Nature metabolism最新文献

{"title":"Diabetes, IL-10 and the brain’s microvascular crisis","authors":"Celine E. Riera","doi":"10.1038/s42255-024-01161-1","DOIUrl":"10.1038/s42255-024-01161-1","url":null,"abstract":"A new study finds that capillary vessels become obstructed in diabetes and that their dysfunction may cause microvascular damage and lead to cognitive deficits. Such obstruction is independent of the elevated blood sugar found in diabetes and is triggered by elevated interleukin-10 cytokine signalling in cerebral blood vessel endothelial cells.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2029-2030"},"PeriodicalIF":18.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of acute exercise in carriers of TBC1D4 mutation","authors":"Leslie J. Baier, Clifton Bogardus","doi":"10.1038/s42255-024-01116-6","DOIUrl":"10.1038/s42255-024-01116-6","url":null,"abstract":"A nonsense mutation in TBC1D4 has previously been associated with hyperinsulinaemia and increased risk of type 2 diabetes mellitus. A new report shows that carriers have isolated muscle insulin resistance that improves after an acute bout of exercise.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2213-2214"},"PeriodicalIF":18.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise","authors":"Jonas M. Kristensen, Rasmus Kjøbsted, Trine J. Larsen, Christian S. Carl, Janne R. Hingst, Johan Onslev, Jesper B. Birk, Anette Thorup, Dorte E. Steenberg, Jonas R. Knudsen, Nicolai S. Henriksen, Elise J. Needham, Jens F. Halling, Anders Gudiksen, Carsten F. Rundsten, Kristian E. Hanghøj, Sara E. Stinson, Birgitte Hoier, Camilla C. Hansen, Thomas E. Jensen, Ylva Hellsten, Henriette Pilegaard, Niels Grarup, Jesper Olesen, Sean J. Humphrey, David E. James, Michael L. Pedersen, Erik A. Richter, Torben Hansen, Marit E. Jørgensen, Jørgen F. P. Wojtaszewski","doi":"10.1038/s42255-024-01153-1","DOIUrl":"10.1038/s42255-024-01153-1","url":null,"abstract":"In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies. In Greenlandic Inuit, a TBC1D4 loss-of-function mutation increases type 2 diabetes risk by tenfold. Carriers show severe muscle insulin resistance, impaired glucose disposal and reduced muscle GLUT4, yet exercise mitigates these defects, offering potential for personalized lifestyle interventions.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2254-2266"},"PeriodicalIF":18.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01153-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555777","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}

{"title":"Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells","authors":"Wusheng Xiao, Nishith Shrimali, Niv Vigder, William M. Oldham, Clary B. Clish, Huamei He, Samantha J. Wong, Bradley M. Wertheim, Elena Arons, Marcia C. Haigis, Jane A. Leopold, Joseph Loscalzo","doi":"10.1038/s42255-024-01150-4","DOIUrl":"10.1038/s42255-024-01150-4","url":null,"abstract":"Hypoxia-inducible factor 1α (HIF1α) is a master regulator of biological processes in hypoxia. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in normal (primary) cells, remain elusive. Here we show that HIF1α signalling is activated in several human primary vascular cells in normoxia and in vascular smooth muscle cells of normal human lungs. Mechanistically, aerobic HIF1α activation is mediated by paracrine secretion of three branched-chain α-ketoacids (BCKAs), which suppress PHD2 activity via direct inhibition and via LDHA-mediated generation of L-2-hydroxyglutarate. BCKA-mediated HIF1α signalling activation stimulated glycolytic activity and governed a phenotypic switch of pulmonary artery smooth muscle cells, which correlated with BCKA metabolic dysregulation and pathophenotypic changes in pulmonary arterial hypertension patients and male rat models. We thus identify BCKAs as previously unrecognized signalling metabolites that aerobically activate HIF1α and that the BCKA–HIF1α pathway modulates vascular smooth muscle cell function, an effect that may be relevant to pulmonary vascular pathobiology. Branched-chain α-ketoacids are shown to aerobically activate HIF1α signalling, which induces a phenotypic switch in vascular smooth muscle cells that is potentially relevant in the context of pulmonary artery hypertension.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2138-2156"},"PeriodicalIF":18.9,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TrkB signalling regulates dopamine circuits and motor function through metabolic pathways","authors":"","doi":"10.1038/s42255-024-01154-0","DOIUrl":"10.1038/s42255-024-01154-0","url":null,"abstract":"A common feature of neurodegenerative diseases is that select neuronal types are particularly sensitive to disease pathology at early stages. Altered TrkB signalling in the neuronal type most affected by Huntington’s disease increased expression of the enzyme GSTO2, leading to dopaminergic dysfunction, impaired energy metabolism, progressive degeneration and hyperkinetic symptoms.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2031-2032"},"PeriodicalIF":18.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired striatal glutathione–ascorbate metabolism induces transient dopamine increase and motor dysfunction","authors":"Mohd Yaseen Malik, Fei Guo, Aman Asif-Malik, Vasileios Eftychidis, Nikolaos Barkas, Elena Eliseeva, Kerstin N. Timm, Aleksandra Wolska, David Bergin, Barbara Zonta, Veronika Ratz-Wirsching, Stephan von Hörsten, Mark E. Walton, Peter J. Magill, Claus Nerlov, Liliana Minichiello","doi":"10.1038/s42255-024-01155-z","DOIUrl":"10.1038/s42255-024-01155-z","url":null,"abstract":"Identifying initial triggering events in neurodegenerative disorders is critical to developing preventive therapies. In Huntington’s disease (HD), hyperdopaminergia—probably triggered by the dysfunction of the most affected neurons, indirect pathway spiny projection neurons (iSPNs)—is believed to induce hyperkinesia, an early stage HD symptom. However, how this change arises and contributes to HD pathogenesis is unclear. Here, we demonstrate that genetic disruption of iSPNs function by Ntrk2/Trkb deletion in mice results in increased striatal dopamine and midbrain dopaminergic neurons, preceding hyperkinetic dysfunction. Transcriptomic analysis of iSPNs at the pre-symptomatic stage showed de-regulation of metabolic pathways, including upregulation of Gsto2, encoding glutathione S-transferase omega-2 (GSTO2). Selectively reducing Gsto2 in iSPNs in vivo effectively prevented dopaminergic dysfunction and halted the onset and progression of hyperkinetic symptoms. This study uncovers a functional link between altered iSPN BDNF-TrkB signalling, glutathione–ascorbate metabolism and hyperdopaminergic state, underscoring the vital role of GSTO2 in maintaining dopamine balance. Malik, Guo et al. show that Ntrk2/Trkb-mediated neurotrophic signalling regulates dopamine levels by controlling glutathione–ascorbate metabolism, thus impacting striatal dopaminergic circuits and motor function","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2100-2117"},"PeriodicalIF":18.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01155-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519518","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}

