Nature metabolism最新文献

Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control. 二甲双胍抑制肠上皮线粒体复合体I促进血糖控制。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-05-08 DOI: 10.1038/s42255-026-01530-y

Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel

{"title":"Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.","authors":"Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel","doi":"10.1038/s42255-026-01530-y","DOIUrl":"https://doi.org/10.1038/s42255-026-01530-y","url":null,"abstract":"Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856815","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

Metformin lowers blood glucose by targeting intestinal mitochondrial complex I. 二甲双胍通过靶向肠道线粒体复合体I降低血糖。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-05-08 DOI: 10.1038/s42255-026-01532-w

引用次数: 0

Surgically reshaping the gut microbiome. 通过手术重塑肠道微生物群。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-05-07 DOI: 10.1038/s42255-026-01517-9

Vance L Albaugh, Sri Lakshmi S Devarakonda

引用次数: 0

Gut microbiota responses to bariatric surgery are associated with metabolic outcomes and type 2 diabetes remission. 肠道菌群对减肥手术的反应与代谢结果和2型糖尿病缓解有关。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-05-07 DOI: 10.1038/s42255-026-01525-9

Lisa M Olsson, Heidi Borgeraas, Rima M Chakaroun, Dag Hofsø, Jens Kristoffer Hertel, Chinmay Dwibedi, Matthias Mitteregger, Jens Juul Holst, Valentina Tremaroli, Jøran Hjelmesæth, Fredrik Bäckhed

{"title":"Gut microbiota responses to bariatric surgery are associated with metabolic outcomes and type 2 diabetes remission.","authors":"Lisa M Olsson, Heidi Borgeraas, Rima M Chakaroun, Dag Hofsø, Jens Kristoffer Hertel, Chinmay Dwibedi, Matthias Mitteregger, Jens Juul Holst, Valentina Tremaroli, Jøran Hjelmesæth, Fredrik Bäckhed","doi":"10.1038/s42255-026-01525-9","DOIUrl":"https://doi.org/10.1038/s42255-026-01525-9","url":null,"abstract":"Bariatric surgeries, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), improve obesity and type 2 diabetes (T2D). Both surgeries affect the gut microbiota, but their contribution to T2D remission remains unclear. In this subanalysis (RYGB, n = 39; SG, n = 38) of the randomized controlled Oseberg trial ( NCT01778738 ), in which participants underwent either RYGB or SG surgery, we profiled the faecal microbiome of individuals with obesity and T2D before and 12 months after surgery. We show that both surgeries altered the microbiome in the same direction, but with larger changes after RYGB. The SG-associated altered microbiome composition correlated positively with circulating glucagon-like peptide 1 levels, beta-cell function and 5 year T2D remission. Remission was also linked to increased gene richness and metabolic potential for fermentation, methanogenesis and butyrate production. Notably, these associations persisted after accounting for the extent of weight loss. Our findings indicate that surgery-specific microbial adaptations influence metabolic improvements and may help to explain heterogeneity in T2D remission after bariatric surgery.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840317","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

Succinate calls a time-out on pyrimidine biosynthesis. 琥珀酸盐在嘧啶的生物合成过程中需要暂停。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-05-04 DOI: 10.1038/s42255-026-01523-x

Désirée Schatton, Christian Frezza

引用次数: 0

Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. 琥珀酸脱氢酶缺失通过琥珀酸介导的天冬氨酸转甲氨基化酶抑制嘧啶生物合成。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-05-04 DOI: 10.1038/s42255-026-01524-w

Madeleine L Hart, David Sokolov, Serwah Danquah, Eric Zheng, Alex D Doan, Kristian Davidsen, David MacPherson, Lucas B Sullivan

{"title":"Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.","authors":"Madeleine L Hart, David Sokolov, Serwah Danquah, Eric Zheng, Alex D Doan, Kristian Davidsen, David MacPherson, Lucas B Sullivan","doi":"10.1038/s42255-026-01524-w","DOIUrl":"https://doi.org/10.1038/s42255-026-01524-w","url":null,"abstract":"Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840443","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

