Pub Date : 2026-04-16DOI: 10.1016/j.cmet.2026.03.013
Erwei Li, Yangmian Yuan, Haijing Sun, Khushi Patel, Nan Zhang, Soumya Nagesh, Juan J. Aristizabal-Henao, Michael Kiebish, Christopher Jacobs, Dave Bridges, Brigid Gregg, Evan D. Rosen
Milk triglycerides, a crucial nutrient source for newborn mammals, can be derived from adipose lipolysis, dietary sources, or de novo synthesis in mammary epithelial cells (MECs). Here, we identify a critical role for the neuropeptide oxytocin (OXT) in providing milk triglyceride needed to sustain neonatal growth, mediated by its actions on adipose lipolysis. Dams lacking OXT receptors (OXTRs) specifically in adipocytes (OxtrΔAd) give birth to pups with reduced weight gain. Oxytocinergic sympathetic neurons are the relevant source of OXT mediating this effect. Milk from OxtrΔAd dams was deficient in triglycerides, which could be rescued by liberalizing dietary fat intake. Finally, single-cell analysis of lactating mammary glands from OxtrΔAd dams revealed a profound shift in the metabolic programming of MECs, indicative of reduced mTOR signaling, increased autophagy, and reduced lipid synthesis. These findings highlight the critical role of OXT-mediated adipose lipolysis in mammalian lactation, demonstrating that lipolysis-derived free fatty acids (FFAs) are essential for normal milk fat and neonatal health.
{"title":"Oxytocin signaling in adipocytes is required for normal milk fat production","authors":"Erwei Li, Yangmian Yuan, Haijing Sun, Khushi Patel, Nan Zhang, Soumya Nagesh, Juan J. Aristizabal-Henao, Michael Kiebish, Christopher Jacobs, Dave Bridges, Brigid Gregg, Evan D. Rosen","doi":"10.1016/j.cmet.2026.03.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.013","url":null,"abstract":"Milk triglycerides, a crucial nutrient source for newborn mammals, can be derived from adipose lipolysis, dietary sources, or <em>de novo</em> synthesis in mammary epithelial cells (MECs). Here, we identify a critical role for the neuropeptide oxytocin (OXT) in providing milk triglyceride needed to sustain neonatal growth, mediated by its actions on adipose lipolysis. Dams lacking OXT receptors (OXTRs) specifically in adipocytes (<em>Oxtr</em><sup>ΔAd</sup>) give birth to pups with reduced weight gain. Oxytocinergic sympathetic neurons are the relevant source of OXT mediating this effect. Milk from <em>Oxtr</em><sup>ΔAd</sup> dams was deficient in triglycerides, which could be rescued by liberalizing dietary fat intake. Finally, single-cell analysis of lactating mammary glands from <em>Oxtr</em><sup>ΔAd</sup> dams revealed a profound shift in the metabolic programming of MECs, indicative of reduced mTOR signaling, increased autophagy, and reduced lipid synthesis. These findings highlight the critical role of OXT-mediated adipose lipolysis in mammalian lactation, demonstrating that lipolysis-derived free fatty acids (FFAs) are essential for normal milk fat and neonatal health.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"408 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147696133","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 : 2026-04-15DOI: 10.1016/j.cmet.2026.03.012
Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A. Zuriaga, José J. Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S. Chandel, Esteban Ballestar, Stefanie K. Wculek, David Sancho
Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by Tet2 deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.
{"title":"Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells","authors":"Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A. Zuriaga, José J. Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S. Chandel, Esteban Ballestar, Stefanie K. Wculek, David Sancho","doi":"10.1016/j.cmet.2026.03.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.012","url":null,"abstract":"Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by <em>Tet2</em> deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695502","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 : 2026-04-06DOI: 10.1016/j.cmet.2026.03.005
Steffen H. Raun, Tang Cam Phung Pham, Mark R. Viggars, Satoru Ato, Yuta Takagaki, Zhen Yan, Katrien De Bock, Troy A. Hornberger, Erik A. Richter, Johan Auwerx, Laurie J. Goodyear, Mark A. Febbraio, Karyn A. Esser, Lykke Sylow
Regular physical activity is fundamental in promoting health and longevity. Numerous studies highlight the beneficial effects of exercise on metabolic parameters, but uncovering the mechanisms underlying the complex cellular responses and adaptations remains challenging in humans. Thus, animal models, in particular rodent models, have been indispensable for unveiling the underlying biological responses to exercise. Studies with precise exercise designs and diverse genetic models are vital for uncovering mechanistic pathways and informing pharmacological and behavioral strategies to combat non-communicable chronic diseases. Despite decades of research, recommendations to design preclinical exercise interventions and to measure key metabolic exercise adaptations in rodents have yet to be established. To enhance animal-to-human translation and ensure reproducibility, exercise studies must be rigorously controlled. Here, we outline key experimental considerations in rodents, including protocol design, exercise modality, sex, age, housing temperature, and circadian rhythm, to guide best practices and promote standardization and translation in future preclinical exercise studies.
