Pub Date : 2025-09-04DOI: 10.1016/j.cmet.2025.08.002
Yuqing Zhang, Zi-Jiang Chen, Han Zhao
Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder characterized by intertwined reproductive and metabolic abnormalities. While its causal origins remain incompletely understood, accumulating evidence suggests metabolic dysfunctions—manifested by insulin resistance, obesity, hyperglycemia, and dyslipidemia—as key contributors to the pathogenesis and progression of PCOS. Emerging interventions targeting these metabolic disturbances, including caloric restriction, GLP-1-based therapies, and bariatric surgery, have shown efficacy in alleviating PCOS symptoms and potentially blocking their inheritance. By addressing the metabolic roots and therapeutic opportunities in PCOS, this perspective highlights a critical shift in fundamentally recognizing PCOS as a metabolic disorder. The future promises more metabolic-focused research to unravel the underlying pathogenesis and develop precise, long-term strategies for managing this complex disease.
{"title":"Polycystic ovary syndrome: A metabolic disorder with therapeutic opportunities","authors":"Yuqing Zhang, Zi-Jiang Chen, Han Zhao","doi":"10.1016/j.cmet.2025.08.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.002","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder characterized by intertwined reproductive and metabolic abnormalities. While its causal origins remain incompletely understood, accumulating evidence suggests metabolic dysfunctions—manifested by insulin resistance, obesity, hyperglycemia, and dyslipidemia—as key contributors to the pathogenesis and progression of PCOS. Emerging interventions targeting these metabolic disturbances, including caloric restriction, GLP-1-based therapies, and bariatric surgery, have shown efficacy in alleviating PCOS symptoms and potentially blocking their inheritance. By addressing the metabolic roots and therapeutic opportunities in PCOS, this perspective highlights a critical shift in fundamentally recognizing PCOS as a metabolic disorder. The future promises more metabolic-focused research to unravel the underlying pathogenesis and develop precise, long-term strategies for managing this complex disease.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"29 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987598","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}
Clinical studies have identified multiple mitochondrial disturbances in the peripheral tissues of patients with autism. However, how neuronal metabolism contributes to the autism-associated phenotype remains unclear. In this study, we focused on the anterior cingulate cortex (ACC) and reported hydrogen sulfide (H2S) elevation as a common outcome to mitochondrial dysfunction in Shank3b−/− and Fmr1−/y neurons. Cystathionine β-synthase overexpression in ACC impaired synaptic transmission and social function in wild-type mice, while its knockdown effectively rescued synaptic and social defects in both autism mouse models. Dramatic changes in synaptic protein sulfhydration were observed in Shank3b−/− ACC, with over-sulfhydration of mGluR5 validated in both models. Ablating mGluR5 sulfhydration partially alleviated social deficits in both strains. Furthermore, sulfur amino acid restriction ameliorated social dysfunction in Shank3b−/− and Fmr1−/y mice and synaptic defects in corresponding human neurons. Our data indicate that excessive H2S and synaptic protein sulfhydration may serve as potential mechanisms underlying the autism-associated social dysfunction.