{"title":"Quantitation of metabolic activity from isotope tracing data using automated methodology","authors":"Shiyu Liu, Xiaojing Liu, Jason W. Locasale","doi":"10.1038/s42255-024-01144-2","DOIUrl":"10.1038/s42255-024-01144-2","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2207-2209"},"PeriodicalIF":18.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Publisher Correction: Exploring pancreatic beta-cell subgroups and their connectivity","authors":"Guy A. Rutter, Anne Gresch, Luis Delgadillo Silva, Richard K. P. Benninger","doi":"10.1038/s42255-024-01141-5","DOIUrl":"10.1038/s42255-024-01141-5","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2205-2205"},"PeriodicalIF":18.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01141-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489502","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}

{"title":"Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling","authors":"Xiaomin Zhang, Yali Chen, Geng Sun, Yankang Fei, Ha Zhu, Yanfang Liu, Junyan Dan, Chunzhen Li, Xuetao Cao, Juan Liu","doi":"10.1038/s42255-024-01149-x","DOIUrl":"10.1038/s42255-024-01149-x","url":null,"abstract":"Cellular metabolism modulates dendritic cell (DC) maturation and activation. Migratory dendritic cells (mig-DCs) travelling from the tissues to draining lymph nodes (dLNs) are critical for instructing adaptive immune responses. However, how lipid metabolites influence mig-DCs in autoimmunity remains elusive. Here, we demonstrate that farnesyl pyrophosphate (FPP), an intermediate of the mevalonate pathway, accumulates in mig-DCs derived from mice with systemic lupus erythematosus (SLE). FPP promotes mig-DC survival and germinal centre responses in the dLNs by coordinating protein geranylgeranylation and mitochondrial remodelling. Mechanistically, FPP-dependent RhoA geranylgeranylation promotes mitochondrial fusion and oxidative respiration through mitochondrial RhoA–MFN interaction, which subsequently facilitates the resolution of endoplasmic reticulum stress in mig-DCs. Simvastatin, a chemical inhibitor of the mevalonate pathway, restores mitochondrial function in mig-DCs and ameliorates systemic pathogenesis in SLE mice. Our study reveals a critical role for FPP in dictating mig-DC survival by reprogramming mitochondrial structure and metabolism, providing new insights into the pathogenesis of DC-dependent autoimmune diseases. The mevalonate pathway intermediate farnesyl pyrophosphate is shown to regulate the survival of migratory dendritic cells by affecting their mitochondrial metabolism, thereby contributing to the pathogenesis of systemic lupus erythematosus.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2118-2137"},"PeriodicalIF":18.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Farnesyl pyrophosphate modulates dendritic cell migration in lupus autoimmunity","authors":"","doi":"10.1038/s42255-024-01148-y","DOIUrl":"10.1038/s42255-024-01148-y","url":null,"abstract":"Farnesyl pyrophosphate (FPP), an intermediate of cholesterol biosynthesis in the mevalonate pathway, prolongs the survival of migratory dendritic cells (mig-DCs) by remodelling mitochondrial structure and metabolism. Treating a mouse model of systemic lupus erythematosus with simvastatin (an inhibitor of this pathway) led to recovery from dysregulation in mig-DCs and ameliorated systemic autoimmune pathogenesis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2033-2034"},"PeriodicalIF":18.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448266","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}