Brain cells refine nitrogen choice with maturity. 随着成熟，脑细胞对氮的选择更加精细。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-04-29 DOI: 10.1038/s42255-026-01519-7

Andrew J Scott, Costas A Lyssiotis, Daniel R Wahl

引用次数: 0

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice. 氮代谢谱揭示细胞状态特异性嘧啶合成途径选择。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-04-29 DOI: 10.1038/s42255-026-01520-0

Milan R Savani, Bingbing Li, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Tracey Shipman, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer

{"title":"Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.","authors":"Milan R Savani, Bingbing Li, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Tracey Shipman, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer","doi":"10.1038/s42255-026-01520-0","DOIUrl":"10.1038/s42255-026-01520-0","url":null,"abstract":"Stable isotope-tracing assays track few metabolites, yet cells use many nutrients to sustain nitrogen metabolism. Here we create a platform for tracing 30 nitrogen isotope-labelled metabolites in parallel to enable a system-level understanding of cellular nitrogen metabolism. This platform reveals that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine. This link between cell state and pyrimidine synthesis pathway preference persists in murine and human tissues. Mechanistically, we find that S1900 phosphorylation of CAD, the first enzyme of the de novo pathway, is induced by uridine deprivation in differentiated cells and constitutively enriched in primitive cells. Mimicking CAD S1900 phosphorylation in differentiated cells constitutively activates de novo pyrimidine synthesis, while blocking this modification impairs the cellular response to uridine starvation. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777007","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

Good things come in twos 好事成双

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-04-28 DOI: 10.1038/s42255-026-01522-y

引用次数: 0

FXR-YAP signalling maintains biliary epithelial cell identity and preserves liver homeostasis. FXR-YAP信号传导维持胆道上皮细胞的身份并维持肝脏稳态。

IF 20.8 1区医学

Nature metabolism Pub Date : 2026-04-28 DOI: 10.1038/s42255-026-01521-z

Paula Sánchez-Sánchez,Zhaoshuo Wang,Sladjana Zagorac,María Domínguez,Jasminka Boskovic,Ajay Nair,Andrea Macías-Camero,Alma Villaseñor,Robert F Schwabe,Nabil Djouder

{"title":"FXR-YAP signalling maintains biliary epithelial cell identity and preserves liver homeostasis.","authors":"Paula Sánchez-Sánchez,Zhaoshuo Wang,Sladjana Zagorac,María Domínguez,Jasminka Boskovic,Ajay Nair,Andrea Macías-Camero,Alma Villaseñor,Robert F Schwabe,Nabil Djouder","doi":"10.1038/s42255-026-01521-z","DOIUrl":"https://doi.org/10.1038/s42255-026-01521-z","url":null,"abstract":"Bile acids (BAs) flow through ducts lined by biliary epithelial cells (BECs), which preserve ductal integrity and liver homeostasis. Failure of this barrier causes BA accumulation in the liver parenchyma, and ultimately fibrosis. Here we show that BECs safeguard biliary barrier integrity and restrain BA-induced fibrogenesis through a cell-intrinsic mechanism involving farnesoid-X-receptor (FXR)-YAP signalling. Using a combination of mouse genetics, computational analysis and human samples, we show that BECs express FXR, which transcriptionally activates YAP to maintain their adhesion, thereby preventing BA efflux and subsequent FXR-dependent hepatic stellate cell activation and fibrosis in BA-dysregulated liver disease models. Genetic ablation of FXR or YAP in mouse BECs triggers β-catenin activation, mesenchymal-like conversion and BEC proliferation, promoting fibrosis-to-cirrhosis progression. Diminished FXR-YAP signalling in human BECs also parallels fibrosis severity. Consistently, obeticholic acid worsens fibrogenesis in mice with FXR-depleted BECs. Thus, BAs reprogram BECs into active guardians of tissue integrity via FXR-YAP-β-catenin signalling, preserving biliary identity and maintaining liver homeostasis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"33 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754740","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