Cell metabolismPub Date : 2025-11-19DOI: 10.1016/j.cmet.2025.10.014
Junzhe Huang, Andrew J. Kwok, Jason Chak Yan Li, Clement Lek Hin Chiu, Bonaventure Y. Ip, Lok Yi Tung, Roy C.H. Chan, Danny C.W. Chan, Ziyu Wang, Xianyi Zheng, Hoi Tung Chow, Michelle P.S. Lo, Zhongqi Li, Nenghan Lin, Manyu Wang, Leo Y.C. Yan, William K.K. Wu, Kim Hei-Man Chow, Wei-Jye Lin, Yamei Tang, Ho Ko
{"title":"Body-wide multi-omic counteraction of aging with GLP-1R agonism","authors":"Junzhe Huang, Andrew J. Kwok, Jason Chak Yan Li, Clement Lek Hin Chiu, Bonaventure Y. Ip, Lok Yi Tung, Roy C.H. Chan, Danny C.W. Chan, Ziyu Wang, Xianyi Zheng, Hoi Tung Chow, Michelle P.S. Lo, Zhongqi Li, Nenghan Lin, Manyu Wang, Leo Y.C. Yan, William K.K. Wu, Kim Hei-Man Chow, Wei-Jye Lin, Yamei Tang, Ho Ko","doi":"10.1016/j.cmet.2025.10.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.014","url":null,"abstract":"Identifying practical ways to counteract aging and associated degenerative disorders is urgently needed. We performed deep molecular profiling and functional assessments in aging male mice to show that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment broadly counteracts age-related changes. In mice treated with a GLP-1RA from 11 months for 30 weeks, we observed strong body-wide multi-omic age-counteracting effects and improved selected physical functions. Importantly, the effects were specific to aged mice, not young adults, and were attained with a relatively low dose that minimally affected food intake or body weight. With GLP-1RA treatment beginning at 18 months for 13 weeks, the molecular age-counteracting effects were even stronger and largely dependent on hypothalamic GLP-1R, pointing to a brain-body axis of aging modulation. Comparison with mammalian target of rapamycin (mTOR) inhibition, a proven anti-aging strategy, revealed strong multi-omic similarities. Our findings have broad implications for the mechanisms behind GLP-1RAs’ pleiotropic benefits, guiding clinical trials, and informing development of anti-aging-based therapeutics.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-11-18DOI: 10.1016/j.cmet.2025.10.013
Yao Wang, Jiaming Wu, Jianyu Yao, Jiarui Chen, Kenneth K.Y. Cheng, Melody Yuen-man Ho, Chi Ho Lee, Karen Siu-Ling Lam, Michael Andrew Tse, Gianni Panagiotou, Aimin Xu
{"title":"Gut microbiome-adipose crosstalk modulates soluble IL-6 receptor influencing exercise responsiveness in glycemic control and insulin sensitivity","authors":"Yao Wang, Jiaming Wu, Jianyu Yao, Jiarui Chen, Kenneth K.Y. Cheng, Melody Yuen-man Ho, Chi Ho Lee, Karen Siu-Ling Lam, Michael Andrew Tse, Gianni Panagiotou, Aimin Xu","doi":"10.1016/j.cmet.2025.10.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.013","url":null,"abstract":"Exercise is an effective intervention for the prevention and management of diabetes, but the high interpersonal variability in response to exercise impedes its widespread implementation. Herein, we identify adipocyte-derived soluble interleukin-6 receptor (sIL-6R) as a key exerkine determining exercise efficacy in improving metabolic health. In individuals with obesity who underwent a 12-week exercise intervention, circulating sIL-6R level exhibits dichotomous changes between exercise responders (Rs) and non-responders (NRs), in close association with exercise-mediated alterations in insulin sensitivity and glycemic control. Mechanistically, elevated gut microbiome-mediated leucine in NR acts on white adipocytes to promote disintegrin and metalloproteinase 17 (ADAM17)-mediated sIL-6R production via the mammalian target of rapamycin (mTOR)-hypoxia-inducible factor 1α (HIF1α) pathway, which in turn impairs the metabolic benefits of exercise through interleukin (IL)-6 <em>trans</em>-signaling-induced adipose inflammation. Adipocyte-selective ablation of ADAM17 prevents the effects of fecal microbiota transplantation from NR on elevation of sIL-6R, thereby restoring the efficacy of exercise-shaped gut microbiome in counteracting glucose intolerance and insulin resistance in obese mice. Thus, therapeutic interventions targeting adipocyte-derived sIL-6R represent a promising strategy for maximizing exercise efficacy in personalized diabetes prevention.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"65 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2025-11-17DOI: 10.1016/j.cmet.2025.10.012
L.Felipe Barros, Ignacio Fernández-Moncada, Giovanni Marsicano, Iván Ruminot, Aiman S. Saab, Bruno Weber
{"title":"Scale-spanning crosstalk between metabolism and information processing","authors":"L.Felipe Barros, Ignacio Fernández-Moncada, Giovanni Marsicano, Iván Ruminot, Aiman S. Saab, Bruno Weber","doi":"10.1016/j.cmet.2025.10.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.012","url":null,"abstract":"The research fields of brain intercellular signaling and brain energy metabolism evolved separately. One dealt with neurotransmission and the assembly of neural circuits and networks. The other focused on enzyme reactions and the compartmentation of biochemical processes between neurons and glial cells. High-order brain functions like cognition operate over long distances and can be fast. By contrast, metabolism is slow and, being limited by diffusion, operates over short distances. However, this comfortable division is now being challenged by the realization that lactate, beta-hydroxybutyrate, ATP/adenosine, and other key elements of the universal metabolic core also play the role of intercellular signals, acting via G protein-coupled receptors and other targets to modulate neural network activity, as showcased by exercise, fasting, and sleep. Here, we discuss the possible physiological meaning of such promiscuity. By arguing that it is no longer possible to understand signaling without understanding metabolism, and vice versa, the purpose of this feature is to raise awareness of the ongoing convergence and foster interdisciplinary collaboration.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"26 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"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}
Cell metabolismPub Date : 2025-11-13DOI: 10.1016/j.cmet.2025.10.011
Matthias Van Hul, Patrice D. Cani
{"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}
Cell metabolismPub 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
{"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}
Cell metabolismPub 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
{"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}
Cell metabolismPub 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
{"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}
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