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}
Pub Date : 2025-10-14DOI: 10.1038/s42255-025-01388-6
Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard
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. FGF21 levels increase in response to acute mental stress in individuals with impaired mitochondrial OxPhos capacity, and correlate with stress-related neuroendocrine hormones and trait-level psychosocial factors.
{"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":"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. FGF21 levels increase in response to acute mental stress in individuals with impaired mitochondrial OxPhos capacity, and correlate with stress-related neuroendocrine hormones and trait-level psychosocial factors.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2212-2220"},"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}
Pub Date : 2025-10-13DOI: 10.1038/s42255-025-01387-7
Kasper T. Vinten, Maria M. Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E. Janssens, Riekelt H. Houtkooper
Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism. This Review summarizes existing data, as well as crucial knowledge gaps, emerging from clinical trials involving NAD+ precursor supplementation in humans.
{"title":"NAD+ precursor supplementation in human ageing: clinical evidence and challenges","authors":"Kasper T. Vinten, Maria M. Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E. Janssens, Riekelt H. Houtkooper","doi":"10.1038/s42255-025-01387-7","DOIUrl":"10.1038/s42255-025-01387-7","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism. This Review summarizes existing data, as well as crucial knowledge gaps, emerging from clinical trials involving NAD+ precursor supplementation in humans.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1974-1990"},"PeriodicalIF":20.8,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283545","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}
Infants undergo distinct ketogenesis during the preweaning period, yet its physiological implications remain unclear. Here, we show that preweaning ketosis promotes beige fat biogenesis and improves health outcomes in adulthood. Loss of ketogenesis in neonatal mice by early weaning or ablation of Hmgcs2 hinders beige adipogenesis, subsequently exacerbating metabolic dysregulation in high-fat diet-induced obesity. Enhanced ketogenesis during lactation through exogenous ketone supplements enhances energy expenditure, beige fat formation, and mitochondrial biogenesis and respiration. Using single-cell RNA sequencing, we identified a subset of β-hydroxybutyrate-responsive adipocyte progenitor cells (APCs) expressing Cd81 that showed high beige adipogenic potential. Enhanced ketogenesis promotes the recruitment of beige APCs and their differentiation into beige adipocytes. Mechanistically, ketogenesis-derived βHB induces a switch in the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes. Notably, enhanced ketogenesis during lactation alleviates adverse metabolic effects predisposed by parental obesity. Our study highlights that targeting preweaning ketosis to drive beige adipogenesis may offer a therapeutic approach to combat obesity and metabolic diseases in adulthood. In the context of parental or diet-induced obesity, preweaning ketosis contributes to improved health outcomes, particularly by regulating the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes.
{"title":"Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome","authors":"Chung-Lin Jiang, Pei-Hsiang Lai, Po-Cheng Yang, Chia-Jung Lien, Hsueh-Ping Catherine Chu, Jian-Da Lin, Sung-Jan Lin, I-Shing Yu, Fu-Jung Lin","doi":"10.1038/s42255-025-01378-8","DOIUrl":"10.1038/s42255-025-01378-8","url":null,"abstract":"Infants undergo distinct ketogenesis during the preweaning period, yet its physiological implications remain unclear. Here, we show that preweaning ketosis promotes beige fat biogenesis and improves health outcomes in adulthood. Loss of ketogenesis in neonatal mice by early weaning or ablation of Hmgcs2 hinders beige adipogenesis, subsequently exacerbating metabolic dysregulation in high-fat diet-induced obesity. Enhanced ketogenesis during lactation through exogenous ketone supplements enhances energy expenditure, beige fat formation, and mitochondrial biogenesis and respiration. Using single-cell RNA sequencing, we identified a subset of β-hydroxybutyrate-responsive adipocyte progenitor cells (APCs) expressing Cd81 that showed high beige adipogenic potential. Enhanced ketogenesis promotes the recruitment of beige APCs and their differentiation into beige adipocytes. Mechanistically, ketogenesis-derived βHB induces a switch in the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes. Notably, enhanced ketogenesis during lactation alleviates adverse metabolic effects predisposed by parental obesity. Our study highlights that targeting preweaning ketosis to drive beige adipogenesis may offer a therapeutic approach to combat obesity and metabolic diseases in adulthood. In the context of parental or diet-induced obesity, preweaning ketosis contributes to improved health outcomes, particularly by regulating the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2045-2066"},"PeriodicalIF":20.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254656","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：