Pub Date : 2025-11-11DOI: 10.1016/j.cmet.2025.10.005
Jin Wang, Xuhong Zhang, Ye Zhu, Haixiang Sun, Xuetao Chen, Zhicong Zhao, Nina Zhang, Chenyu Zhang, Liang Li, Yan Bi
The exact mechanisms underlying leptin resistance, the central mechanism of obesity, remain elusive. Herein, we demonstrate that adipocyte-derived extracellular vesicles (Ad-EVs) serve as key regulatory factors of hypothalamic circuits governing food intake and body weight by modulating leptin responsiveness. Specifically, we identified a subset of microRNA (miRNA) within Ad-EVs that exerts leptin-sensitizing effects by inhibiting negative feedback regulators of leptin receptor signaling. Loss of these leptin-sensitizing miRNAs in Ad-EVs contributes to leptin resistance and subsequent weight gain in obesity. Of note, we developed engineered EVs modified with specific Ad-EV membrane proteins for targeted delivery of leptin-sensitizing miRNAs to the central nervous system, which reversed central leptin resistance and induced significant weight loss in obese mice. These findings highlight the critical role of Ad-EVs in central leptin sensitivity regulation, offering new insights into the role of the adipose tissue-brain axis in maintaining energy balance and potential pharmacological targets for obesity treatment.
{"title":"Adipocyte-derived extracellular vesicles are key regulators of central leptin sensitivity and energy homeostasis","authors":"Jin Wang, Xuhong Zhang, Ye Zhu, Haixiang Sun, Xuetao Chen, Zhicong Zhao, Nina Zhang, Chenyu Zhang, Liang Li, Yan Bi","doi":"10.1016/j.cmet.2025.10.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.005","url":null,"abstract":"The exact mechanisms underlying leptin resistance, the central mechanism of obesity, remain elusive. Herein, we demonstrate that adipocyte-derived extracellular vesicles (Ad-EVs) serve as key regulatory factors of hypothalamic circuits governing food intake and body weight by modulating leptin responsiveness. Specifically, we identified a subset of microRNA (miRNA) within Ad-EVs that exerts leptin-sensitizing effects by inhibiting negative feedback regulators of leptin receptor signaling. Loss of these leptin-sensitizing miRNAs in Ad-EVs contributes to leptin resistance and subsequent weight gain in obesity. Of note, we developed engineered EVs modified with specific Ad-EV membrane proteins for targeted delivery of leptin-sensitizing miRNAs to the central nervous system, which reversed central leptin resistance and induced significant weight loss in obese mice. These findings highlight the critical role of Ad-EVs in central leptin sensitivity regulation, offering new insights into the role of the adipose tissue-brain axis in maintaining energy balance and potential pharmacological targets for obesity treatment.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"47 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485829","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 : 2025-11-06DOI: 10.1016/j.cmet.2025.10.007
Kendra Klag, Darci Ott, Trevor S. Tippetts, Rebekah J. Nicolson, Sean M. Tatum, Kaylyn M. Bauer, Emmanuel Stephen-Victor, Allison M. Weis, Rickesha Bell, James Weagley, J. Alan Maschek, Dai Long Vu, Stacey Heaver, Ruth Ley, Ryan O’Connell, William L. Holland, Scott A. Summers, W. Zac Stephens, June L. Round
The microbiota influences metabolic health; however, few specific microbial molecules and mechanisms have been identified. We isolated a Turicibacter strain from a community of spore-forming bacteria that promotes leanness in mice. Human metagenomic analysis demonstrates reduced Turicibacter abundance in individuals with obesity. Similarly, a high-fat diet reduces Turicibacter colonization, preventing its weight-suppressive effects, which can be overcome with continuous Turicibacter supplementation. Ceramides accumulate during a high-fat diet and promote weight gain. Transcriptomics and lipidomics reveal that the spore-forming community and Turicibacter suppress host ceramides. Turicibacter produces unique lipids, which are reduced during a high-fat diet. These lipids can be transferred to host epithelial cells, reduce ceramide production, and decrease fat uptake. Treatment of animals with purified Turicibacter lipids prevents obesity, demonstrating that bacterial lipids can promote host metabolic health. These data identify a lipid metabolic circuit between bacteria and host that is disrupted by diet and can be targeted therapeutically.
