Nature metabolism最新文献_第4页

Metabolites are not genes — avoiding the misuse of pathway analysis in metabolomics 代谢物不是基因-避免误用代谢组学途径分析

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-10 DOI: 10.1038/s42255-025-01283-0

Kil Sun Lee, Xiaoyang Su, Tao Huan

引用次数: 0

Incretin-based therapeutics for the treatment of neurodegenerative diseases 以肠促胰岛素为基础的神经退行性疾病的治疗

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-10 DOI: 10.1038/s42255-025-01263-4

Anika Vear, Michael T. Heneka, Christoffer Clemmensen

{"title":"Incretin-based therapeutics for the treatment of neurodegenerative diseases","authors":"Anika Vear, Michael T. Heneka, Christoffer Clemmensen","doi":"10.1038/s42255-025-01263-4","DOIUrl":"https://doi.org/10.1038/s42255-025-01263-4","url":null,"abstract":"Neurodegenerative diseases (NDDs) represent a heterogeneous group of disorders characterized by progressive neuronal loss, which results in significant deficits in memory, cognition, motor skills, and sensory functions. As the prevalence of NDDs rises, there is an urgent unmet need for effective therapies. Current drug development approaches primarily target single pathological features of the disease, which could explain the limited efficacy observed in late-stage clinical trials. Originally developed for the treatment of obesity and diabetes, incretin-based therapies, particularly long-acting GLP-1 receptor (GLP-1R) agonists and GLP-1R–gastric inhibitory polypeptide receptor (GIPR) dual agonists, are emerging as promising treatments for NDDs. Despite limited conclusive preclinical evidence, their pleiotropic ability to reduce neuroinflammation, enhance neuronal energy metabolism and promote synaptic plasticity positions them as potential disease-modifying NDD interventions. In anticipation of results from larger clinical trials, continued advances in next-generation incretin mimetics offer the potential for improved brain access and enhanced neuroprotection, paving the way for incretin-based therapies as a future cornerstone in the management of NDDs.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"59 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

UPRmt controls the mesenchymal-to-epithelial transition UPRmt控制间质到上皮的转变

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-09 DOI: 10.1038/s42255-025-01260-7

Marine Barthez, Danica Chen

引用次数: 0

The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming 线粒体未折叠蛋白反应抑制体细胞重编程中的多能性获得和间充质到上皮的转变

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-09 DOI: 10.1038/s42255-025-01261-6

Zhongfu Ying, Yanmin Xin, Zihuang Liu, Tianxin Tan, Yile Huang, Yingzhe Ding, Xuejun Hong, Qiuzhi Li, Chong Li, Jingyi Guo, Gaoshen Liu, Qi Meng, Shihe Zhou, Wenxin Li, Yao Yao, Ge Xiang, Linpeng Li, Yi Wu, Yang Liu, Miaohui Mu, Zifeng Ruan, Wenxi Liang, Junwei Wang, Yaofeng Wang, Baojian Liao, Yang Liu, Wuming Wang, Gang Lu, Dajiang Qin, Duanqing Pei, Wai-Yee Chan, Xingguo Liu

