Obesity impairs the function of multiple organs, but its effect on gut regeneration remains poorly defined. Here, we show that adipocyte fatty acid-binding protein (AFABP), an adipokine involved in fatty acid transport, impedes intestinal repair by disrupting iron homeostasis in intestinal stem cells (ISCs). Mechanistically, elevated AFABP secretion in obesity binds to plasma transferrin, leading to iron accumulation in ISCs. This accumulation disrupts peroxisome-mediated ISC differentiation, which is essential for intestinal repair following injury. Notably, AFABP overexpression in adipocytes of lean mice impedes ISC differentiation and gut repair. Conversely, AFABP depletion or the administration of AFABP inhibitors, iron chelators or peroxisome activators effectively mitigates colitis in obese animals. Overall, our findings reveal a mechanistic link between obesity and intestinal repair, and identify the adipose–gut axis as a therapeutic target for obesity-associated intestinal disorders. Elevated adipocyte-derived AFABP in obesity disrupts iron homeostasis in intestinal stem cells (ISCs), which impairs PPARα signalling and blocks ISC differentiation after injury.
{"title":"Obesity impairs gut repair via AFABP-mediated iron overload in intestinal stem cells","authors":"Zhiming Liu, Yi Chen, Jinhua Yan, Yu Yuan, Qianyi Wan, Rui Zhao, Fang Fu, Xinxin Fan, Yawen Deng, Xiaoxin Guo, Haiou Chen, Xingzhu Liu, Jinbao Ye, Haiyang Chen","doi":"10.1038/s42255-025-01425-4","DOIUrl":"10.1038/s42255-025-01425-4","url":null,"abstract":"Obesity impairs the function of multiple organs, but its effect on gut regeneration remains poorly defined. Here, we show that adipocyte fatty acid-binding protein (AFABP), an adipokine involved in fatty acid transport, impedes intestinal repair by disrupting iron homeostasis in intestinal stem cells (ISCs). Mechanistically, elevated AFABP secretion in obesity binds to plasma transferrin, leading to iron accumulation in ISCs. This accumulation disrupts peroxisome-mediated ISC differentiation, which is essential for intestinal repair following injury. Notably, AFABP overexpression in adipocytes of lean mice impedes ISC differentiation and gut repair. Conversely, AFABP depletion or the administration of AFABP inhibitors, iron chelators or peroxisome activators effectively mitigates colitis in obese animals. Overall, our findings reveal a mechanistic link between obesity and intestinal repair, and identify the adipose–gut axis as a therapeutic target for obesity-associated intestinal disorders. Elevated adipocyte-derived AFABP in obesity disrupts iron homeostasis in intestinal stem cells (ISCs), which impairs PPARα signalling and blocks ISC differentiation after injury.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"74-95"},"PeriodicalIF":20.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919977","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 : 2026-01-08DOI: 10.1038/s42255-025-01432-5
Jiyeon Kim, Angelika Harbauer
Integrating work–life balance while pursuing exciting scientific questions and navigating the publishing process as a senior author are challenges that researchers often encounter, particularly in their transition to independence. In this instalment of our Career Pathways series, Jiyeon Kim and Angelika Harbauer reflect on how they have experienced this process.
{"title":"Career pathways, part 18","authors":"Jiyeon Kim, Angelika Harbauer","doi":"10.1038/s42255-025-01432-5","DOIUrl":"10.1038/s42255-025-01432-5","url":null,"abstract":"Integrating work–life balance while pursuing exciting scientific questions and navigating the publishing process as a senior author are challenges that researchers often encounter, particularly in their transition to independence. In this instalment of our Career Pathways series, Jiyeon Kim and Angelika Harbauer reflect on how they have experienced this process.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"1-3"},"PeriodicalIF":20.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934404","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 : 2026-01-05DOI: 10.1038/s42255-025-01427-2
Pamela Kakimoto, Natalie Krahmer
Sex profoundly shapes liver metabolism, with oestrogens conferring protection against metabolic liver disease. In this study, Yang, Wang and colleagues identify the orphan G protein-coupled receptor GPR110 as a liver-specific brake on oestrogen signalling, bridging GPCR and nuclear receptor pathways, thus pointing to GPR110 as a target for sex-specific therapy in liver disease.
