Nature metabolism最新文献

{"title":"Separate orexigenic hippocampal ensembles shape dietary choice by enhancing contextual memory and motivation","authors":"Mingxin Yang, Arashdeep Singh, Alan de Araujo, Molly McDougle, Hillary Ellis, Léa Décarie-Spain, Scott E. Kanoski, Guillaume de Lartigue","doi":"10.1038/s42255-024-01194-6","DOIUrl":"10.1038/s42255-024-01194-6","url":null,"abstract":"The hippocampus (HPC) has emerged as a critical player in the control of food intake, beyond its well-known role in memory. While previous studies have primarily associated the HPC with food intake inhibition, recent research suggests a role in appetitive processes. Here we identified spatially distinct neuronal populations within the dorsal HPC (dHPC) that respond to either fats or sugars, potent natural reinforcers that contribute to obesity development. Using activity-dependent genetic capture of nutrient-responsive dHPC neurons, we demonstrate a causal role of both populations in promoting nutrient-specific intake through different mechanisms. Sugar-responsive neurons encoded spatial memory for sugar location, whereas fat-responsive neurons selectively enhanced the preference and motivation for fat intake. Importantly, stimulation of either nutrient-responsive dHPC neurons increased food intake, while ablation differentially impacted obesogenic diet consumption and prevented diet-induced weight gain. Collectively, these findings uncover previously unknown orexigenic circuits underlying macronutrient-specific consumption and provide a foundation for developing potential obesity treatments. Yang et al. identify and characterize distinct sugar- and fat-responsive neuronal populations in the dorsal hippocampus and their contribution to the development of obesity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 2","pages":"276-296"},"PeriodicalIF":18.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01194-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feeding the hippocampus … with specific nutrients","authors":"Pierre Trifilieff, Guillaume Ferreira","doi":"10.1038/s42255-024-01180-y","DOIUrl":"10.1038/s42255-024-01180-y","url":null,"abstract":"The hippocampus is well known to control cognitive processes, but increasing evidence emphasizes its central role in the regulation of feeding behaviour. Yang et al. unravel segregated hippocampal populations responding to either sugar or fat that participate in memory and motivational control of food intake.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 2","pages":"234-235"},"PeriodicalIF":18.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981353","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}

{"title":"Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity","authors":"Janine Tutas, Marianna Tolve, Ebru Özer-Yildiz, Lotte Ickert, Ines Klein, Quinn Silverman, Filip Liebsch, Frederik Dethloff, Patrick Giavalisco, Heike Endepols, Theodoros Georgomanolis, Bernd Neumaier, Alexander Drzezga, Guenter Schwarz, Bernard Thorens, Graziana Gatto, Christian Frezza, Natalia L. Kononenko","doi":"10.1038/s42255-024-01196-4","DOIUrl":"10.1038/s42255-024-01196-4","url":null,"abstract":"Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain. Tutas et al. show an unconventional role for autophagy in the regulation of glycolytic flux in cerebellar Purkinje cells by maintaining the levels of the glucose transporter GLUT2.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 2","pages":"297-320"},"PeriodicalIF":18.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01196-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiplex genome editing eliminates lactate production without impacting growth rate in mammalian cells","authors":"Hooman Hefzi, Iván Martínez-Monge, Igor Marin de Mas, Nicholas Luke Cowie, Alejandro Gomez Toledo, Soo Min Noh, Karen Julie la Cour Karottki, Marianne Decker, Johnny Arnsdorf, Jose Manuel Camacho-Zaragoza, Stefan Kol, Sanne Schoffelen, Nuša Pristovšek, Anders Holmgaard Hansen, Antonio A. Miguez, Sara Petersen Bjørn, Karen Kathrine Brøndum, Elham Maria Javidi, Kristian Lund Jensen, Laura Stangl, Emanuel Kreidl, Thomas Beuchert Kallehauge, Daniel Ley, Patrice Ménard, Helle Munck Petersen, Zulfiya Sukhova, Anton Bauer, Emilio Casanova, Niall Barron, Johan Malmström, Lars K. Nielsen, Gyun Min Lee, Helene Faustrup Kildegaard, Bjørn G. Voldborg, Nathan E. Lewis","doi":"10.1038/s42255-024-01193-7","DOIUrl":"10.1038/s42255-024-01193-7","url":null,"abstract":"The Warburg effect, which describes the fermentation of glucose to lactate even in the presence of oxygen, is ubiquitous in proliferative mammalian cells, including cancer cells, but poses challenges for biopharmaceutical production as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production in cells for bioprocessing have failed as lactate dehydrogenase is essential for cell growth. Here, we effectively eliminate lactate production in Chinese hamster ovary and in the human embryonic kidney cell line HEK293 by simultaneous knockout of lactate dehydrogenases and pyruvate dehydrogenase kinases, thereby removing a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA. These cells, which we refer to as Warburg-null cells, maintain wild-type growth rates while producing negligible lactate, show a compensatory increase in oxygen consumption, near total reliance on oxidative metabolism, and higher cell densities in fed-batch cell culture. Warburg-null cells remain amenable for production of diverse biotherapeutic proteins, reaching industrially relevant titres and maintaining product glycosylation. The ability to eliminate lactate production may be useful for biotherapeutic production and provides a tool for investigating a common metabolic phenomenon. Hefzi et al. engineer cells to nearly eliminate lactate production and increase mitochondrial use of pyruvate by deleting both lactate dehydrogenases and pyruvate dehydrogenase kinases with the goal of circumventing pH and osmolarity issues that arise in bioreactor-based production of biopharmaceuticals.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"212-227"},"PeriodicalIF":18.9,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975087","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}

