Pub Date : 2025-10-30DOI: 10.1038/s42255-025-01404-9
Juan P. Bolaños, Pierre J. Magistretti
Over the past years, substantial advances have deepened our understanding of the cellular and molecular drivers of brain energy metabolism. Enabled by transformative technologies offering cellular-level resolution, these insights have revealed a highly regulated and dynamic metabolic interplay among brain cell types, particularly between neurons and astrocytes. In this Review, we shed light on the intricate ways in which neurons and astrocytes operate as a metabolically coupled unit, optimized to sustain the energetic demands of neurotransmission while ensuring neuroprotection. We highlight intercellular cooperation as a key determinant of brain function and provide examples of how disruption of the neuron–astrocyte metabolic unit contributes to numerous diseases of the nervous system, underscoring the critical importance of continued fundamental research to dissect the regulatory principles and vulnerabilities of this intercellular metabolic axis and identify potential therapeutic targets. Bolaños and Magistretti illustrate how intercellular metabolic cooperation underpins brain function and provide examples of how disruption of the neuron–astrocyte metabolic unit contributes to diseases of the nervous system.
{"title":"The neuron–astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease","authors":"Juan P. Bolaños, Pierre J. Magistretti","doi":"10.1038/s42255-025-01404-9","DOIUrl":"10.1038/s42255-025-01404-9","url":null,"abstract":"Over the past years, substantial advances have deepened our understanding of the cellular and molecular drivers of brain energy metabolism. Enabled by transformative technologies offering cellular-level resolution, these insights have revealed a highly regulated and dynamic metabolic interplay among brain cell types, particularly between neurons and astrocytes. In this Review, we shed light on the intricate ways in which neurons and astrocytes operate as a metabolically coupled unit, optimized to sustain the energetic demands of neurotransmission while ensuring neuroprotection. We highlight intercellular cooperation as a key determinant of brain function and provide examples of how disruption of the neuron–astrocyte metabolic unit contributes to numerous diseases of the nervous system, underscoring the critical importance of continued fundamental research to dissect the regulatory principles and vulnerabilities of this intercellular metabolic axis and identify potential therapeutic targets. Bolaños and Magistretti illustrate how intercellular metabolic cooperation underpins brain function and provide examples of how disruption of the neuron–astrocyte metabolic unit contributes to diseases of the nervous system.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2414-2423"},"PeriodicalIF":20.8,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396873","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}
Pub Date : 2025-10-22DOI: 10.1038/s42255-025-01392-w
Andrew R. Tee
Oligodendrocyte progenitor cells harness aldolase C–TRPV–AMPK signalling in a bespoke way to sense glucose availability and prioritize energy towards remyelination.
{"title":"Sweet signals for myelin: glucose sensing redirected to regeneration","authors":"Andrew R. Tee","doi":"10.1038/s42255-025-01392-w","DOIUrl":"10.1038/s42255-025-01392-w","url":null,"abstract":"Oligodendrocyte progenitor cells harness aldolase C–TRPV–AMPK signalling in a bespoke way to sense glucose availability and prioritize energy towards remyelination.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2189-2191"},"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}
Pub Date : 2025-10-22DOI: 10.1038/s42255-025-01386-8
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
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. Inhibition of AMPK activation under low glucose conditions in oligodendrocyte precursor cells is shown to be important for myelination during development and remyelination in neuronal disorders.
{"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":"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. Inhibition of AMPK activation under low glucose conditions in oligodendrocyte precursor cells is shown to be important for myelination during development and remyelination in neuronal disorders.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2324-2345"},"PeriodicalIF":20.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01386-8.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub 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
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. The gut microbiota-derived metabolite indole-3-propionic acid (IPA) is found to enhance mitochondrial fatty acid and amino acid oxidation in CD4+ T cells. In mice, IPA-mediated metabolic reprogramming of CD4+ T cells exerts anti-inflammatory effects and protects against colitis.
{"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":"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. The gut microbiota-derived metabolite indole-3-propionic acid (IPA) is found to enhance mitochondrial fatty acid and amino acid oxidation in CD4+ T cells. In mice, IPA-mediated metabolic reprogramming of CD4+ T cells exerts anti-inflammatory effects and protects against colitis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2510-2530"},"PeriodicalIF":20.8,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01396-6.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1038/s42255-025-01401-y
Jacy Scott, Chaoran Li
Microbiota-derived metabolites shape intestinal health by modulating T cell metabolism. Li et al. show that indole-3-propionic acid (IPA) promotes mitochondrial respiration to suppress pro-inflammatory T cell differentiation, thereby alleviating inflammatory bowel disease in humans and mice.