{"title":"A sex-specific brake on liver oestrogen signalling","authors":"Pamela Kakimoto, Natalie Krahmer","doi":"10.1038/s42255-025-01427-2","DOIUrl":"10.1038/s42255-025-01427-2","url":null,"abstract":"Sex profoundly shapes liver metabolism, with oestrogens conferring protection against metabolic liver disease. In this study, Yang, Wang and colleagues identify the orphan G protein-coupled receptor GPR110 as a liver-specific brake on oestrogen signalling, bridging GPCR and nuclear receptor pathways, thus pointing to GPR110 as a target for sex-specific therapy in liver disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"8-9"},"PeriodicalIF":20.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902654","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}
Metabolic dysfunction-associated steatohepatitis (MASH) is an important phase in the progression of metabolic dysfunction-associated steatotic liver disease to end-stage liver diseases, posing an increasing threat to public health worldwide with limited treatment options. Here we show that GPR110 is a liver-selective G-protein-coupled receptor closely associated with MASH in a sex-specific manner. Hepatocyte-specific Gpr110 knockout protects against MASH in female, but not male mice. The GPR110 variant rs937057 T > C is associated with a higher prevalence of metabolic dysfunction-associated steatotic liver disease in women. The improved liver phenotypes in female mice are abrogated by knocking down the expression of hepatic oestrogen receptor alpha (Esr1). Mechanistically, GPR110 couples to Gαs and activates protein kinase A, thereby inducing phosphorylation of NFAT2, which inhibits its nuclear translocation and transcriptional activity, leading to suppressed Esr1 transcription in hepatocytes. Taken together, these results demonstrate a sex-specific role of GPR110 in MASH by regulating hepatic oestrogen sensitivity, suggesting inhibition of GPR110 as a potential sex-specific therapy for MASH. Hepatocyte-specific GPR110 mediates metabolic dysfunction-associated steatohepatitis progression by regulating hepatic oestrogen sensitivity in a sex-specific manner, specifically in female mice.
代谢功能障碍相关脂肪性肝炎（MASH）是代谢功能障碍相关脂肪性肝病向终末期肝病发展的一个重要阶段，在治疗选择有限的情况下，对全球公众健康构成越来越大的威胁。在这里，我们发现GPR110是一种肝脏选择性g蛋白偶联受体，以性别特异性的方式与MASH密切相关。肝细胞特异性Gpr110敲除对雌性小鼠的MASH有保护作用，但对雄性小鼠没有作用。GPR110变异rs937057 T >； C与女性代谢功能障碍相关的脂肪变性肝病的较高患病率相关。雌性小鼠肝脏表型的改善是通过降低肝脏雌激素受体α (Esr1)的表达而消除的。在机制上，GPR110与Gαs结合，激活蛋白激酶A，从而诱导NFAT2磷酸化，抑制其核易位和转录活性，导致肝细胞Esr1转录受到抑制。综上所述，这些结果表明GPR110通过调节肝脏雌激素敏感性在MASH中具有性别特异性作用，表明抑制GPR110可能是一种潜在的性别特异性治疗MASH的方法。肝细胞特异性GPR110通过以性别特异性方式调节肝脏雌激素敏感性介导代谢功能障碍相关的脂肪性肝炎进展，特别是在雌性小鼠中。
{"title":"Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling","authors":"Fang Yang, Wei Wang, Feng Qiu, Rui Qing, Qingying Gao, Xingqun Yan, Donghai Wu, Hannah Xiaoyan Hui, Rui Dang, Guozhi Jiang, Liyuan Han, Chunhao Long, Shuang Hua, Yixuan Zhang, Siwei Ji, Lu Xu, Chen Zhou, Daiqiang Xu, Alessandro Cherubini, Luca Valenti, Ping Gu, Shufei Zang, Weimin Jiang, Zhe Huang","doi":"10.1038/s42255-025-01436-1","DOIUrl":"10.1038/s42255-025-01436-1","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) is an important phase in the progression of metabolic dysfunction-associated steatotic liver disease to end-stage liver diseases, posing an increasing threat to public health worldwide with limited treatment options. Here we show that GPR110 is a liver-selective G-protein-coupled receptor closely associated with MASH in a sex-specific manner. Hepatocyte-specific Gpr110 knockout protects against MASH in female, but not male mice. The GPR110 variant rs937057 T > C is associated with a higher prevalence of metabolic dysfunction-associated steatotic liver disease in women. The improved liver phenotypes in female mice are abrogated by knocking down the expression of hepatic oestrogen receptor alpha (Esr1). Mechanistically, GPR110 couples to Gαs and