Cell metabolism最新文献_第3页

Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism 遗传-营养相互作用控制增强子-启动子动态和肝脏脂质代谢

IF 29 1区生物学

Cell metabolism Pub Date : 2025-08-25 DOI: 10.1016/j.cmet.2025.07.010

Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S. Julie-Ann Lloyd, Cam Mong La, Inna I. Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A. An, Zheng Sun, Mark A. Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D. Rabinowitz, Dongyin Guan

{"title":"Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism","authors":"Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S. Julie-Ann Lloyd, Cam Mong La, Inna I. Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A. An, Zheng Sun, Mark A. Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D. Rabinowitz, Dongyin Guan","doi":"10.1016/j.cmet.2025.07.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.010","url":null,"abstract":"The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to diet in mice, while single-nucleotide polymorphisms (SNPs) associated with rhythmic gene expression are enriched in E-PIs in steatotic human livers and correlate with lipid metabolism traits. These findings reveal a previously underappreciated temporal aspect of genetics-environment interaction in regulating lipid metabolic traits, with implications for individual variations in obesity-associated disease susceptibility and personalized chronotherapy.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"15 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900555","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}

引用次数: 0

Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism 少突胶质细胞中葡萄糖依赖的嗜胰岛素多肽受体信号增加GLP-1R激动作用的减肥作用

IF 29 1区生物学

Cell metabolism Pub Date : 2025-08-13 DOI: 10.1016/j.cmet.2025.07.009

Robert Hansford, Sophie Buller, Anthony H. Tsang, Simon Benoit, Anna G. Roberts, Emmy Erskine, Thomas Brown, Valentina Pirro, Frank Reimann, Norio Harada, Nobuya Inagaki, Ricardo J. Samms, Johannes Broichhagen, David J. Hodson, Alice Adriaenssens, Soyoung Park, Clemence Blouet

{"title":"Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism","authors":"Robert Hansford, Sophie Buller, Anthony H. Tsang, Simon Benoit, Anna G. Roberts, Emmy Erskine, Thomas Brown, Valentina Pirro, Frank Reimann, Norio Harada, Nobuya Inagaki, Ricardo J. Samms, Johannes Broichhagen, David J. Hodson, Alice Adriaenssens, Soyoung Park, Clemence Blouet","doi":"10.1016/j.cmet.2025.07.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.009","url":null,"abstract":"The next generation of obesity medicines harness the activity of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors (GIPR and GLP-1R), but their mechanism of action remains unclear. Here, we report that the GIPR is enriched in oligodendrocytes and GIPR signaling bidirectionally regulates oligodendrogenesis. In mice with adult-onset deletion of GIPR in oligodendrocytes, GIPR agonism fails to enhance the weight-loss effects of GLP-1R agonism. Mechanistically, GIPR agonism increases brain access of GLP-1R agonists, and GIPR signaling in oligodendrocytes is required for this effect. In addition, we show that vasopressin neurons of the paraventricular hypothalamus are necessary for the weight-loss response to GLP-1R activation, targeted by peripherally administered GLP-1R agonists via their axonal compartment, and this access is increased by activation of the GIPR in oligodendrocytes. Collectively, our findings identify a novel mechanism by which incretin therapies may function to promote synergistic weight loss in the management of excess adiposity.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"53 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825263","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}

引用次数: 0

Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development 代谢应激下通过乳酸感知介导的肿瘤相关雪旺细胞重塑调控了胰腺导管腺癌的发展

IF 29 1区生物学

Cell metabolism Pub Date : 2025-08-12 DOI: 10.1016/j.cmet.2025.07.008

Yihao Liu, Jiayu Lin, Zhengwei Yu, Xueying Li, Xueqi Lv, Pengyi Liu, Xiuqiao Sun, Zhen Zhang, Xia Gao, Keyan Sun, Dan Li, Jingfeng Li, Yang Liu, Yu Jiang, Siyi Zou, Jianping Lin, Baofa Sun, Da Fu, Baiyong Shen

