Nature metabolismPub Date : 2025-10-22DOI: 10.1038/s42255-025-01392-w
Andrew R Tee
{"title":"Sweet signals for myelin: glucose sensing redirected to regeneration.","authors":"Andrew R Tee","doi":"10.1038/s42255-025-01392-w","DOIUrl":"https://doi.org/10.1038/s42255-025-01392-w","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"37 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339425","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":"Oligodendrocyte precursor cell-specific blocking of low-glucose-induced activation of AMPK ensures myelination and remyelination.","authors":"Yuxia Sun,Wei-Wei Zhang,Lu Men,Jianfeng Wu,Luming Yao,Xi Huang,Yaying Wu,Cixiong Zhang,Ying Chen,David Carling,Chen-Song Zhang,Sheng-Cai Lin","doi":"10.1038/s42255-025-01386-8","DOIUrl":"https://doi.org/10.1038/s42255-025-01386-8","url":null,"abstract":"It has been shown that in most cells, low glucose leads to activation of AMP-activated protein kinase (AMPK) via the lysosomal glucose-sensing pathway, where glycolytic aldolase acts as the glucose sensor. Here, we show that ALDOC (aldolase C), the predominant isozyme of aldolase in mouse and rat oligodendrocyte precursor cells (OPCs), is acetylated at lysine 14, making the lysosomal glucose-sensing AMPK pathway unable to operate. We find that the blockage of AMPK activation is required for the proper proliferation and differentiation of OPCs into mature oligodendrocytes for myelination during development and for remyelination in areas of demyelination where the local glucose levels are low. Therefore, the acetylation of aldolase acts as a checkpoint for AMPK activation in response to low glucose to ensure the proliferation and differentiation of OPCs for myelination, and remyelination of demyelinated neurons.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"127 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339424","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}
Nature metabolismPub Date : 2025-10-21DOI: 10.1038/s42255-025-01396-6
Qing Li,Rodrigo de Oliveira Formiga,Virginie Puchois,Laura Creusot,Ahmad Haidar Ahmad,Salomé Amouyal,Márcio Augusto Campos-Ribeiro,Yining Zhao,Danielle M M Harris,Frederic Lasserre,Sandrine Ellero-Simatos,Hervé Guillou,Zhan Huang,Loic Brot,Yuhang Hu,Loic Chollet,Camille Danne,Cyril Scandola,Tatiana Ledent,Guillaume Chevreux,Rafael J Argüello,Marcelo De Carvalho Bittencourt,Jessica Bettinger,Maud D'Aveni-Piney,David Moulin,Stefan Schreiber,Konrad Aden,Nathalie Rolhion,Marie-Laure Michel,Timothy Wai,Harry Sokol
{"title":"Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation.","authors":"Qing Li,Rodrigo de Oliveira Formiga,Virginie Puchois,Laura Creusot,Ahmad Haidar Ahmad,Salomé Amouyal,Márcio Augusto Campos-Ribeiro,Yining Zhao,Danielle M M Harris,Frederic Lasserre,Sandrine Ellero-Simatos,Hervé Guillou,Zhan Huang,Loic Brot,Yuhang Hu,Loic Chollet,Camille Danne,Cyril Scandola,Tatiana Ledent,Guillaume Chevreux,Rafael J Argüello,Marcelo De Carvalho Bittencourt,Jessica Bettinger,Maud D'Aveni-Piney,David Moulin,Stefan Schreiber,Konrad Aden,Nathalie Rolhion,Marie-Laure Michel,Timothy Wai,Harry Sokol","doi":"10.1038/s42255-025-01396-6","DOIUrl":"https://doi.org/10.1038/s42255-025-01396-6","url":null,"abstract":"The gut microbiota and its metabolites critically regulate immune cell phenotype, function and energy metabolism. We screened a collection of gut microbiota-related metabolites to identify modulators of mitochondrial metabolism in T cells. Here we show that indole-3-propionic acid (IPA) stimulates mitochondrial respiration of CD4+ T cells by increasing fatty acid oxidation (FAO) and amino acid oxidation (AAO), while inhibiting glycolytic capacity. IPA also impacts CD4+ T cell behaviour by inhibiting their differentiation to type 1 and type 17 helper T cell phenotypes. Mechanistically, the metabolic and immune effects of IPA are mediated by peroxisome proliferator-activated receptor-β/δ. The administration of IPA rescues mitochondria respiration in mice with gut bacteria depletion or colitis by enhancing FAO and AAO in colonic CD4+ T cells. Adoptive transfer experiments show that IPA acts on CD4+ T cells to exert its protective effect against inflammation. Collectively, our study reveals that the anti-inflammatory effects of IPA are mediated by metabolic reprogramming of CD4+ T cells toward the enhancement of mitochondrial respiration.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"32 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338529","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}
Nature metabolismPub Date : 2025-10-20DOI: 10.1038/s42255-025-01398-4
{"title":"A lactate-acetate interaction between macrophages and cancer cells drives metastasis.","authors":"","doi":"10.1038/s42255-025-01398-4","DOIUrl":"https://doi.org/10.1038/s42255-025-01398-4","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"17 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331579","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}
Nature metabolismPub Date : 2025-10-20DOI: 10.1038/s42255-025-01393-9
Li Shen,Shenghao Wang,Chao Gao,Qin Li,Shuya Feng,Weiyan Sun,Xu Liu,Yiyi Ba,Yihui Chu,Yu Zhou,Junjie Pan,Hao Xu,Xu Zhang,Wenwei Zhu,Lunxiu Qin,Ming Lu
