Nature metabolism最新文献_第2页

Triglycerides are an important fuel reserve for synapse function in the brain 甘油三酯是大脑突触功能的重要燃料储备

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-07-01 DOI: 10.1038/s42255-025-01321-x

Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L. Pontius, Daehun Park, Rose E. Witte, Rachel McAllister, Kallol Gupta, Kartik N. Rajagopalan, Pietro De Camilli, Timothy A. Ryan

{"title":"Triglycerides are an important fuel reserve for synapse function in the brain","authors":"Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L. Pontius, Daehun Park, Rose E. Witte, Rachel McAllister, Kallol Gupta, Kartik N. Rajagopalan, Pietro De Camilli, Timothy A. Ryan","doi":"10.1038/s42255-025-01321-x","DOIUrl":"https://doi.org/10.1038/s42255-025-01321-x","url":null,"abstract":"Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"3 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521051","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

A derivative of the ancient drug salicylate for obesity treatment 用于治疗肥胖的古代药物水杨酸盐的衍生物

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-06-30 DOI: 10.1038/s42255-025-01312-y

引用次数: 0

Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction 神经元糖原分解通过戊糖-磷酸盐途径介导的氧化应激减少减轻tau病

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-06-30 DOI: 10.1038/s42255-025-01314-w

Sudipta Bar, Kenneth A. Wilson, Tyler A. U. Hilsabeck, Sydney Alderfer, Eric B. Dammer, Jordan B. Burton, Samah Shah, Anja Holtz, Enrique M. Carrera, Jennifer N. Beck, Jackson H. Chen, Grant Kauwe, Fatemeh Seifar, Ananth Shantaraman, Tara E. Tracy, Nicholas T. Seyfried, Birgit Schilling, Lisa M. Ellerby, Pankaj Kapahi

{"title":"Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction","authors":"Sudipta Bar, Kenneth A. Wilson, Tyler A. U. Hilsabeck, Sydney Alderfer, Eric B. Dammer, Jordan B. Burton, Samah Shah, Anja Holtz, Enrique M. Carrera, Jennifer N. Beck, Jackson H. Chen, Grant Kauwe, Fatemeh Seifar, Ananth Shantaraman, Tara E. Tracy, Nicholas T. Seyfried, Birgit Schilling, Lisa M. Ellerby, Pankaj Kapahi","doi":"10.1038/s42255-025-01314-w","DOIUrl":"https://doi.org/10.1038/s42255-025-01314-w","url":null,"abstract":"Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), for which there are currently no successful treatments. Here, we show impaired glycogen metabolism in the brain of a tauopathy Drosophila melanogaster model and people with AD, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC)-derived neurons from people with FTLD-tau. Glycogen breakdown redirects glucose flux to the pentose phosphate pathway and alleviates oxidative stress. Our findings uncover a critical role for the neuroprotective effects of dietary restriction (DR) by increasing glycogen breakdown. Mechanistically, we show a potential interaction between tau protein and glycogen, suggesting a vicious cycle in which tau binding promotes glycogen accumulation in neurons, which in turn exacerbates tau accumulation which further disrupts cellular homeostasis. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy and other neurodegenerative diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"16 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515969","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

Dietary control of peripheral adipose storage capacity through membrane lipid remodelling 饮食通过膜脂重塑控制外周脂肪储存能力

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-06-27 DOI: 10.1038/s42255-025-01320-y

Marcus J. Tol, Yuta Shimanaka, Alexander H. Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P. Kennelly, Stephen D. Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J. Mack, Thomas A. Weston, Kevin J. Williams, Baolong Su, Calvin Pan, Aldons J. Lusis, Daniel P. Pike, Alex Reed, Natalia Milosevich, Benjamin F. Cravatt, Makoto Arita, Stephen G. Young, David A. Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz

{"title":"Dietary control of peripheral adipose storage capacity through membrane lipid remodelling","authors":"Marcus J. Tol, Yuta Shimanaka, Alexander H. Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P. Kennelly, Stephen D. Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J. Mack, Thomas A. Weston, Kevin J. Williams, Baolong Su, Calvin Pan, Aldons J. Lusis, Daniel P. Pike, Alex Reed, Natalia Milosevich, Benjamin F. Cravatt, Makoto Arita, Stephen G. Young, David A. Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz","doi":"10.1038/s42255-025-01320-y","DOIUrl":"https://doi.org/10.1038/s42255-025-01320-y","url":null,"abstract":"Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in ‘lipodystrophic’ Lpcat3–/– adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER–lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ–LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"17 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500474","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

Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD 通过ACSL4的成纤维细胞脂质代谢调节IBD中上皮对铁下垂的敏感性

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-06-26 DOI: 10.1038/s42255-025-01313-x

Wesley Huang, Yuezhong Zhang, Nupur K. Das, Sumeet Solanki, Chesta Jain, Marwa O. El-Derany, Imhoi Koo, Hannah N. Bell, Noora Aabed, Rashi Singhal, Cristina Castillo, Kathryn Buscher, Yinzhi Ying, James Dimitroff, Ankit Sharma, Jiaqi Shi, Simon P. Hogan, Michael K. Dame, Peter D. R. Higgins, Justin A. Colacino, Tae Gyu Oh, Jason R. Spence, Andrew D. Patterson, Andrew S. Greenberg, Joel K. Greenson, Asma Nusrat, Yatrik M. Shah

{"title":"Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD","authors":"Wesley Huang, Yuezhong Zhang, Nupur K. Das, Sumeet Solanki, Chesta Jain, Marwa O. El-Derany, Imhoi Koo, Hannah N. Bell, Noora Aabed, Rashi Singhal, Cristina Castillo, Kathryn Buscher, Yinzhi Ying, James Dimitroff, Ankit Sharma, Jiaqi Shi, Simon P. Hogan, Michael K. Dame, Peter D. R. Higgins, Justin A. Colacino, Tae Gyu Oh, Jason R. Spence, Andrew D. Patterson, Andrew S. Greenberg, Joel K. Greenson, Asma Nusrat, Yatrik M. Shah","doi":"10.1038/s42255-025-01313-x","DOIUrl":"https://doi.org/10.1038/s42255-025-01313-x","url":null,"abstract":"Increased reactive oxygen species (ROS) levels are a hallmark of inflammatory bowel disease (IBD) and constitute a major mechanism of epithelial cell death. Approaches to broadly inhibit ROS have had limited efficacy in treating IBD. Here we show that lipid peroxidation contributes to the pathophysiology of IBD by promoting ferroptosis, an iron-dependent form of programmed cell death. Mechanistically, we provide evidence of heterocellular crosstalk between intestinal fibroblasts and epithelial cells. In IBD tissues and mouse models of chronic colitis, acyl-CoA synthetase long-chain family 4 (ACSL4) is overexpressed in fibroblasts. ACSL4 in fibroblasts reprograms lipid metabolism and mediates intestinal epithelial cell sensitivity to ferroptosis. In mouse models, overexpressing ACSL4 in fibroblasts results in increased intestinal epithelial ferroptosis and worsened colitis, while pharmacological inhibition or deletion of fibroblast ACSL4 ameliorates colitis. Our work provides a targeted approach to therapeutic antioxidant treatments for IBD.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"648 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488723","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

When gut fibroblasts feed epithelial cells to death 当肠成纤维细胞喂养上皮细胞致死时

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-06-26 DOI: 10.1038/s42255-025-01315-9

Jong Woo Kim, Byeong Jun Jeong, Eun-Woo Lee

引用次数: 0

Metabolic Messengers: oestradiol 代谢信使：雌二醇

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-06-24 DOI: 10.1038/s42255-025-01317-7

Andrea L. Hevener, Stephanie M. Correa

引用次数: 0

Calopy — an advanced framework for the integration and analysis of indirect calorimetry data 一个先进的框架，用于集成和分析间接量热数据

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-06-24 DOI: 10.1038/s42255-025-01316-8

Stefan Loipfinger, Matthias Grosholz, Santhosh Kumar, Helin Erbilir, Kenneth Allen Dyar, Timo Dirk Müller, Stephan Grein, Jan Rozman, Martin Klingenspor, Carola Meyer, Dominik Lutter