{"title":"How to train your rodent: Recommendations for the preclinical study of exercise-induced benefits in metabolic research","authors":"Steffen H. Raun, Tang Cam Phung Pham, Mark R. Viggars, Satoru Ato, Yuta Takagaki, Zhen Yan, Katrien De Bock, Troy A. Hornberger, Erik A. Richter, Johan Auwerx, Laurie J. Goodyear, Mark A. Febbraio, Karyn A. Esser, Lykke Sylow","doi":"10.1016/j.cmet.2026.03.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.005","url":null,"abstract":"Regular physical activity is fundamental in promoting health and longevity. Numerous studies highlight the beneficial effects of exercise on metabolic parameters, but uncovering the mechanisms underlying the complex cellular responses and adaptations remains challenging in humans. Thus, animal models, in particular rodent models, have been indispensable for unveiling the underlying biological responses to exercise. Studies with precise exercise designs and diverse genetic models are vital for uncovering mechanistic pathways and informing pharmacological and behavioral strategies to combat non-communicable chronic diseases. Despite decades of research, recommendations to design preclinical exercise interventions and to measure key metabolic exercise adaptations in rodents have yet to be established. To enhance animal-to-human translation and ensure reproducibility, exercise studies must be rigorously controlled. Here, we outline key experimental considerations in rodents, including protocol design, exercise modality, sex, age, housing temperature, and circadian rhythm, to guide best practices and promote standardization and translation in future preclinical exercise studies.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"425 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147630088","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 : 2026-04-03DOI: 10.1016/j.cmet.2026.03.016
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, Yun Zhang, Weihong Song, Billy Wai-Lung Ng, Sunny H. Wong, Thomas W. Leung, Vincent C.T. Mok, Ho Ko
{"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, Yun Zhang, Weihong Song, Billy Wai-Lung Ng, Sunny H. Wong, Thomas W. Leung, Vincent C.T. Mok, Ho Ko","doi":"10.1016/j.cmet.2026.03.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.016","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"3 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147598166","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 : 2026-04-01DOI: 10.1016/j.cmet.2026.03.018
Thomas Marjot, Kieran Smith, Felix Westcott, Sarah White, Elspeth Johnson, Nikola Srnic, Amy Barrett, Ellis Hall, Kate Gralton, Kaitlyn Dennis, Hamish Miller, Riccardo Pofi, Jeremy F.L. Cobbold, Rebecca Richmond, Fredrik Karpe, Ronnie Blazev, Matthew J. Watt, Benjamin L. Parker, Leanne Hodson, David W. Ray, Jeremy W. Tomlinson
(Cell Metabolism 38, 474–492.e1–e6; March 3, 2026)
（细胞代谢38,474-492.e1-e6； 2026年3月3日）
{"title":"Human MASLD is a diurnal disease driven by multisystem insulin resistance and reduced insulin availability at night","authors":"Thomas Marjot, Kieran Smith, Felix Westcott, Sarah White, Elspeth Johnson, Nikola Srnic, Amy Barrett, Ellis Hall, Kate Gralton, Kaitlyn Dennis, Hamish Miller, Riccardo Pofi, Jeremy F.L. Cobbold, Rebecca Richmond, Fredrik Karpe, Ronnie Blazev, Matthew J. Watt, Benjamin L. Parker, Leanne Hodson, David W. Ray, Jeremy W. Tomlinson","doi":"10.1016/j.cmet.2026.03.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.018","url":null,"abstract":"(Cell Metabolism <em>38</em>, 474–492.e1–e6; March 3, 2026)","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"61 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147586416","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 : 2026-04-01DOI: 10.1016/j.cmet.2026.03.003
Ting-Ting Wang, Yan-Jia Luo, Wen Feng, Lian-Xiang Jiang, Qing-Song Yu, Yu-Ting He, Lizhi Guan, Bing-Qian Zhu, Hong Jiang, Min Li, Ruixin Liu, Jing Wang, Ya-Dong Li
Gut microbiota modulate emotion, yet mechanistic insight and therapeutic targets remain limited. Here, we identify reduced gut microbiota-derived indole causally modulating emotion through hippocampal aryl hydrocarbon receptor (AhR). We found that decreased abundance of Alistipes shahii reduced intestinal indole levels via loss of tryptophanase, the rate-limiting step for indole production in microbial tryptophan metabolism, in irritable bowel syndrome (IBS) patients and model mice. In the brain, indole acts via AhR, which is enriched in the ventral dentate gyrus (vDG), a hub in regulating emotion. Reduced indole diminished nuclear AhR expression and vDG granule cell activity, leading to affective symptoms. Tryptophanase-producing microbiota transplantation, indole/tryptophanase supplementation, chemogenetic activation of vDG neurons, or diosmin, a clinically approved AhR agonist, rescued emotional symptoms in IBS mice. Together, these findings define an Alistipes shahii-tryptophanase-indole-AhR-vDG pathway as a mechanistic and translationally tractable gut-brain axis underlying affective disturbances.