activates protein kinase A, thereby inducing phosphorylation of NFAT2, which inhibits its nuclear translocation and transcriptional activity, leading to suppressed Esr1 transcription in hepatocytes. Taken together, these results demonstrate a sex-specific role of GPR110 in MASH by regulating hepatic oestrogen sensitivity, suggesting inhibition of GPR110 as a potential sex-specific therapy for MASH. Hepatocyte-specific GPR110 mediates metabolic dysfunction-associated steatohepatitis progression by regulating hepatic oestrogen sensitivity in a sex-specific manner, specifically in female mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"116-138"},"PeriodicalIF":20.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902653","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}
Systemic characterization of genes and pathways underlying the genetic architecture of type 2 diabetes (T2D) requires scalable functional genomics approaches. Molecular readouts from CRISPR perturbations can effectively uncover the mechanistic effects of underexplored genes. Here we performed single-cell RNA sequencing on pooled CRISPR screens (Perturb-seq) of 61 T2D-associated genes and 40 ribosome-associated quality control (RQC) genes in human pancreatic β cells (EndoC-βH1) for investigations of insulin production and T2D pathology. We identified 21 functional genes, including the uncharacterized KLHL42 and ZZEF1. Findings from global and β cell-specific knockout male mice, islet organoids and human islets reveal that ZZEF1 is a regulator of insulin synthesis and β cell stress through ribosomal stress-surveillance pathways in working and stress status-defined β cell subtypes. ZZEF1 deficiency impairs β cell function by inhibiting the RQC sensor EDF1, which could be improved by azoramide and ISRIB treatments. These Perturb-seq analyses and identification of functional RQC-related genes can provide potential therapeutic targets for T2D. The authors use Perturb-seq analysis in human pancreatic islet beta cells, as well as in vivo and in vitro analyses, to identify potential therapeutic targets for type 2 diabetes, including ZZEF1, which regulates insulin synthesis and cellular stress in islet β cells.
{"title":"Single-cell perturbations decipher ribosomal stress-surveillance regulators in type 2 diabetes","authors":"Jingminjie Nan, Xianglong He, Xiaoping Liu, Jianrong Ran, Jiahuan Chen, Pengxiao Li, Dongxue Liu, Yanan Sun, Aijing Shan, Xiuli Jiang, Jing Xie, Weiqing Wang, Guang Ning, Yanan Cao","doi":"10.1038/s42255-025-01407-6","DOIUrl":"10.1038/s42255-025-01407-6","url":null,"abstract":"Systemic characterization of genes and pathways underlying the genetic architecture of type 2 diabetes (T2D) requires scalable functional genomics approaches. Molecular readouts from CRISPR perturbations can effectively uncover the mechanistic effects of underexplored genes. Here we performed single-cell RNA sequencing on pooled CRISPR screens (Perturb-seq) of 61 T2D-associated genes and 40 ribosome-associated quality control (RQC) genes in human pancreatic β cells (EndoC-βH1) for investigations of insulin production and T2D pathology. We identified 21 functional genes, including the uncharacterized KLHL42 and ZZEF1. Findings from global and β cell-specific knockout male mice, islet organoids and human islets reveal that ZZEF1 is a regulator of insulin synthesis and β cell stress through ribosomal stress-surveillance pathways in working and stress status-defined β cell subtypes. ZZEF1 deficiency impairs β cell function by inhibiting the RQC sensor EDF1, which could be improved by azoramide and ISRIB treatments. These Perturb-seq analyses and identification of functional RQC-related genes can provide potential therapeutic targets for T2D. The authors use Perturb-seq analysis in human pancreatic islet beta cells, as well as in vivo and in vitro analyses, to identify potential therapeutic targets for type 2 diabetes, including ZZEF1, which regulates insulin synthesis and cellular stress in islet β cells.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"139-158"},"PeriodicalIF":20.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892764","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 : 2025-12-10DOI: 10.1038/s42255-025-01416-5