{"title":"Diabetes in China: epidemiology, pathophysiology and multi-omics","authors":"Weiping Jia, Juliana CN Chan, Tien Y. Wong, Edwin B. Fisher","doi":"10.1038/s42255-024-01190-w","DOIUrl":"10.1038/s42255-024-01190-w","url":null,"abstract":"Although diabetes is now a global epidemic, China has the highest number of affected people, presenting profound public health and socioeconomic challenges. In China, rapid ecological and lifestyle shifts have dramatically altered diabetes epidemiology and risk factors. In this Review, we summarize the epidemiological trends and the impact of traditional and emerging risk factors on Chinese diabetes prevalence. We also explore recent genetic, metagenomic and metabolomic studies of diabetes in Chinese, highlighting their role in pathogenesis and clinical management. Although heterogeneity across these multidimensional areas poses major analytic challenges in classifying patterns or features, they have also provided an opportunity to increase the accuracy and specificity of diagnosis for personalized treatment and prevention. National strategies and ongoing research are essential for improving diabetes detection, prevention and control, and for personalizing care to alleviate societal impacts and maintain quality of life. In this Review, the authors summarize epidemiological trends of type 2 diabetes in China, discuss unique risk factors contributing to diabetes risk in the Chinese population and highlight how recent advances from multi-omics studies can affect treatment of diabetes in China.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"16-34"},"PeriodicalIF":18.9,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974544","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}

{"title":"Early prediction of healthy ageing and age-related diseases using blood protein biomarkers","authors":"","doi":"10.1038/s42255-024-01199-1","DOIUrl":"10.1038/s42255-024-01199-1","url":null,"abstract":"Ageing is associated with proteomic changes in the blood. However, most research on the ageing blood proteome is cross-sectional in nature. Using a longitudinal analysis, we identified 86 ageing-related blood proteins and further revealed a subset of 22 protein biomarkers that, in combination, predict healthy ageing status and age-related cardiometabolic disease risk.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"14-15"},"PeriodicalIF":18.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968262","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}

{"title":"Longitudinal serum proteome mapping reveals biomarkers for healthy ageing and related cardiometabolic diseases","authors":"Jun Tang, Liang Yue, Ying Xu, Fengzhe Xu, Xue Cai, Yuanqing Fu, Zelei Miao, Wanglong Gou, Wei Hu, Zhangzhi Xue, Kui Deng, Luqi Shen, Zengliang Jiang, Menglei Shuai, Xinxiu Liang, Congmei Xiao, Yuting Xie, Tiannan Guo, Yu-ming Chen, Ju-Sheng Zheng","doi":"10.1038/s42255-024-01185-7","DOIUrl":"10.1038/s42255-024-01185-7","url":null,"abstract":"The blood proteome contains biomarkers of ageing and age-associated diseases, but such markers are rarely validated longitudinally. Here we map the longitudinal proteome in 7,565 serum samples from a cohort of 3,796 middle-aged and elderly adults across three time points over a 9-year follow-up period. We pinpoint 86 ageing-related proteins that exhibit signatures associated with 32 clinical traits and the incidence of 14 major ageing-related chronic diseases. Leveraging a machine-learning model, we pick 22 of these proteins to generate a proteomic healthy ageing score (PHAS), capable of predicting the incidence of cardiometabolic diseases. We further identify the gut microbiota as a modifiable factor influencing the PHAS. Our data constitute a valuable resource and offer useful insights into the roles of serum proteins in ageing and age-associated cardiometabolic diseases, providing potential targets for intervention with therapeutics to promote healthy ageing. Tang, Yue, Xu and colleagues map the proteome of several thousand individuals over a 9-year period to identify potential biomarkers of ageing and of age-associated diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"166-181"},"PeriodicalIF":18.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01185-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes","authors":"Shauni Loopmans, Katerina Rohlenova, Thomas van Brussel, Ingrid Stockmans, Karen Moermans, Nicolas Peredo, Peter Carmeliet, Diether Lambrechts, Steve Stegen, Geert Carmeliet","doi":"10.1038/s42255-024-01187-5","DOIUrl":"10.1038/s42255-024-01187-5","url":null,"abstract":"Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis. Loopmans et al. show that the pentose phosphate pathway in chondrocytes provides reducing power to ensure proteostasis necessary for bone lengthening.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"182-195"},"PeriodicalIF":18.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01187-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TM6SF2 as new intestinal lipid player","authors":"Herbert Tilg, Christoph Grander","doi":"10.1038/s42255-024-01156-y","DOIUrl":"10.1038/s42255-024-01156-y","url":null,"abstract":"The gut–liver axis is of crucial importance in health and disease. TM6SF2 is a genetic risk factor for metabolic dysfunction-associated steatotic liver disease. Zhang, Yu et al. reveal that intestinal TM6SF2 critically affects the gut–liver axis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"4-5"},"PeriodicalIF":18.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961484","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}

{"title":"Divergent roles for propionate and butyrate in colorectal cancer epigenetics","authors":"Yuen Jian Cheong, Sophie Trefely","doi":"10.1038/s42255-024-01186-6","DOIUrl":"10.1038/s42255-024-01186-6","url":null,"abstract":"The intestinal short chain fatty acids (SCFAs) propionate and butyrate directly contribute to epigenetic regulation by supplying precursor molecules for histone lysine modifications. Nshanian et al. examine how propionate and butyrate supplementation affects gene regulation in colorectal cancer (CRC) cells, revealing distinct effects for each. Comparing normal cells with cancer cells shows context-dependent responses that might inform metabolic interventions.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"11-13"},"PeriodicalIF":18.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936912","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}