{"title":"Gut microbial metabolism via hippocampal indole-AhR signaling regulates emotional symptoms","authors":"Ting-Ting Wang, Yan-Jia Luo, Wen Feng, Lian-Xiang Jiang, Qing-Song Yu, Yu-Ting He, Lizhi Guan, Bing-Qian Zhu, Hong Jiang, Min Li, Ruixin Liu, Jing Wang, Ya-Dong Li","doi":"10.1016/j.cmet.2026.03.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.003","url":null,"abstract":"Gut microbiota modulate emotion, yet mechanistic insight and therapeutic targets remain limited. Here, we identify reduced gut microbiota-derived indole causally modulating emotion through hippocampal aryl hydrocarbon receptor (AhR). We found that decreased abundance of <em>Alistipes shahii</em> reduced intestinal indole levels via loss of tryptophanase, the rate-limiting step for indole production in microbial tryptophan metabolism, in irritable bowel syndrome (IBS) patients and model mice. In the brain, indole acts via AhR, which is enriched in the ventral dentate gyrus (vDG), a hub in regulating emotion. Reduced indole diminished nuclear AhR expression and vDG granule cell activity, leading to affective symptoms. Tryptophanase-producing microbiota transplantation, indole/tryptophanase supplementation, chemogenetic activation of vDG neurons, or diosmin, a clinically approved AhR agonist, rescued emotional symptoms in IBS mice. Together, these findings define an <em>Alistipes shahii</em>-tryptophanase-indole-AhR-vDG pathway as a mechanistic and translationally tractable gut-brain axis underlying affective disturbances.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"12 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147586726","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 : 2026-03-31DOI: 10.1016/j.cmet.2026.03.002
Cheng-Lin Lu, Jing Ren, Yueshiyuan Lei, Xiao-Ying Lian, Hao-Tian Jiang, Fang Guo, Liang-Yu Chen, Jia-Wen Mo, Hongyun Mao, Jun Fan, Guangyan Wu, Wan-Qian Ye, You-Lu Wen, Haitao Sun, Yan He, Jiubo Zhao, Xiong Cao
Although peripheral-brain crosstalk regulates energy metabolism, its role in depression remains unclear. Here, we used metabolic profiling to reveal elevated fecal creatine alongside reduced plasma and cerebrospinal fluid creatine in both patients with depression and mouse depression models. Exogenous creatine produced antidepressant-like effects mediated by gut microbiota. Bifidobacterium pseudolongum was identified as a significantly reduced gut bacterial species in depression, correlating with impaired creatine absorption. Subsequent supplementation with Bifidobacterium enhanced the antidepressant effects of creatine. Mechanistically, B. pseudolongum-derived acetate promoted the creatine transporter (Slc6a8) expression in intestinal epithelial cells via histone acetylation. The Slc6a8 mediated the antidepressant-like effects of creatine. Neuronal creatine deficiency influenced energetic metabolism and neurophysiological function. In patients with depression taking antidepressants, co-administration of creatine and Bifidobacterium increased plasma creatine levels and reduced depression scores. These findings identify the Bifidobacterium-creatine combination as a promising antidepressant strategy and highlight the critical role of gut-brain energy metabolism in depression.
