternal exercise influences exercise capacity and metabolic health of offspring, but the underlying mechanisms remain poorly understood. We demonstrate that offspring sired by exercise-trained fathers display intrinsic exercise adaptations and improved metabolic parameters compared with those sired by sedentary fathers. Similarly, offspring born to transgenic mice with muscle-specific overexpression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a booster of mitochondrial function, exhibit improved endurance capacity and metabolic traits, even in the absence of the inherited PGC-1α transgene. Injecting sperm small RNAs from exercised fathers into normal zygotes recapitulates exercise-trained phenotypes in offspring at the behavioral, metabolic, and molecular levels. Mechanistically, exercise training and muscular PGC-1α overexpression remodel sperm microRNAs, which directly suppress nuclear receptor corepressor 1 (NCoR1), a functional antagonist of PGC-1α, in early embryos, thereby reprogramming transcriptional networks to promote mitochondrial biogenesis and oxidative metabolism. Overall, this study underscores a causal role for paternal PGC-1α, sperm microRNAs, and embryonic NCoR1 in transmitting exercise-induced phenotypes and metabolic adaptations to offspring.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"16 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229363","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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