{"title":"Mitochondrial dysfunction reveals H2S-mediated synaptic sulfhydration as a potential mechanism for autism-associated social defects","authors":"Panpan Xian, Mengmeng Wang, Rougang Xie, Hongyu Ma, Weian Zheng, Junjun Kang, Yujiang Chen, Hanze Liu, Songqi Dong, Haiying Liu, Wenle Zhang, Honghui Mao, Fang Wang, Ning Yang, Jun Yu, Ningxia Zhao, Yazhou Wang, Shengxi Wu","doi":"10.1016/j.cmet.2025.08.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.003","url":null,"abstract":"Clinical studies have identified multiple mitochondrial disturbances in the peripheral tissues of patients with autism. However, how neuronal metabolism contributes to the autism-associated phenotype remains unclear. In this study, we focused on the anterior cingulate cortex (ACC) and reported hydrogen sulfide (H<sub>2</sub>S) elevation as a common outcome to mitochondrial dysfunction in <em>Shank3b</em><sup>−/−</sup> and <em>Fmr1</em><sup><em>−/y</em></sup> neurons. Cystathionine β-synthase overexpression in ACC impaired synaptic transmission and social function in wild-type mice, while its knockdown effectively rescued synaptic and social defects in both autism mouse models. Dramatic changes in synaptic protein sulfhydration were observed in <em>Shank3b</em><sup>−/−</sup> ACC, with over-sulfhydration of mGluR5 validated in both models. Ablating mGluR5 sulfhydration partially alleviated social deficits in both strains. Furthermore, sulfur amino acid restriction ameliorated social dysfunction in <em>Shank3b</em><sup>−/−</sup> and <em>Fmr1</em><sup><em>−/y</em></sup> mice and synaptic defects in corresponding human neurons. Our data indicate that excessive H<sub>2</sub>S and synaptic protein sulfhydration may serve as potential mechanisms underlying the autism-associated social dysfunction.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"29 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930484","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 : 2025-09-02DOI: 10.1016/j.cmet.2025.06.012
Chi Kin Wong, Bernardo Yusta, Jason C.L. Tong, Johannes Broichhagen, David J. Hodson, Daniel J. Drucker
Glucagon-like peptide 1 receptor (GLP-1R) agonists exhibit anti-inflammatory actions, yet the importance of direct immune cell GLP-1R signaling remains uncertain. Although T cells respond to GLP-1, low receptor abundance and suboptimal antisera complicate efforts to characterize immune cell GLP-1R signaling. Here, we evaluate three frequently utilized GLP-1R antibodies, revealing that one of several antibodies, AGR-021, lack ideal specificity for detecting the GLP-1R in mice. Immunostaining with AGR-021 using tissues from two independent GLP-1R knockout mouse lines reveals persistent immunoreactive signals in GLP-1R-null pancreatic islets. Similarly, flow cytometry using AGR-021 reveals no reduction in AGR-021 immunoreactivity in GLP-1R-null splenic T cells. Moreover, western blotting detects AGR-021-immunoreactive proteins from a GLP-1R-negative cell line and fails to detect immunoreactive GLP-1R of the correct size upon overexpression of the receptor. Our findings reveal caveats governing use of multiple widely used GLP-1R antibodies, reemphasizing the importance of rigorous antibody validation for inferring accurate GLP-1R expression.
{"title":"Reassessment of antibody-based detection of the murine T cell GLP-1 receptor","authors":"Chi Kin Wong, Bernardo Yusta, Jason C.L. Tong, Johannes Broichhagen, David J. Hodson, Daniel J. Drucker","doi":"10.1016/j.cmet.2025.06.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.012","url":null,"abstract":"Glucagon-like peptide 1 receptor (GLP-1R) agonists exhibit anti-inflammatory actions, yet the importance of direct immune cell GLP-1R signaling remains uncertain. Although T cells respond to GLP-1, low receptor abundance and suboptimal antisera complicate efforts to characterize immune cell GLP-1R signaling. Here, we evaluate three frequently utilized GLP-1R antibodies, revealing that one of several antibodies, AGR-021, lack ideal specificity for detecting the GLP-1R in mice. Immunostaining with AGR-021 using tissues from two independent GLP-1R knockout mouse lines reveals persistent immunoreactive signals in GLP-1R-null pancreatic islets. Similarly, flow cytometry using AGR-021 reveals no reduction in AGR-021 immunoreactivity in GLP-1R-null splenic T cells. Moreover, western blotting detects AGR-021-immunoreactive proteins from a GLP-1R-negative cell line and fails to detect immunoreactive GLP-1R of the correct size upon overexpression of the receptor. Our findings reveal caveats governing use of multiple widely used GLP-1R antibodies, reemphasizing the importance of rigorous antibody validation for inferring accurate GLP-1R expression.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"42 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928466","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 : 2025-08-28DOI: 10.1016/j.cmet.2025.08.004
Jessica M. Preston, Jo Iversen, Antonia Hufnagel, Line Hjort, Jodie Taylor, Clara Sanchez, Victoria George, Ann N. Hansen, Lars Ängquist, Susan Hermann, Jeffrey M. Craig, Signe Torekov, Christian Lindh, Karin S. Hougaard, Marcelo A. Nóbrega, Stephen J. Simpson, Romain Barrès
Consumption of ultra-processed food is associated with increased caloric intake and impaired health. Here, we conducted a nutrition trial (NCT05368194) with controlled, 2 × 2 crossover design and tested whether ultra-processed food impairs reproductive and metabolic fitness, with further aggravation by excess caloric intake. Comparing the response from an unprocessed to ultra-processed diet identified increased body weight and low-density lipoprotein (LDL):high-density lipoprotein (HDL) ratio, independent of caloric load. Several hormones involved in energy metabolism and spermatogenesis were affected, including decreased levels of growth/differentiation factor 15 and follicle-stimulating hormone. Sperm quality trended toward impairment, with a decrease in total motility. Differential accumulation of pollutants between the discordant diets were detected, such as decreased plasma lithium and a trend for increased levels of the phthalate mono(4-methyl-7-carboxyheptyl)phthalate (cxMINP) in serum, following the ultra-processed diet. Alteration in caloric load alone had distinct effects on the measured outcomes. This study provides evidence that consumption of ultra-processed food is detrimental for cardiometabolic and reproductive outcomes, regardless of excessive caloric intake.