{"title":"The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming","authors":"Zhongfu Ying, Yanmin Xin, Zihuang Liu, Tianxin Tan, Yile Huang, Yingzhe Ding, Xuejun Hong, Qiuzhi Li, Chong Li, Jingyi Guo, Gaoshen Liu, Qi Meng, Shihe Zhou, Wenxin Li, Yao Yao, Ge Xiang, Linpeng Li, Yi Wu, Yang Liu, Miaohui Mu, Zifeng Ruan, Wenxi Liang, Junwei Wang, Yaofeng Wang, Baojian Liao, Yang Liu, Wuming Wang, Gang Lu, Dajiang Qin, Duanqing Pei, Wai-Yee Chan, Xingguo Liu","doi":"10.1038/s42255-025-01261-6","DOIUrl":"https://doi.org/10.1038/s42255-025-01261-6","url":null,"abstract":"The mitochondrial unfolded protein response (UPRmt), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans1,2. However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPRmt activation occurs during somatic reprogramming in mouse embryonic fibroblasts. We observe a c-Myc-dependent, transient decrease in mitochondrial proteolysis, accompanied by UPRmt activation at the early phase of pluripotency acquisition. UPRmt impedes the mesenchymal-to-epithelial transition (MET) through c-Jun, thereby inhibiting pluripotency acquisition. Mechanistically, c-Jun enhances the expression of acetyl-CoA metabolic enzymes and reduces acetyl-CoA levels, thereby affecting levels of H3K9Ac, linking mitochondrial signalling to the epigenetic state of the cell and cell fate decisions. c-Jun also decreases the occupancy of H3K9Ac at MET genes, further inhibiting MET. Our findings reveal the crucial role of mitochondrial UPR-modulated MET in pluripotent stem cell plasticity. Additionally, we demonstrate that the UPRmt promotes cancer cell migration and invasion by enhancing epithelial-to-mesenchymal transition (EMT). Given the crucial role of EMT in tumour metastasis3,4, our findings on the connection between the UPRmt and EMT have important pathological implications and reveal potential targets for tumour treatment.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"95 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux TMEM65调节并需要nclx依赖的线粒体钙外排

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-08 DOI: 10.1038/s42255-025-01250-9

Joanne F. Garbincius, Oniel Salik, Henry M. Cohen, Carmen Choya-Foces, Adam S. Mangold, Angelina D. Makhoul, Anna E. Schmidt, Dima Y. Khalil, Joshua J. Doolittle, Anya S. Wilkinson, Emma K. Murray, Michael P. Lazaropoulos, Alycia N. Hildebrand, Dhanendra Tomar, John W. Elrod

{"title":"TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux","authors":"Joanne F. Garbincius, Oniel Salik, Henry M. Cohen, Carmen Choya-Foces, Adam S. Mangold, Angelina D. Makhoul, Anna E. Schmidt, Dima Y. Khalil, Joshua J. Doolittle, Anya S. Wilkinson, Emma K. Murray, Michael P. Lazaropoulos, Alycia N. Hildebrand, Dhanendra Tomar, John W. Elrod","doi":"10.1038/s42255-025-01250-9","DOIUrl":"https://doi.org/10.1038/s42255-025-01250-9","url":null,"abstract":"The balance between mitochondrial calcium (mCa2+) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of mCa2+ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic mCa2+ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na+)-dependent mCa2+ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in mCa2+ efflux, and loss-of-function studies show that TMEM65 is required for Na+-dependent mCa2+ efflux. In line with these findings, knockdown of Tmem65 in mice promotes mCa2+ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent mCa2+ efflux, causing pathogenic mCa2+ overload, cell death, and organ-level dysfunction. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent mCa2+ efflux and suggest modulation of TMEM65 as a therapeutic strategy for a variety of diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"74 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TMEM65 joins the mitochondrial Ca2+ club TMEM65加入线粒体Ca2+俱乐部

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-08 DOI: 10.1038/s42255-025-01271-4

Yasemin Sancak

引用次数: 0

Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans 人类棕色脂肪介导的能量消耗的受精前起源保存

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-07 DOI: 10.1038/s42255-025-01249-2

Takeshi Yoneshiro, Mami Matsushita, Sayuri Fuse-Hamaoka, Miyuki Kuroiwa, Yuko Kurosawa, Yosuke Yamada, Makoto Arai, Yuchen Wei, Makoto Iida, Kenichi Kuma, Toshimitsu Kameya, Tomoya Harada, Yoshihiro Matsumura, Tsuyoshi Osawa, Yoshiko Aoki, Hisashi Nakamura, Takafumi Hamaoka, Juro Sakai, Masayuki Saito