{"title":"Calopy — an advanced framework for the integration and analysis of indirect calorimetry data","authors":"Stefan Loipfinger, Matthias Grosholz, Santhosh Kumar, Helin Erbilir, Kenneth Allen Dyar, Timo Dirk Müller, Stephan Grein, Jan Rozman, Martin Klingenspor, Carola Meyer, Dominik Lutter","doi":"10.1038/s42255-025-01316-8","DOIUrl":"https://doi.org/10.1038/s42255-025-01316-8","url":null,"abstract":"Here we introduce Calopy, an innovative software suite for the intuitive and comprehensive analysis of indirect calorimetry data. Calopy is an open-source, web-based Shiny for Python application that is accessible online or locally; it is platform-independent and available via any web browser at https://www.calopy.app.Indirect calorimetry is a widely used technique for measuring energy metabolism in both humans and animals1. At its core, indirect calorimetry tracks oxygen consumption ((dot{V}{mathrm{O}}_{2})) and carbon dioxide production ((dot{V}{mathrm{CO}}_{2})) to analyse energy metabolism through parameters such as energy expenditure and resting metabolic rate (RMR)2 or respiratory exchange ratio (RER), a key indicator of substrate utilization3. In comprehensive indirect calorimetry systems for animals, additional relevant metabolic parameters such as locomotor activity, food and water intake, and body temperature can also be measured at high temporal resolution, along with environmental factors such as cage temperature, lighting and humidity. Continuous or categorical phenotypic variables, such as body weight, genotype and treatments, are also recorded. Noteworthy indirect calorimetry data may further be affected through factors that entail mutual dependencies such as circadian rhythms, food intake, environmental conditions and data noise, which adds further complexity4. Together, these data form a complex set of time-resolved, continuous and categorical variables, which require sophisticated statistics and methods for their analysis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"19 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370460","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

Author Correction: The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid. 作者更正：鞘氨醇-1-磷酸受体1介导二十碳五烯酸的动脉粥样硬化保护作用。

IF 18.9 1区医学

Nature metabolism Pub Date : 2025-06-20 DOI: 10.1038/s42255-025-01335-5

Ting Zhou, Jie Cheng, Shuo He, Chao Zhang, Ming-Xin Gao, Li-Jun Zhang, Jin-Peng Sun, Yi Zhu, Ding Ai

引用次数: 0

Upper-gastrointestinal tract metabolite profile regulates glycaemic and satiety responses to meals with contrasting structure: a pilot study 上消化道代谢物谱调节血糖和饱腹反应的膳食结构对比：一项试点研究

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-06-20 DOI: 10.1038/s42255-025-01309-7

Mingzhu Cai, Shilpa Tejpal, Martina Tashkova, Peter Ryden, Natalia Perez-Moral, Shikha Saha, Isabel Garcia-Perez, Jose Ivan Serrano Contreras, Julien Wist, Elaine Holmes, Andres Bernal, Bowen Dou, Georgia Franco Becker, Gary Frost, Cathrina Edwards

{"title":"Upper-gastrointestinal tract metabolite profile regulates glycaemic and satiety responses to meals with contrasting structure: a pilot study","authors":"Mingzhu Cai, Shilpa Tejpal, Martina Tashkova, Peter Ryden, Natalia Perez-Moral, Shikha Saha, Isabel Garcia-Perez, Jose Ivan Serrano Contreras, Julien Wist, Elaine Holmes, Andres Bernal, Bowen Dou, Georgia Franco Becker, Gary Frost, Cathrina Edwards","doi":"10.1038/s42255-025-01309-7","DOIUrl":"https://doi.org/10.1038/s42255-025-01309-7","url":null,"abstract":"Dietary interventions to combat non-communicable diseases focus on optimizing food intake but overlook the influence of food structure. Here, we investigate how food structure influences digestion. In a randomized crossover study, ten healthy participants were fitted with nasoenteric tubes that allow simultaneous gastric and duodenal sampling, before consuming iso-nutrient chickpea meals with contrasting cellular structures. The primary outcome is gut hormone response. Secondary outcomes are intestinal content analysis, blood glucose and insulin response, subjective appetite changes and ad libitum energy intake. We show that the ‘Broken’ and ‘Intact’ cell structures of meals result in different digestive and metabolomic profiles, leading to distinct postprandial gut hormones, glycaemia and satiety responses. ‘Broken’ meal structure elicits higher glucose-dependent insulinotropic peptide, glucagon-like peptide-1 and blood glycaemia, driven by high starch digestibility and a sharp rise in gastric maltose within 30 min. ‘Intact’ meal structure produces a prolonged release of glucagon-like peptide-1 and peptide-YY, elevated duodenal amino acids and undigested starch at 120 min. This work highlights how food structure alters upper gastrointestinal nutrient-sensing hormones, providing insights into the adverse effects of modern diets on obesity and type 2 diabetes. ISRCTN registration: ISRCTN18097249.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"40 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329041","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