Nature metabolism最新文献

Itaconate modulates immune responses via inhibition of peroxiredoxin 5

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-18 DOI: 10.1038/s42255-025-01275-0

Tomas Paulenda, Barbora Echalar, Lucie Potuckova, Veronika Vachova, Denis A. Kleverov, Johannes Mehringer, Ekaterina Potekhina, Alex Jacoby, Devashish Sen, Chris Nelson, Rick Stegeman, Vladimir Sukhov, Danielle Kemper, Cheryl F. Lichti, Nicholas J. Day, Tong Zhang, Kamila Husarcikova, Monika Bambouskova, Daved H. Fremont, Wei-jun Qian, Sergej Djuranovic, Slavica Pavlovic-Djuranovic, Vsevolod V. Belousov, Andrzej M. Krezel, Maxim N. Artyomov

{"title":"Itaconate modulates immune responses via inhibition of peroxiredoxin 5","authors":"Tomas Paulenda, Barbora Echalar, Lucie Potuckova, Veronika Vachova, Denis A. Kleverov, Johannes Mehringer, Ekaterina Potekhina, Alex Jacoby, Devashish Sen, Chris Nelson, Rick Stegeman, Vladimir Sukhov, Danielle Kemper, Cheryl F. Lichti, Nicholas J. Day, Tong Zhang, Kamila Husarcikova, Monika Bambouskova, Daved H. Fremont, Wei-jun Qian, Sergej Djuranovic, Slavica Pavlovic-Djuranovic, Vsevolod V. Belousov, Andrzej M. Krezel, Maxim N. Artyomov","doi":"10.1038/s42255-025-01275-0","DOIUrl":"https://doi.org/10.1038/s42255-025-01275-0","url":null,"abstract":"The immunoregulatory metabolite itaconate accumulates in innate immune cells upon Toll-like receptor stimulation. In response to macrophage activation by lipopolysaccharide, itaconate inhibits inflammasome activation and boosts type I interferon signalling; however, the molecular mechanism of this immunoregulation remains unclear. Here, we show that the enhancement of type I interferon secretion by itaconate depends on the inhibition of peroxiredoxin 5 and on mitochondrial reactive oxygen species. We find that itaconate non-covalently inhibits peroxiredoxin 5, leading to the modulation of mitochondrial peroxide in activating macrophages. Through genetic manipulation, we confirm that peroxiredoxin 5 modulates type I interferon secretion in macrophages. The non-electrophilic itaconate mimetic 2-methylsuccinate inhibits peroxiredoxin 5 and phenocopies immunoregulatory action of itaconate on type I interferon and inflammasome activation, providing further support for a non-covalent inhibition of peroxiredoxin 5 by itaconate. Our work provides insight into the molecular mechanism of actions and biological rationale for the predominantly immune specification of itaconate.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847061","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}

引用次数: 0

Itaconate boosts type I IFN response by disrupting cytoprotection

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-18 DOI: 10.1038/s42255-025-01274-1

Theresa Ramalho, Ricardo Tostes Gazzinelli

引用次数: 0

Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-16 DOI: 10.1038/s42255-025-01265-2

Ying Liu, Ezequiel Dantas, Miriam Ferrer, Ting Miao, Mujeeb Qadiri, Yifang Liu, Aram Comjean, Emma E. Davidson, Tiffany Perrier, Tanvir Ahmed, Yanhui Hu, Marcus D. Goncalves, Tobias Janowitz, Norbert Perrimon

{"title":"Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice","authors":"Ying Liu, Ezequiel Dantas, Miriam Ferrer, Ting Miao, Mujeeb Qadiri, Yifang Liu, Aram Comjean, Emma E. Davidson, Tiffany Perrier, Tanvir Ahmed, Yanhui Hu, Marcus D. Goncalves, Tobias Janowitz, Norbert Perrimon","doi":"10.1038/s42255-025-01265-2","DOIUrl":"https://doi.org/10.1038/s42255-025-01265-2","url":null,"abstract":"Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6–JAK–STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"16 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836759","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}