{"title":"Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.","authors":"Li Shen,Shenghao Wang,Chao Gao,Qin Li,Shuya Feng,Weiyan Sun,Xu Liu,Yiyi Ba,Yihui Chu,Yu Zhou,Junjie Pan,Hao Xu,Xu Zhang,Wenwei Zhu,Lunxiu Qin,Ming Lu","doi":"10.1038/s42255-025-01393-9","DOIUrl":"https://doi.org/10.1038/s42255-025-01393-9","url":null,"abstract":"Increased acetyl-coenzyme A (acetyl-CoA) generation facilitates cancer metastasis and represents a critical metabolic characteristic of metastatic cancers. To maintain high acetyl-CoA levels, cancer cells often enhance the uptake of acetate for acetyl-CoA biosynthesis. However, the microenvironmental source of acetate remains largely unknown. Here we demonstrate that acetate is secreted by tumour-associated macrophages (TAMs) and taken up by hepatocellular carcinoma (HCC) cells to support acetate accumulation. Mechanistically, HCC cell-derived lactate activates the lipid peroxidation-aldehyde dehydrogenase 2 (ALDH2) pathway in TAMs, which promotes the TAMs' acetate production and secretion. Inhibition of ALDH2 or of lipid peroxidation in TAMs abrogates acetate-induced migration of HCC cells in vitro. In an orthotopic HCC model involving male mice, genetic ablation of ALDH2 in TAMs reduces HCC cell acetate levels and HCC lung metastases. Collectively, our findings reveal a metabolic interaction between HCC cells and TAMs-involving lactate, lipid peroxidation and acetate-and position TAMs as an acetate reservoir that drives HCC metastasis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"134 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331578","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}
Nature metabolismPub Date : 2025-10-17DOI: 10.1038/s42255-025-01394-8
Rosellina M Mancina,Luca Valenti,Stefano Romeo
{"title":"Human genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism.","authors":"Rosellina M Mancina,Luca Valenti,Stefano Romeo","doi":"10.1038/s42255-025-01394-8","DOIUrl":"https://doi.org/10.1038/s42255-025-01394-8","url":null,"abstract":"Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease or NAFLD) is a prevalent and heterogeneous condition affecting nearly 30% of the global population. MASLD is defined as excessive hepatic lipid accumulation with at least one feature of insulin resistance, with potential progression to metabolic dysfunction-associated steatohepatitis, cirrhosis and hepatocellular carcinoma. The disease often coexists with insulin resistance and cardiovascular and chronic kidney diseases. Human genetics has shed light on MASLD predisposition and its causal association with type 2 diabetes and insulin resistance, enabling the field to progress towards precision-medicine therapeutics. Convergent selection of somatic mutations in genes involved in glucose and lipid metabolism in cirrhotic livers suggests adaptive responses to gluco-lipotoxicity that influence end-stage liver disease. Recently, two distinct types of MASLD, with specific clinical trajectories, were identified on the basis of partitioned polygenic risk scores. Future studies are needed to integrate this knowledge, enabling earlier detection, risk stratification and targeted therapies.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"1 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311701","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}
Nature metabolismPub Date : 2025-10-16DOI: 10.1038/s42255-025-01389-5
Anna K Greda, Jemila P Gomes, Vanessa Schmidt-Krueger, Ewa Zurawska-Plaksej, Raphaela Fritsche-Guenther, Ina-Maria Rudolph, Narasimha S Telugu, Cagla Cömert, Jennifer Kirwan, Séverine Kunz, Michael Rothe, Mogens Johannsen, Sebastian Diecke, Peter Bross, Thomas E Willnow
{"title":"Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel.","authors":"Anna K Greda, Jemila P Gomes, Vanessa Schmidt-Krueger, Ewa Zurawska-Plaksej, Raphaela Fritsche-Guenther, Ina-Maria Rudolph, Narasimha S Telugu, Cagla Cömert, Jennifer Kirwan, Séverine Kunz, Michael Rothe, Mogens Johannsen, Sebastian Diecke, Peter Bross, Thomas E Willnow","doi":"10.1038/s42255-025-01389-5","DOIUrl":"https://doi.org/10.1038/s42255-025-01389-5","url":null,"abstract":"<p><p>Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolaemia, explained by its ability to control hepatic output of lipoproteins. Although SORT1 also shows genome-wide association with Alzheimer disease and frontotemporal lobe dementia, the most prevalent forms of age-related dementias, sortilin's contribution to human brain lipid metabolism and health remains unclear. Here we show that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apolipoprotein E (apoE). Using humanized mouse strains and induced pluripotent stem cell-based cell models of brain lipid homeostasis, we demonstrate that internalized lipids are converted into ligands for peroxisome proliferator-activated receptor alpha inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel when glucose is limited. This pathway works with apoE3 but cannot operate with the Alzheimer disease risk factor apoE4, which disrupts sortilin's endocytic activity. Our data indicate a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, which may be crucial when glucose supply is limited, such as in the ageing brain.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308602","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":"Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.","authors":"Mangesh Kurade,Natalia Bobba-Alves,Catherine Kelly,Alexander Behnke,Quinn Conklin,Robert-Paul Juster,Michio Hirano,Caroline Trumpff,Martin Picard","doi":"10.1038/s42255-025-01388-6","DOIUrl":"https://doi.org/10.1038/s42255-025-01388-6","url":null,"abstract":"Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P < 0.0001) in healthy controls, but increases FGF21 by 32% (P < 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"215 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288594","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}