Alice Pavlowsky, Bryon Silva, Ruchira Basu, Amandine Correia Delecourt, David Geny, Lydia Danglot, Pierre-Yves Plaçais, Thomas Preat
Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands1–3. In contrast, neurons, which are major energy consumers, are considered to rely essentially on glucose and its derivatives to support their metabolism. Here, using Drosophila melanogaster, we show that memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) β-oxidation to produce ATP in neurons of the mushroom body (MB), a major integrative centre in insect brains. We identify cortex glia as the provider of lipids to sustain the usage of FAs for this type of memory. Furthermore, we demonstrate that massed training is associated with mitochondria network remodelling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioural level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, revealing, on the contrary, that in vivo neuronal FA oxidation has an essential role in cognitive function, including memory formation. Neurons are shown to use fatty acid β-oxidation as a fuel source for memory formation upon intensive learning in Drosophila, challenging the view that neurons are unable to use fatty acids for energy production.
{"title":"Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila","authors":"Alice Pavlowsky, Bryon Silva, Ruchira Basu, Amandine Correia Delecourt, David Geny, Lydia Danglot, Pierre-Yves Plaçais, Thomas Preat","doi":"10.1038/s42255-025-01416-5","DOIUrl":"10.1038/s42255-025-01416-5","url":null,"abstract":"Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands1–3. In contrast, neurons, which are major energy consumers, are considered to rely essentially on glucose and its derivatives to support their metabolism. Here, using Drosophila melanogaster, we show that memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) β-oxidation to produce ATP in neurons of the mushroom body (MB), a major integrative centre in insect brains. We identify cortex glia as the provider of lipids to sustain the usage of FAs for this type of memory. Furthermore, we demonstrate that massed training is associated with mitochondria network remodelling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioural level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, revealing, on the contrary, that in vivo neuronal FA oxidation has an essential role in cognitive function, including memory formation. Neurons are shown to use fatty acid β-oxidation as a fuel source for memory formation upon intensive learning in Drosophila, challenging the view that neurons are unable to use fatty acids for energy production.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2438-2450"},"PeriodicalIF":20.8,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01416-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711560","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 : 2025-12-09DOI: 10.1038/s42255-025-01415-6
Brandon M. Oswald, Lisa M. DeCamp, Joseph Longo, Michael S. Dahabieh, Nicholas Bunda, Benjamin K. Johnson, McLane J. Watson, Shixin Ma, Samuel E. J. Preston, Ryan D. Sheldon, Michael P. Vincent, Abigail E. Ellis, Molly T. Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S. Williams, Peter A. Crawford, Susan Kaech, H. Josh Jang, Evan C. Lien, Connie M. Krawczyk, Russell G. Jones
Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity. Dietary restriction promotes the expansion of effector T cells via ketone bodies, which enhances anti-tumour immunity and synergizes with immunotherapy in mice.
