Nature metabolism最新文献

{"title":"Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology","authors":"A. L. Madsen, S. Bonàs-Guarch, S. Gheibi, R. Prasad, J. Vangipurapu, V. Ahuja, L. R. Cataldo, O. Dwivedi, G. Hatem, G. Atla, M. Guindo-Martínez, A. M. Jørgensen, A. E. Jonsson, I. Miguel-Escalada, S. Hassan, A. Linneberg, Tarunveer S. Ahluwalia, T. Drivsholm, O. Pedersen, T. I. A. Sørensen, A. Astrup, D. Witte, P. Damm, T. D. Clausen, E. Mathiesen, T. H. Pers, R. J. F. Loos, L. Hakaste, M. Fex, N. Grarup, T. Tuomi, M. Laakso, H. Mulder, J. Ferrer, T. Hansen","doi":"10.1038/s42255-024-01140-6","DOIUrl":"10.1038/s42255-024-01140-6","url":null,"abstract":"The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies3–7, large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants10–14. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in β-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology. In a genome-wide association study for traits related to pancreatic beta-cell function in 26,000 individuals, 55 independent associations mapping to 44 genetic loci are identified.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1897-1912"},"PeriodicalIF":18.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01140-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443866","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":"Genetics brings new insight to β-cell function","authors":"Amélie Bonnefond, Philippe Froguel","doi":"10.1038/s42255-024-01131-7","DOIUrl":"10.1038/s42255-024-01131-7","url":null,"abstract":"A meta-analysis of genome-wide association study for eight traits related to pancreatic β-cell function, based on 26,000 individuals, identified 55 independent association signals mapping to 44 loci. This study highlighted new effectors of β-cell function.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1848-1849"},"PeriodicalIF":18.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443864","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":"Itaconate modulates mitochondria for antiviral IFN-β","authors":"Thekla Cordes, Karsten Hiller","doi":"10.1038/s42255-024-01146-0","DOIUrl":"10.1038/s42255-024-01146-0","url":null,"abstract":"Itaconate is an immunomodulatory metabolite that influences the outcome of infections and inflammatory diseases. New evidence indicates that itaconate-induced inhibition of succinate dehydrogenase regulates type 1 interferon production via the release of mitochondrial RNA, linking TCA cycle modulation to antiviral interferon responses.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2027-2028"},"PeriodicalIF":18.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440032","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":"Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes","authors":"","doi":"10.1038/s42255-024-01152-2","DOIUrl":"10.1038/s42255-024-01152-2","url":null,"abstract":"Brown adipose tissue (BAT) facilitates thermogenesis through fatty acid oxidation (FAO). Paradoxically, BAT simultaneously increases anabolic fatty acid synthesis (FAS), the reason for which is unclear. We provide evidence that thermogenic mitochondria within brown adipocytes export TCA cycle intermediates that fuel de novo lipid synthesis, in part to protect against metabolic stress.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2037-2038"},"PeriodicalIF":18.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440355","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":"Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase","authors":"Shane M. O’Carroll, Christian G. Peace, Juliana E. Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J. O’Sullivan, Aline Zoller, Anne F. Mcgettrick, Emily A. Day, Maria Simarro, Neali Armstrong, Justin P. Annes, Luke A. J. O’Neill","doi":"10.1038/s42255-024-01145-1","DOIUrl":"10.1038/s42255-024-01145-1","url":null,"abstract":"Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release. O’Carroll and Peace et al. provide a mechanism for the induction of type I interferons by the immunomodulatory compound itaconate, which involves inhibition of succinate dehydrogenase and release of mitochondrial double-stranded RNA.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2060-2069"},"PeriodicalIF":18.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440033","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":"Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress","authors":"Ekaterina D. Korobkina, Camila Martinez Calejman, John A. Haley, Miranda E. Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L. Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M. Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R. Green, Paula Vo, Clay F. Semenkovich, Jason R. Pitarresi, Jessica B. Spinelli, Ozkan Aydemir, Christian M. Metallo, Matthew D. Lynes, Cholsoon Jang, Nathaniel W. Snyder, Kathryn E. Wellen, David A. Guertin","doi":"10.1038/s42255-024-01143-3","DOIUrl":"10.1038/s42255-024-01143-3","url":null,"abstract":"Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT. Korobkina et al. show that ACLY in brown fat prevents metabolic overload in the tricarboxylic acid cycle, thus ensuring adequate thermogenesis by avoiding cellular stress.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2187-2202"},"PeriodicalIF":18.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431686","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":"David H. Wasserman (1958–2024)","authors":"Julio E. Ayala, Owen P. McGuinness, Antentor Hinton Jr","doi":"10.1038/s42255-024-01151-3","DOIUrl":"10.1038/s42255-024-01151-3","url":null,"abstract":"We have lost a distinguished scientist who made indelible contributions to our knowledge of exercise physiology and diabetes and was an advocate for mentoring and transparency in research.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2025-2026"},"PeriodicalIF":18.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01151-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431685","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":"Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis","authors":"Sandeep Das, Alexandra C. Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H. Pearson-Gallion, M. Peyton McKinney, Koral S. E. Richard, Jose A. Gomez-Vidal, Chowdhury S. Abdullah, Elizabeth D. Cockerham, Joseph Eniafe, Andrew D. Yurochko, Tarek Magdy, Christopher B. Pattillo, Christopher G. Kevil, Babak Razani, Md. Shenuarin Bhuiyan, Erin H. Seeley, Gretchen E. Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T. Garcia-Barrio, Philip L. Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A. Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y. Eugene Chen, Nirav Dhanesha, Paul T. Thevenot, Ari J. Cohen, Arif Yurdagul Jr, Oren Rom","doi":"10.1038/s42255-024-01134-4","DOIUrl":"10.1038/s42255-024-01134-4","url":null,"abstract":"The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH. Genetic and pharmacological inhibition of the overproduction of oxalate in the liver alleviates metabolic dysfunction-associated steatohepatitis in male mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1939-1962"},"PeriodicalIF":18.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01134-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325570","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":"Causal drivers of human proteome variation in health and disease","authors":"Paul W. Franks, Daniel E. Coral","doi":"10.1038/s42255-024-01138-0","DOIUrl":"10.1038/s42255-024-01138-0","url":null,"abstract":"In this issue of Nature Metabolism, Carrasco-Zanini et al. describe sets of modifiable and non-modifiable drivers of human plasma proteins. These findings may inform the design of precision prevention programs and highlight novel therapeutic targets.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1854-1855"},"PeriodicalIF":18.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321822","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":"Identification and characterization of human GDF15 knockouts","authors":"Allan M. Gurtan, Shareef Khalid, Christopher Koch, Maleeha Zaman Khan, Lindsey B. Lamarche, Igor Splawski, Elizabeth Dolan, Ana M. Carrion, Richard Zessis, Matthew E. Clement, Zhiping Chen, Loren D. Lindsley, Yu-Hsin Chiu, Ryan S. Streeper, Daniel P. Denning, Allison B. Goldfine, Brian Doyon, Ali Abbasi, Jennifer L. Harrow, Kazuhisa Tsunoyama, Makoto Asaumi, Ikuyo Kou, Alan R. Shuldiner, Juan L. Rodriguez-Flores, Asif Rasheed, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Syed Shahzaib Raza, Riffat Sultana, Anjum Jalal, Muhammad Hamid Saeed, Shahid Abbas, Fazal Rehman Memon, Mohammad Ishaq, John E. Dominy, Danish Saleheen","doi":"10.1038/s42255-024-01135-3","DOIUrl":"10.1038/s42255-024-01135-3","url":null,"abstract":"Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss2, and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3–7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G3. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous (‘knockouts’) and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15. This study reports and characterizes the impact of loss-of-function GDF15 variants in human individuals.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1913-1921"},"PeriodicalIF":18.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321824","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}