{"title":"Effect of ultra-processed food consumption on male reproductive and metabolic health","authors":"Jessica M. Preston, Jo Iversen, Antonia Hufnagel, Line Hjort, Jodie Taylor, Clara Sanchez, Victoria George, Ann N. Hansen, Lars Ängquist, Susan Hermann, Jeffrey M. Craig, Signe Torekov, Christian Lindh, Karin S. Hougaard, Marcelo A. Nóbrega, Stephen J. Simpson, Romain Barrès","doi":"10.1016/j.cmet.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.004","url":null,"abstract":"Consumption of ultra-processed food is associated with increased caloric intake and impaired health. Here, we conducted a nutrition trial (NCT05368194) with controlled, 2 × 2 crossover design and tested whether ultra-processed food impairs reproductive and metabolic fitness, with further aggravation by excess caloric intake. Comparing the response from an unprocessed to ultra-processed diet identified increased body weight and low-density lipoprotein (LDL):high-density lipoprotein (HDL) ratio, independent of caloric load. Several hormones involved in energy metabolism and spermatogenesis were affected, including decreased levels of growth/differentiation factor 15 and follicle-stimulating hormone. Sperm quality trended toward impairment, with a decrease in total motility. Differential accumulation of pollutants between the discordant diets were detected, such as decreased plasma lithium and a trend for increased levels of the phthalate mono(4-methyl-7-carboxyheptyl)phthalate (cxMINP) in serum, following the ultra-processed diet. Alteration in caloric load alone had distinct effects on the measured outcomes. This study provides evidence that consumption of ultra-processed food is detrimental for cardiometabolic and reproductive outcomes, regardless of excessive caloric intake.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"28 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144911214","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 : 2025-08-27DOI: 10.1016/j.cmet.2025.08.001
Moubin Lin, Juan Wang, Yongshuai Chai, Xin Chen, Danyang Zhao, Zhangdan Xie, Jiebang Jiang, Hong Li, Li Huang, Siwei Xing, Dashi Qi, Xinyu Mei
Inflammation and its metabolic-network interactions generate novel regulatory molecules with translational implications. Here, we identify the immunometabolic crosstalk that generates homocysitaconate, a metabolite formed by homocysteine and itaconate adduction catalyzed by S-adenosyl-L-homocysteine hydrolase (AHCY). Homocysitaconate increases 152-fold during inflammation and exhibits anti-inflammatory effects. Mechanistically, homocysitaconate binds to the D312 residue of the pro-inflammatory protein methionyl-tRNA synthetase (MARS), inhibiting its function and reshaping methionine metabolism to feedback-brake the early activation of the N-homocysteinylation pathway. This metabolic switch facilitates NLR family pyrin domain-containing 3 (NLRP3) ubiquitination to control inflammation. Homocysitaconate demonstrates therapeutic effects in sepsis, high-fat-diet-induced inflammation, and colitis models. Boosting endogenous homocysitaconate synthesis through nicotinamide adenine dinucleotide (NAD+)-dependent AHCY activation (using nicotinamide riboside and pyruvate) also inhibits inflammation by targeting the MARS/NLRP3-N-homocysteinylation cascade. This study establishes homocysitaconate as an anti-inflammatory metabolite that serves as a homeostatic governor by reprogramming protein modification switches, introducing both metabolic timing regulation and clinical strategies to manage inflammatory complications.