引用次数: 0

Signalling from adipose tissue to the brain is not just about leptin

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-15 DOI: 10.1038/s42255-025-01277-y

Peter Arner

引用次数: 0

GDF15 links adipose tissue lipolysis with anxiety

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-15 DOI: 10.1038/s42255-025-01264-3

Logan K. Townsend, Dongdong Wang, Carly M. Knuth, Russta Fayyazi, Ahmad Mohammad, Léa J. Becker, Evangelia E. Tsakiridis, Eric M. Desjardins, Zeel Patel, Celina M. Valvano, Junfeng Lu, Alice E. Payne, Ofure Itua, Kyle D. Medak, Daniel M. Marko, Jonathan D. Schertzer, David C. Wright, Shawn M. Beaudette, Katherine M. Morrison, André C. Carpentier, Denis P. Blondin, Rebecca E. K. MacPherson, Jordan G. McCall, Marc G. Jeschke, Gregory R. Steinberg

{"title":"GDF15 links adipose tissue lipolysis with anxiety","authors":"Logan K. Townsend, Dongdong Wang, Carly M. Knuth, Russta Fayyazi, Ahmad Mohammad, Léa J. Becker, Evangelia E. Tsakiridis, Eric M. Desjardins, Zeel Patel, Celina M. Valvano, Junfeng Lu, Alice E. Payne, Ofure Itua, Kyle D. Medak, Daniel M. Marko, Jonathan D. Schertzer, David C. Wright, Shawn M. Beaudette, Katherine M. Morrison, André C. Carpentier, Denis P. Blondin, Rebecca E. K. MacPherson, Jordan G. McCall, Marc G. Jeschke, Gregory R. Steinberg","doi":"10.1038/s42255-025-01264-3","DOIUrl":"https://doi.org/10.1038/s42255-025-01264-3","url":null,"abstract":"Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15–GFRAL signalling might reduce acute anxiety.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"49 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831695","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}

引用次数: 0

A gut hormone governing protein appetite and longevity

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-14 DOI: 10.1038/s42255-025-01278-x

Chisako Sakuma, Fumiaki Obata

引用次数: 0

Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-14 DOI: 10.1038/s42255-025-01267-0

Nadja Ahrentløv, Olga Kubrak, Mette Lassen, Alina Malita, Takashi Koyama, Amalie S. Frederiksen, Casper M. Sigvardsen, Alphy John, Pernille E. H. Madsen, Kenneth V. Halberg, Stanislav Nagy, Cordelia Imig, Erik A. Richter, Michael J. Texada, Kim Rewitz

{"title":"Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan","authors":"Nadja Ahrentløv, Olga Kubrak, Mette Lassen, Alina Malita, Takashi Koyama, Amalie S. Frederiksen, Casper M. Sigvardsen, Alphy John, Pernille E. H. Madsen, Kenneth V. Halberg, Stanislav Nagy, Cordelia Imig, Erik A. Richter, Michael J. Texada, Kim Rewitz","doi":"10.1038/s42255-025-01267-0","DOIUrl":"https://doi.org/10.1038/s42255-025-01267-0","url":null,"abstract":"Animals select food based on hungers that reflect dynamic macronutrient needs, but the hormonal mechanisms underlying nutrient-specific appetite regulation remain poorly defined. Here, we identify tachykinin (Tk) as a protein-responsive gut hormone in Drosophila and female mice, regulated by conserved environmental and nutrient-sensing mechanisms. Protein intake activates Tk-expressing enteroendocrine cells (EECs), driving the release of gut Tk through mechanisms involving target of rapamycin (TOR) and transient receptor potential A1 (TrpA1). In flies, we delineate a pathway by which gut Tk controls selective appetite and sleep after protein ingestion, mediated by glucagon-like adipokinetic hormone (AKH) signalling to neurons and adipose tissue. This mechanism suppresses protein appetite, promotes sugar hunger and modulates wakefulness to align behaviour with nutritional needs. Inhibiting protein-responsive gut Tk prolongs lifespan through AKH, revealing a role for nutrient-dependent gut hormone signalling in longevity. Our results provide a framework for understanding EEC-derived nutrient-specific satiety signals and the role of gut hormones in regulating food choice, sleep and lifespan.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"40 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827646","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}