{"title":"IPA brews metabolic balance in gut immunity","authors":"Jacy Scott, Chaoran Li","doi":"10.1038/s42255-025-01401-y","DOIUrl":"10.1038/s42255-025-01401-y","url":null,"abstract":"Microbiota-derived metabolites shape intestinal health by modulating T cell metabolism. Li et al. show that indole-3-propionic acid (IPA) promotes mitochondrial respiration to suppress pro-inflammatory T cell differentiation, thereby alleviating inflammatory bowel disease in humans and mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2385-2387"},"PeriodicalIF":20.8,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338532","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}
Pub Date : 2025-10-20DOI: 10.1038/s42255-025-01398-4
Cancer cells often increase their uptake of acetate for acetyl-coenzyme A biosynthesis, a mechanism that facilitates cancer metastasis. We found that, in hepatocellular carcinoma, cancer cells induce acetate secretion from tumour-associated macrophages, driven by a cell–cell metabolic interaction involving lactate, the lipid peroxidation–aldehyde dehydrogenase 2 pathway and acetate.
{"title":"A lactate–acetate interaction between macrophages and cancer cells drives metastasis","authors":"","doi":"10.1038/s42255-025-01398-4","DOIUrl":"10.1038/s42255-025-01398-4","url":null,"abstract":"Cancer cells often increase their uptake of acetate for acetyl-coenzyme A biosynthesis, a mechanism that facilitates cancer metastasis. We found that, in hepatocellular carcinoma, cancer cells induce acetate secretion from tumour-associated macrophages, driven by a cell–cell metabolic interaction involving lactate, the lipid peroxidation–aldehyde dehydrogenase 2 pathway and acetate.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2195-2196"},"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}
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. Acetate accumulation and metastasis of hepatocarcinoma cells is driven by a metabolic interaction involving HCC-derived lactate and acetate secretion from tumour-associated macrophages.
{"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":"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. Acetate accumulation and metastasis of hepatocarcinoma cells is driven by a metabolic interaction involving HCC-derived lactate and acetate secretion from tumour-associated macrophages.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2268-2283"},"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}
Pub Date : 2025-10-17DOI: 10.1038/s42255-025-01394-8
Rosellina M. Mancina, Luca Valenti, Stefano Romeo
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. This Review summarizes our current knowledge about the genetic underpinnings of metabolic-dysfunction-associated steatotic liver disease and highlights its causal association with type 2 diabetes and insulin resistance.
{"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":"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. This Review summarizes our current knowledge about the genetic underpinnings of metabolic-dysfunction-associated steatotic liver disease and highlights its causal association with type 2 diabetes and insulin resistance.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2199-2211"},"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}
Pub 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
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. Greda et al. show that sortilin and apolipoprotein E3 mediate import and utilization of long-chain fatty acids as a metabolic fuel in neurons after glucose restriction.
{"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":"10.1038/s42255-025-01389-5","url":null,"abstract":"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. Greda et al. show that sortilin and apolipoprotein E3 mediate import and utilization of long-chain fatty acids as a metabolic fuel in neurons after glucose restriction.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2346-2365"},"PeriodicalIF":20.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01389-5.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-15DOI: 10.1038/s42255-025-01400-z
Eléna Morin, Emmanuel Doumard, Lisa M. Hartnell, Beñat Salegi Ansa, Jean-Philippe Leduc-Gaudet, Aurélie Quillien, Jean Nakhle, Séverine Ethuin, Dominique Goudounèche, Bruno Payré, Vanessa Soldan, Stéphanie Balor, Anna Mattout, Jacques Rouquette, Laurence Dubois, Coralie Sengenès, Valérie Planat, Louis Casteilla, Armelle Yart, Cédric Dray, Julien Aligon, Luigi Ferrucci, Élise Duchesne, Sabah N. A. Hussain, Gilles Gouspillou, Laura Formentini, Arnaud Mourier, Olivier R. Baris, Philippe Valet, Harold Parpex, Paul Monsarrat, Mathieu Vigneau, Jean-Philippe Pradère
{"title":"EMito-Metrix enables automated evaluation of mitochondrial morphology across species","authors":"Eléna Morin, Emmanuel Doumard, Lisa M. Hartnell, Beñat Salegi Ansa, Jean-Philippe Leduc-Gaudet, Aurélie Quillien, Jean Nakhle, Séverine Ethuin, Dominique Goudounèche, Bruno Payré, Vanessa Soldan, Stéphanie Balor, Anna Mattout, Jacques Rouquette, Laurence Dubois, Coralie Sengenès, Valérie Planat, Louis Casteilla, Armelle Yart, Cédric Dray, Julien Aligon, Luigi Ferrucci, Élise Duchesne, Sabah N. A. Hussain, Gilles Gouspillou, Laura Formentini, Arnaud Mourier, Olivier R. Baris, Philippe Valet, Harold Parpex, Paul Monsarrat, Mathieu Vigneau, Jean-Philippe Pradère","doi":"10.1038/s42255-025-01400-z","DOIUrl":"10.1038/s42255-025-01400-z","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2179-2182"},"PeriodicalIF":20.8,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296046","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}
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