{"title":"Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans","authors":"Takeshi Yoneshiro, Mami Matsushita, Sayuri Fuse-Hamaoka, Miyuki Kuroiwa, Yuko Kurosawa, Yosuke Yamada, Makoto Arai, Yuchen Wei, Makoto Iida, Kenichi Kuma, Toshimitsu Kameya, Tomoya Harada, Yoshihiro Matsumura, Tsuyoshi Osawa, Yoshiko Aoki, Hisashi Nakamura, Takafumi Hamaoka, Juro Sakai, Masayuki Saito","doi":"10.1038/s42255-025-01249-2","DOIUrl":"https://doi.org/10.1038/s42255-025-01249-2","url":null,"abstract":"Environmental thermal stress substantially affects cellular plasticity of thermogenic adipocytes and energy balance through transcriptional and epigenetic mechanisms in rodents. However, roles of cold-adaptive epigenetic regulation of brown adipose tissue (BAT) in systemic energy metabolism in humans remained poorly understood. Here we report that individuals whose mothers conceived during cold seasons exhibit higher BAT activity, adaptive thermogenesis, increased daily total energy expenditure and lower body mass index and visceral fat accumulation. Structural equation modelling indicated that conception during the cold season protects against age-associated increase in body mass index through BAT activation in offspring. Meteorological analysis revealed that lower outdoor temperatures and greater fluctuations in daily temperatures during the fertilization period are key determinants of BAT activity. These findings suggest that BAT metabolic fate and susceptibility of metabolic diseases are preprogrammed by the epigenetic inheritance of cold exposure before the fertilization in humans.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"43 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intergenerational metabolic effects of cold exposure 低温暴露对代际代谢的影响

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-07 DOI: 10.1038/s42255-025-01222-z

R. Teperino

引用次数: 0

Alterations in intestinal bile acid transport provide a therapeutic target in patients with post-bariatric hypoglycaemia 肠道胆汁酸转运的改变为减肥后低血糖患者提供了治疗目标

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-04 DOI: 10.1038/s42255-025-01262-5

Snehal N. Chaudhari, Yingjia Chen, Rafael Ferraz-Bannitz, Cameron Cummings, Amanda Sheehan, Pilar Casanova Querol, Berkcan Ozturk, Hanna Wang, Gabriel D’Agostino, Fei Ye, Eric G. Sheu, A. Sloan Devlin, Mary-Elizabeth Patti

{"title":"Alterations in intestinal bile acid transport provide a therapeutic target in patients with post-bariatric hypoglycaemia","authors":"Snehal N. Chaudhari, Yingjia Chen, Rafael Ferraz-Bannitz, Cameron Cummings, Amanda Sheehan, Pilar Casanova Querol, Berkcan Ozturk, Hanna Wang, Gabriel D’Agostino, Fei Ye, Eric G. Sheu, A. Sloan Devlin, Mary-Elizabeth Patti","doi":"10.1038/s42255-025-01262-5","DOIUrl":"https://doi.org/10.1038/s42255-025-01262-5","url":null,"abstract":"While Roux-en-Y gastric bypass is an effective treatment for obesity and type 2 diabetes, up to one-third of patients develop post-bariatric hypoglycaemia (PBH). Individuals with PBH exhibit increased postprandial secretion of the intestinal hormone fibroblast growth factor 19 (FGF19, Fgf15 in mice). However, the underlying mechanisms contributing to PBH remain uncertain. Here we demonstrate that faecal and plasma bile acid (BA) profiles are significantly altered in postoperative individuals with PBH versus those without hypoglycaemia. Furthermore, altered BAs in PBH induce FGF19 secretion in intestinal cells in a manner dependent on the apical sodium-dependent BA transporter (ASBT). We demonstrate that ASBT inhibition reduces Fgf15 expression and increases postprandial glucose in hypoglycaemic mice. Our data suggest that dysregulation of luminal BA profiles and transport may contribute to PBH and provide proof of concept that ASBT inhibition could be developed as a new therapeutic strategy for PBH.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"10 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The emerging role of protein l-lactylation in metabolic regulation and cell signalling 蛋白质l-乳酸化在代谢调节和细胞信号传导中的新作用

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-02 DOI: 10.1038/s42255-025-01259-0

Haowen Ren, Yuwei Tang, Di Zhang

引用次数: 0