引用次数: 0

NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection 源自 NK 细胞的 IFNγ 能调动脂肪组织中的游离脂肪酸，促进病毒感染过程中早期 B 细胞的活化

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-11 DOI: 10.1038/s42255-025-01273-2

Mia Krapić, Inga Kavazović, Sanja Mikašinović, Karlo Mladenić, Fran Krstanović, Gönül Seyhan, Sabine Helmrath, Elena Camerini, Ilija Brizić, Fleur S. Peters, Marc Schmidt-Supprian, Bojan Polić, Tamara Turk Wensveen, Felix M. Wensveen

{"title":"NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection","authors":"Mia Krapić, Inga Kavazović, Sanja Mikašinović, Karlo Mladenić, Fran Krstanović, Gönül Seyhan, Sabine Helmrath, Elena Camerini, Ilija Brizić, Fleur S. Peters, Marc Schmidt-Supprian, Bojan Polić, Tamara Turk Wensveen, Felix M. Wensveen","doi":"10.1038/s42255-025-01273-2","DOIUrl":"https://doi.org/10.1038/s42255-025-01273-2","url":null,"abstract":"The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8+ T cells. Inhibiting lipid uptake by activated B cells impaired CD8+ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"68 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819151","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}

引用次数: 0

The art of war: burning stores to fuel anti-viral immunity 战争的艺术：燃烧储存以增强抗病毒免疫力

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-11 DOI: 10.1038/s42255-025-01257-2

Sarah Q. Crome, Sue Tsai

引用次数: 0

Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-10 DOI: 10.1038/s42255-025-01268-z

Meng Yu, Bing Feng, Jonathan C. Bean, Qianru Zhao, Yongjie Yang, Hailan Liu, Yongxiang Li, Benjamin P. Eappen, Hesong Liu, Longlong Tu, Kristine M. Conde, Mengjie Wang, Xi Chen, Na Yin, Darah Ave Threat, Nathan Xu, Junying Han, Peiyu Gao, Yi Zhu, Darryl L. Hadsell, Yang He, Pingwen Xu, Yanlin He, Chunmei Wang

{"title":"Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice","authors":"Meng Yu, Bing Feng, Jonathan C. Bean, Qianru Zhao, Yongjie Yang, Hailan Liu, Yongxiang Li, Benjamin P. Eappen, Hesong Liu, Longlong Tu, Kristine M. Conde, Mengjie Wang, Xi Chen, Na Yin, Darah Ave Threat, Nathan Xu, Junying Han, Peiyu Gao, Yi Zhu, Darryl L. Hadsell, Yang He, Pingwen Xu, Yanlin He, Chunmei Wang","doi":"10.1038/s42255-025-01268-z","DOIUrl":"https://doi.org/10.1038/s42255-025-01268-z","url":null,"abstract":"17β-oestradiol (E2) inhibits overeating and promotes brown adipose tissue (BAT) thermogenesis, whereas prolactin (PRL) does the opposite. During lactation, the simultaneous decline in E2 and surge in PRL contribute to maternal metabolic adaptations, including hyperphagia and suppressed BAT thermogenesis. However, the underlying neuroendocrine mechanisms remain unclear. Here, we find that oestrogen receptor alpha (ERα)-expressing neurons in the medial basal hypothalamus (MBH), specifically the arcuate nucleus of the hypothalamus and the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH), are suppressed during lactation. Deletion of ERα from MBH neurons in virgin female mice induces metabolic phenotypes characteristic of lactation, including hyperprolactinemia, hyperphagia and suppressed BAT thermogenesis. By contrast, activation of ERαvlVMH neurons in lactating mice attenuates these phenotypes. Overall, our study reveals an inhibitory effect of E2–ERαvlVMH signalling on PRL production, which is suppressed during lactation to sustain hyperprolactinemia and metabolic adaptations.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"34 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814052","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}

引用次数: 0