{"title":"Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development","authors":"Yihao Liu, Jiayu Lin, Zhengwei Yu, Xueying Li, Xueqi Lv, Pengyi Liu, Xiuqiao Sun, Zhen Zhang, Xia Gao, Keyan Sun, Dan Li, Jingfeng Li, Yang Liu, Yu Jiang, Siyi Zou, Jianping Lin, Baofa Sun, Da Fu, Baiyong Shen","doi":"10.1016/j.cmet.2025.07.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.008","url":null,"abstract":"Diabetes mellitus (DM) is a known risk factor for pancreatic cancer, but the underlying mechanisms remain elusive. Here, we identify lactate-driven remodeling of tumor-associated Schwann cells (TASCs) as a key mediator of immunosuppression in diabetic pancreatic ductal adenocarcinoma (PDAC). Single-cell RNA sequencing revealed a c1-Mettl16+Cd276+Nectin2+ TASC subpopulation enriched in diabetic tumors that impairs CD8+ T cell function and promotes PD-1 resistance. Mechanistically, lactate enters TASCs via MCT1/MCT4, binds METTL16, and induces K269 lactylation, enhancing m6A-dependent CTCF stabilization and transcriptional activation of immunosuppressive ligands. Targeting METTL16 restores immune surveillance and sensitizes tumors to PD-1 blockade. Retrospective analyses confirmed therapeutic benefit in patients with diabetic PDAC receiving rosuvastatin. These findings uncover a lactate-METTL16-CTCF axis that links metabolic stress to epitranscriptomic reprogramming and immune evasion, offering a promising strategy to potentiate immunotherapy in metabolically dysregulated PDAC.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"143 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819964","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}

引用次数: 0

HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes HNF1A和A1CF协调β细胞转录剪接轴，该轴在2型糖尿病中被破坏

IF 29 1区生物学

Cell metabolism Pub Date : 2025-08-06 DOI: 10.1016/j.cmet.2025.07.007

Edgar Bernardo, Matías Gonzalo De Vas, Diego Balboa, Mirabai Cuenca-Ardura, Sílvia Bonàs-Guarch, Mercè Planas-Fèlix, Fanny Mollandin, Miquel Torrens-Dinarès, Miguel Angel Maestro, Javier García-Hurtado, Sonia Moratinos, Philippe Ravassard, Haiqiang Dou, Holger Heyn, Alexander van Oudenaarden, Nathalie Groen, Eelco de Koning, Christian Conrad, Roland Eils, Santiago Vernia, Jorge Ferrer

{"title":"HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes","authors":"Edgar Bernardo, Matías Gonzalo De Vas, Diego Balboa, Mirabai Cuenca-Ardura, Sílvia Bonàs-Guarch, Mercè Planas-Fèlix, Fanny Mollandin, Miquel Torrens-Dinarès, Miguel Angel Maestro, Javier García-Hurtado, Sonia Moratinos, Philippe Ravassard, Haiqiang Dou, Holger Heyn, Alexander van Oudenaarden, Nathalie Groen, Eelco de Koning, Christian Conrad, Roland Eils, Santiago Vernia, Jorge Ferrer","doi":"10.1016/j.cmet.2025.07.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.07.007","url":null,"abstract":"Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic β cell dysfunction and insulin resistance, whose pathophysiology remains poorly understood. HNF1A, which encodes transcription factor hepatocyte nuclear factor-1 alpha, is the most commonly mutated gene in Mendelian diabetes. HNF1A also carries loss- or gain-of-function coding variants that respectively predispose to or protect against polygenic T2D. The mechanisms underlying HNF1A-deficient diabetes, however, are still unclear. We now demonstrate that diabetes arises from β cell-autonomous defects and identify direct β cell genomic targets of HNF1A. This uncovered a regulatory axis where HNF1A controls transcription of A1CF, which orchestrates an RNA splicing program encompassing genes that regulate β cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in β cells from T2D individuals, while genetic variants reducing pancreatic islet A1CF are associated with increased glycemia and T2D susceptibility. Our findings, therefore, identify a linear hierarchy that coordinates β cell-specific transcription and splicing programs and link this pathway to T2D pathogenesis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792323","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}

引用次数: 0

Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer’s disease 小胶质细胞中的胰岛素信号传导：阿尔茨海默病中控制神经炎症和淀粉样蛋白病理的代谢开关

IF 29 1区生物学

Cell metabolism Pub Date : 2025-08-05 DOI: 10.1016/j.cmet.2025.06.005

Eugenio Barone, D. Allan Butterfield

引用次数: 0

Calories to satiation—A new predictor of anti-obesity therapy outcome? 卡路里饱腹率——抗肥胖治疗结果的新预测指标？

IF 29 1区生物学

Cell metabolism Pub Date : 2025-08-05 DOI: 10.1016/j.cmet.2025.07.003

Sharmili Edwin Thanarajah, Sita Arjune, Ruth Hanssen

引用次数: 0

Missed signals: How PET imaging may fail to capture the addictive potential of ultra-processed foods 错过的信号：PET成像可能无法捕捉到超加工食品的潜在成瘾性