{"title":"Dietary fat disrupts a commensal-host lipid network that promotes metabolic health","authors":"Kendra Klag, Darci Ott, Trevor S. Tippetts, Rebekah J. Nicolson, Sean M. Tatum, Kaylyn M. Bauer, Emmanuel Stephen-Victor, Allison M. Weis, Rickesha Bell, James Weagley, J. Alan Maschek, Dai Long Vu, Stacey Heaver, Ruth Ley, Ryan O’Connell, William L. Holland, Scott A. Summers, W. Zac Stephens, June L. Round","doi":"10.1016/j.cmet.2025.10.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.007","url":null,"abstract":"The microbiota influences metabolic health; however, few specific microbial molecules and mechanisms have been identified. We isolated a <em>Turicibacter</em> strain from a community of spore-forming bacteria that promotes leanness in mice. Human metagenomic analysis demonstrates reduced <em>Turicibacter</em> abundance in individuals with obesity. Similarly, a high-fat diet reduces <em>Turicibacter</em> colonization, preventing its weight-suppressive effects, which can be overcome with continuous <em>Turicibacter</em> supplementation. Ceramides accumulate during a high-fat diet and promote weight gain. Transcriptomics and lipidomics reveal that the spore-forming community and <em>Turicibacter</em> suppress host ceramides. <em>Turicibacter</em> produces unique lipids, which are reduced during a high-fat diet. These lipids can be transferred to host epithelial cells, reduce ceramide production, and decrease fat uptake. Treatment of animals with purified <em>Turicibacter</em> lipids prevents obesity, demonstrating that bacterial lipids can promote host metabolic health. These data identify a lipid metabolic circuit between bacteria and host that is disrupted by diet and can be targeted therapeutically.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447678","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 : 2025-11-05DOI: 10.1016/j.cmet.2025.10.019
Luiz Osório Leiria, Chih-Hao Wang, Matthew D. Lynes, Kunyan Yang, Farnaz Shamsi, Mari Sato, Satoru Sugimoto, Emily Y. Chen, Valerie Bussberg, Niven R. Narain, Brian E. Sansbury, Justin Darcy, Tian Lian Huang, Sean D. Kodani, Masaji Sakaguchi, Andréa L. Rocha, Tim J. Schulz, Alexander Bartelt, Gökhan S. Hotamisligil, Michael F. Hirshman, Yu-Hua Tseng
(Cell Metabolism 30, 768–783.e1–e7; October 1, 2019)
（细胞代谢30,768-783.e1-e7； 2019年10月1日）
{"title":"12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat","authors":"Luiz Osório Leiria, Chih-Hao Wang, Matthew D. Lynes, Kunyan Yang, Farnaz Shamsi, Mari Sato, Satoru Sugimoto, Emily Y. Chen, Valerie Bussberg, Niven R. Narain, Brian E. Sansbury, Justin Darcy, Tian Lian Huang, Sean D. Kodani, Masaji Sakaguchi, Andréa L. Rocha, Tim J. Schulz, Alexander Bartelt, Gökhan S. Hotamisligil, Michael F. Hirshman, Yu-Hua Tseng","doi":"10.1016/j.cmet.2025.10.019","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.019","url":null,"abstract":"(Cell Metabolism <em>30</em>, 768–783.e1–e7; October 1, 2019)","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"40 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442010","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 : 2025-11-05DOI: 10.1016/j.cmet.2025.10.020
Sabina Chubanava, Iuliia Karavaeva, Amy M. Ehrlich, Roger M. Justicia, Astrid L. Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R. Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N. Rodrigues, Jesper F. Havelund, Farina L. Schlabs, Steen Larsen, Caio Y. Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R. Zierath, Kei Sakamoto, Thomas E. Jensen, Nils J. Færgeman, Gareth G. Lavery, Atul S. Deshmukh, Jonas T. Treebak
{"title":"NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging","authors":"Sabina Chubanava, Iuliia Karavaeva, Amy M. Ehrlich, Roger M. Justicia, Astrid L. Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R. Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N. Rodrigues, Jesper F. Havelund, Farina L. Schlabs, Steen Larsen, Caio Y. Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R. Zierath, Kei Sakamoto, Thomas E. Jensen, Nils J. Færgeman, Gareth G. Lavery, Atul S. Deshmukh, Jonas T. Treebak","doi":"10.1016/j.cmet.2025.10.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.020","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"39 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441526","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 : 2025-11-04DOI: 10.1016/j.cmet.2025.10.008
Gregory S. Ducker, Jared Rutter
How metabolites regulate protein function is still poorly understood. Leveraging the power of genetic variation, Xiao et al. built a global protein-metabolite covariation dataset to reveal novel protein-metabolite regulations in mouse that led to the discovery of cysteine catabolism as an unexpected regulator of cholesterol.