{"title":"The gut microbiota alleviates depression by remodeling gut-brain energy metabolism","authors":"Cheng-Lin Lu, Jing Ren, Yueshiyuan Lei, Xiao-Ying Lian, Hao-Tian Jiang, Fang Guo, Liang-Yu Chen, Jia-Wen Mo, Hongyun Mao, Jun Fan, Guangyan Wu, Wan-Qian Ye, You-Lu Wen, Haitao Sun, Yan He, Jiubo Zhao, Xiong Cao","doi":"10.1016/j.cmet.2026.03.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.002","url":null,"abstract":"Although peripheral-brain crosstalk regulates energy metabolism, its role in depression remains unclear. Here, we used metabolic profiling to reveal elevated fecal creatine alongside reduced plasma and cerebrospinal fluid creatine in both patients with depression and mouse depression models. Exogenous creatine produced antidepressant-like effects mediated by gut microbiota. <em>Bifidobacterium pseudolongum</em> was identified as a significantly reduced gut bacterial species in depression, correlating with impaired creatine absorption. Subsequent supplementation with <em>Bifidobacterium</em> enhanced the antidepressant effects of creatine. Mechanistically, <em>B. pseudolongum</em>-derived acetate promoted the creatine transporter (<em>Slc6a8</em>) expression in intestinal epithelial cells via histone acetylation. The <em>Slc6a8</em> mediated the antidepressant-like effects of creatine. Neuronal creatine deficiency influenced energetic metabolism and neurophysiological function. In patients with depression taking antidepressants, co-administration of creatine and <em>Bifidobacterium</em> increased plasma creatine levels and reduced depression scores. These findings identify the <em>Bifidobacterium</em>-creatine combination as a promising antidepressant strategy and highlight the critical role of gut-brain energy metabolism in depression.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"103 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147586418","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 : 2026-03-27DOI: 10.1016/j.cmet.2026.03.010
Filip J. Larsen
(Cell Metabolism 38, 257–259; February 3, 2026)
（细胞代谢38,257 - 259；2026年2月3日）
{"title":"Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise","authors":"Filip J. Larsen","doi":"10.1016/j.cmet.2026.03.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.010","url":null,"abstract":"(Cell Metabolism <em>38</em>, 257–259; February 3, 2026)","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147536608","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}
Type 2 diabetes is a major risk factor for fragility fractures, yet the contributors to skeletal fragility remain unclear. Through integrated clinical metabolomics, in vivo, and in vitro analyses, we identify maltol—a widely used food additive—as a previously unrecognized risk factor for hyperglycemia-associated bone fragility. Metabolomic profiling of femoral neck tissue from individuals with fragility fractures showed diabetes-associated maltol accumulation, and elevated circulating maltol levels correlated with increased fracture incidence. Mechanistically, maltol inhibits osteoblast differentiation via Wnt/β-catenin and promotes osteoclast maturation through nuclear factor κB (NF-κB) signaling, disrupting bone remodeling. These effects are amplified under hyperglycemia, while insulin reversal of glucose levels mitigates maltol-induced skeletal deterioration in mouse models. Given the widespread use of maltol in processed foods, these findings suggest that food additive safety should consider metabolic context and call for disease-specific dietary exposure guidelines to reduce fracture risk in diabetes.
{"title":"Maltol induces diabetic fragility fractures by disrupting the balance of bone remodeling","authors":"Jinyang Wang, Ziyuan Wang, Jinyi Feng, Ying Zhang, Lizheng Yao, Yiran Zhang, Ruijie Zhang, Jingyi Cai, Hao Yu, Songhan Deng, Xinrui Chen, Rui Liang, Caoxin Huang, Jia Li, Xuejun Li, Qinxi Li, Xiulin Shi","doi":"10.1016/j.cmet.2026.03.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.001","url":null,"abstract":"Type 2 diabetes is a major risk factor for fragility fractures, yet the contributors to skeletal fragility remain unclear. Through integrated clinical metabolomics, <em>in vivo</em>, and <em>in vitro</em> analyses, we identify maltol—a widely used food additive—as a previously unrecognized risk factor for hyperglycemia-associated bone fragility. Metabolomic profiling of femoral neck tissue from individuals with fragility fractures showed diabetes-associated maltol accumulation, and elevated circulating maltol levels correlated with increased fracture incidence. Mechanistically, maltol inhibits osteoblast differentiation via Wnt/β-catenin and promotes osteoclast maturation through nuclear factor κB (NF-κB) signaling, disrupting bone remodeling. These effects are amplified under hyperglycemia, while insulin reversal of glucose levels mitigates maltol-induced skeletal deterioration in mouse models. Given the widespread use of maltol in processed foods, these findings suggest that food additive safety should consider metabolic context and call for disease-specific dietary exposure guidelines to reduce fracture risk in diabetes.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"15 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147518785","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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