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}
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}
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