{"title":"Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses","authors":"Brandon M. Oswald, Lisa M. DeCamp, Joseph Longo, Michael S. Dahabieh, Nicholas Bunda, Benjamin K. Johnson, McLane J. Watson, Shixin Ma, Samuel E. J. Preston, Ryan D. Sheldon, Michael P. Vincent, Abigail E. Ellis, Molly T. Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S. Williams, Peter A. Crawford, Susan Kaech, H. Josh Jang, Evan C. Lien, Connie M. Krawczyk, Russell G. Jones","doi":"10.1038/s42255-025-01415-6","DOIUrl":"10.1038/s42255-025-01415-6","url":null,"abstract":"Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity. Dietary restriction promotes the expansion of effector T cells via ketone bodies, which enhances anti-tumour immunity and synergizes with immunotherapy in mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2489-2509"},"PeriodicalIF":20.8,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01415-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705133","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 : 2025-12-08DOI: 10.1038/s42255-025-01413-8
Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, Liyong Zhang, Hubert Plovier, Antonis Myridakis, Lesley Hoyles, José Maria Moreno-Navarrete, Jèssica Latorre Luque, Viviana Casagrande, Rossella Menghini, Blerina Ahmetaj-Shala, Christine Blancher, Laura Martinez-Gili, Selin Gencer, Jane F. Fearnside, Richard H. Barton, Ana Luisa Neves, Alice R. Rothwell, Christelle Gérard, Sophie Calderari, Mark J. Williamson, Julian E. Fuchs, Lata Govada, Claire L. Boulangé, Saroor Patel, James Scott, Mark Thursz, Naomi Chayen, Robert C. Glen, Nigel J. Gooderham, Jeremy K. Nicholson, Massimo Federici, José Manuel Fernández-Real, Dominique Gauguier, Peter P. Liu, Patrice D. Cani, Marc-Emmanuel Dumas
The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk. The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.
{"title":"Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control","authors":"Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, Liyong Zhang, Hubert Plovier, Antonis Myridakis, Lesley Hoyles, José Maria Moreno-Navarrete, Jèssica Latorre Luque, Viviana Casagrande, Rossella Menghini, Blerina Ahmetaj-Shala, Christine Blancher, Laura Martinez-Gili, Selin Gencer, Jane F. Fearnside, Richard H. Barton, Ana Luisa Neves, Alice R. Rothwell, Christelle Gérard, Sophie Calderari, Mark J. Williamson, Julian E. Fuchs, Lata Govada, Claire L. Boulangé, Saroor Patel, James Scott, Mark Thursz, Naomi Chayen, Robert C. Glen, Nigel J. Gooderham, Jeremy K. Nicholson, Massimo Federici, José Manuel Fernández-Real, Dominique Gauguier, Peter P. Liu, Patrice D. Cani, Marc-Emmanuel Dumas","doi":"10.1038/s42255-025-01413-8","DOIUrl":"10.1038/s42255-025-01413-8","url":null,"abstract":"The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk. The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2531-2547"},"PeriodicalIF":20.8,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01413-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708752","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 : 2025-12-05DOI: 10.1038/s42255-025-01410-x
Amy E. Stewart, Derek K. Zachman, Pol Castellano-Escuder, Lois M. Kelly, Ben Zolyomi, Michael D. I. Aiduk, Christopher D. Delaney, Ian C. Lock, Claudie Bosc, John Bradley, Shane T. Killarney, J. Darren Stuart, Paul A. Grimsrud, Olga R. Ilkayeva, Christopher B. Newgard, Navdeep S. Chandel, Alexandre Puissant, Kris C. Wood, Matthew D. Hirschey
Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene–gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML. A machine-learning-based computational approach to probe pathway coessentiality reveals that complex II of the electron transport chain regulates de novo purine synthesis, and can be targeted to treat acute myeloid leukaemia.
{"title":"Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia","authors":"Amy E. Stewart, Derek K. Zachman, Pol Castellano-Escuder, Lois M. Kelly, Ben Zolyomi, Michael D. I. Aiduk, Christopher D. Delaney, Ian C. Lock, Claudie Bosc, John Bradley, Shane T. Killarney, J. Darren Stuart, Paul A. Grimsrud, Olga R. Ilkayeva, Christopher B. Newgard, Navdeep S. Chandel, Alexandre Puissant, Kris C. Wood, Matthew D. Hirschey","doi":"10.1038/s42255-025-01410-x","DOIUrl":"10.1038/s42255-025-01410-x","url":null,"abstract":"Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene–gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML. A machine-learning-based computational approach to probe pathway coessentiality reveals that complex II of the electron transport chain regulates de novo purine synthesis, and can be targeted to treat acute myeloid leukaemia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2474-2488"},"PeriodicalIF":20.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01410-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680192","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}
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