炎症及其代谢网络相互作用产生具有翻译意义的新型调控分子。在这里，我们鉴定了产生同型半胱氨酸的免疫代谢串，同型半胱氨酸和s -腺苷- l-同型半胱氨酸水解酶（AHCY）催化的衣康酸内聚形成的代谢物。同半胱甘酸在炎症期间增加152倍，并表现出抗炎作用。机制上，同型半胱甘酸结合促炎蛋白蛋氨酸- trna合成酶（MARS）的D312残基，抑制其功能，重塑蛋氨酸代谢，反馈抑制n -同型半胱氨酸化途径的早期激活。这种代谢开关促进NLR家族含pyrin结构域3 （NLRP3）泛素化来控制炎症。高胱甘肽酸在脓毒症、高脂肪饮食引起的炎症和结肠炎模型中显示出治疗效果。通过烟酰胺腺嘌呤二核苷酸（NAD+）依赖的AHCY激活（使用烟酰胺核苷和丙酮酸）促进内源性高胱甘酸合成，也通过靶向MARS/ nlrp3 - n -同型半胱氨酸级联抑制炎症。本研究确立了同半胱甘肽酸作为一种抗炎代谢物，通过重编程蛋白质修饰开关作为一种体内平衡调节剂，引入代谢时间调节和临床策略来管理炎症并发症。
{"title":"Homocysitaconate controls inflammation through reshaping methionine metabolism and N-homocysteinylation","authors":"Moubin Lin, Juan Wang, Yongshuai Chai, Xin Chen, Danyang Zhao, Zhangdan Xie, Jiebang Jiang, Hong Li, Li Huang, Siwei Xing, Dashi Qi, Xinyu Mei","doi":"10.1016/j.cmet.2025.08.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.001","url":null,"abstract":"Inflammation and its metabolic-network interactions generate novel regulatory molecules with translational implications. Here, we identify the immunometabolic crosstalk that generates homocysitaconate, a metabolite formed by homocysteine and itaconate adduction catalyzed by S-adenosyl-L-homocysteine hydrolase (AHCY). Homocysitaconate increases 152-fold during inflammation and exhibits anti-inflammatory effects. Mechanistically, homocysitaconate binds to the D312 residue of the pro-inflammatory protein methionyl-tRNA synthetase (MARS), inhibiting its function and reshaping methionine metabolism to feedback-brake the early activation of the N-homocysteinylation pathway. This metabolic switch facilitates NLR family pyrin domain-containing 3 (NLRP3) ubiquitination to control inflammation. Homocysitaconate demonstrates therapeutic effects in sepsis, high-fat-diet-induced inflammation, and colitis models. Boosting endogenous homocysitaconate synthesis through nicotinamide adenine dinucleotide (NAD<sup>+</sup>)-dependent AHCY activation (using nicotinamide riboside and pyruvate) also inhibits inflammation by targeting the MARS/NLRP3-N-homocysteinylation cascade. This study establishes homocysitaconate as an anti-inflammatory metabolite that serves as a homeostatic governor by reprogramming protein modification switches, introducing both metabolic timing regulation and clinical strategies to manage inflammatory complications.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"24 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906071","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 : 2025-08-25DOI: 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
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.
{"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 <em>Esrrγ</em> 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}
Pub Date : 2025-08-13DOI: 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
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.
{"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}
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.
{"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<sup>+</sup> 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}
Pub Date : 2025-08-06DOI: 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
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.
{"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. <em>HNF1A</em>, which encodes transcription factor hepatocyte nuclear factor-1 alpha, is the most commonly mutated gene in Mendelian diabetes. <em>HNF1A</em> 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 <em>A1CF</em>, which orchestrates an RNA splicing program encompassing genes that regulate β cell function. This <em>HNF1A</em>-<em>A1CF</em> transcription-splicing axis is suppressed in β cells from T2D individuals, while genetic variants reducing pancreatic islet <em>A1CF</em> 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}
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