{"title":"Leveraging genetic and phenotypic variation to discover metabolite-protein interactions","authors":"Gregory S. Ducker, Jared Rutter","doi":"10.1016/j.cmet.2025.10.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.008","url":null,"abstract":"How metabolites regulate protein function is still poorly understood. Leveraging the power of genetic variation, Xiao et al. built a global protein-metabolite covariation dataset to reveal novel protein-metabolite regulations in mouse that led to the discovery of cysteine catabolism as an unexpected regulator of cholesterol.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"130 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434675","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 : 2025-11-04DOI: 10.1016/j.cmet.2025.10.004
Kaylee Zilinger, Rachel J. Perry
Mechanisms that preserve glucose homeostasis are highly conserved across species, with the brain playing a central role in regulating these counterregulatory responses. However, the exact neural circuits underlying this regulation remain poorly understood. The previewed papers illuminate how the ventromedial hypothalamus orchestrates glycemic responses through brain-liver communication during periods of increased glucose demand.
{"title":"The role of the ventromedial hypothalamus in glycemic responses","authors":"Kaylee Zilinger, Rachel J. Perry","doi":"10.1016/j.cmet.2025.10.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.004","url":null,"abstract":"Mechanisms that preserve glucose homeostasis are highly conserved across species, with the brain playing a central role in regulating these counterregulatory responses. However, the exact neural circuits underlying this regulation remain poorly understood. The previewed papers illuminate how the ventromedial hypothalamus orchestrates glycemic responses through brain-liver communication during periods of increased glucose demand.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"112 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434672","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 : 2025-11-04DOI: 10.1016/j.cmet.2025.10.002
Hanieh Yaghootkar
Emerging evidence challenges the view of obesity as a uniform metabolic risk. Spotlighting the recent Nature Medicine study by Chami et al.,1 this piece discusses how “uncoupling” adiposity from its cardiometabolic consequences reveals biologically distinct subtypes of obesity. Integrating imaging and multi-omics offers a promising path toward personalized obesity management and deeper mechanistic insight.
{"title":"When more is not worse: Genetic subtypes of obesity challenge conventional risk paradigms","authors":"Hanieh Yaghootkar","doi":"10.1016/j.cmet.2025.10.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.002","url":null,"abstract":"Emerging evidence challenges the view of obesity as a uniform metabolic risk. Spotlighting the recent <em>Nature Medicine</em> study by Chami et al.,<span><span><sup>1</sup></span></span> this piece discusses how “uncoupling” adiposity from its cardiometabolic consequences reveals biologically distinct subtypes of obesity. Integrating imaging and multi-omics offers a promising path toward personalized obesity management and deeper mechanistic insight.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"43 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434673","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 : 2025-10-31DOI: 10.1016/j.cmet.2025.10.003
Maria-Kyriaki Drekolia, Janina Mettner, Daiyu Wang, Fredy Delgado Lagos, Christian Koch, Dennis Hecker, Jeanette Eresch, Yifang Mao, Marion Bähr, Dieter Weichenhan, Julio Cordero, Janina Wittig, Boran Zhang, Hanyu Cui, Xiaoming Li, James A. Oo, Andreas Weigert, Mauro Siragusa, Stephan Klatt, Ingrid Fleming, Sofia-Iris Bibli
Endothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine de novo biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration.
{"title":"Cystine import and oxidative catabolism fuel vascular growth and repair via nutrient-responsive histone acetylation","authors":"Maria-Kyriaki Drekolia, Janina Mettner, Daiyu Wang, Fredy Delgado Lagos, Christian Koch, Dennis Hecker, Jeanette Eresch, Yifang Mao, Marion Bähr, Dieter Weichenhan, Julio Cordero, Janina Wittig, Boran Zhang, Hanyu Cui, Xiaoming Li, James A. Oo, Andreas Weigert, Mauro Siragusa, Stephan Klatt, Ingrid Fleming, Sofia-Iris Bibli","doi":"10.1016/j.cmet.2025.10.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.003","url":null,"abstract":"Endothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine <em>de novo</em> biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"67 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404394","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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