{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:18:25Z","timestamp":1753877905545,"version":"3.41.2"},"reference-count":37,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000691","name":"Academy of Medical Sciences","doi-asserted-by":"publisher","award":["NIF\/R5A\/0017"],"award-info":[{"award-number":["NIF\/R5A\/0017"]}],"id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/18\/79\/34106"],"award-info":[{"award-number":["PG\/18\/79\/34106"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000361","name":"Diabetes UK","doi-asserted-by":"publisher","award":["19\/0006045"],"award-info":[{"award-number":["19\/0006045"]}],"id":[{"id":"10.13039\/501100000361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF23SA0084103"],"award-info":[{"award-number":["NNF23SA0084103"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>The benefit of salicylate in the treatment of diabetes has been recognized for over a century; however, challenging side effects have prevented widespread use. A better understanding of the relevant enzyme targets mediating its anti\u2010hyperglycaemic effect may lead to the development of novel therapies for diabetes. Here, we investigated the contribution of 5\u2032\u2010adenosine monophosphate (<jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content>)\u2010dependent inhibition of fructose\u20101,6\u2010bisphosphatase 1 (<jats:styled-content style=\"fixed-case\">FBP1<\/jats:styled-content>) to the anti\u2010hyperglycaemic action of salicylate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied <jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content>\u2010insensitive <jats:styled-content style=\"fixed-case\">FBP1 G27P<\/jats:styled-content> knockin (<jats:styled-content style=\"fixed-case\">KI<\/jats:styled-content>) mice through a variety of cellular approaches, including proteomics, Seahorse metabolic analysis, glucose production, and other assays, in addition to a detailed assessment of metabolic responses in\u00a0vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with wild\u2010type littermates, <jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content>\u2010insensitive <jats:styled-content style=\"fixed-case\">FBP1 KI<\/jats:styled-content> mice were resistant to the effects of the drug on body weight, glucose tolerance, pyruvate disposal, liver lipid content and hepatic glucose production. Compared with wild\u2010type, <jats:styled-content style=\"fixed-case\">KI<\/jats:styled-content> hepatocytes exhibited baseline differences in glycolytic, <jats:styled-content style=\"fixed-case\">TCA<\/jats:styled-content> cycle and fatty acid oxidation enzyme levels, potentially linking gluconeogenic dysregulation and its reversal to non\u2010carbohydrate fuel management.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, our data highlight a novel mechanism of action for the effects of salicylate on glycaemia and weight gain, which depends on AMP\u2010mediated allosteric inhibition of FBP1.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.70058","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T07:44:04Z","timestamp":1747899844000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Ancient Drug Salicylate Indirectly Targets Fructose\u20101,6\u2010Bisphosphatase to Suppress Liver Glucose Production in Diet\u2010Induced Obese Mice"],"prefix":"10.1111","volume":"241","author":[{"given":"Raid B.","family":"Nisr","sequence":"first","affiliation":[{"name":"Division of Diabetes, Endocrinology and Reproductive Biology, School of Medicine University of Dundee  Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdelmadjid","family":"Atrih","sequence":"additional","affiliation":[{"name":"Centre for Advanced Scientific Technologies, School of Life Sciences University of Dundee  Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika J. Gutierrez","family":"Lara","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Reproductive Biology, School of Medicine University of Dundee  Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas","family":"Lamont","sequence":"additional","affiliation":[{"name":"Centre for Advanced Scientific Technologies, School of Life Sciences University of Dundee  Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarzyna M.","family":"Luda","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rory J.","family":"McCrimmon","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Reproductive Biology, School of Medicine University of Dundee  Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9121-1350","authenticated-orcid":false,"given":"Graham","family":"Rena","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Reproductive Biology, School of Medicine University of Dundee  Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison D.","family":"McNeilly","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Reproductive Biology, School of Medicine University of Dundee  Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13340-014-0177-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21674"},{"volume-title":"The Salicylates","year":"1948","author":"Gross M.","key":"e_1_2_10_4_1"},{"key":"e_1_2_10_5_1","first-page":"337","article-title":"Zur Therapie Des Diabetes Mellitus, Insbesondere \u00dcber Die Anwendung Des Salicylsauren Natron Bei Demselben","volume":"13","author":"Ebstein W.","year":"1876","journal-title":"Berliner Klinische Wochenschrift"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.5053.1071"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.01911.x"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0214955"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1061620"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2016.04.015"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1215327"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0564"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0159-7"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3480607"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI40671"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308445"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02629084"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.05.021"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2022.101661"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101725"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2023.101750"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmccpl.2025.100285"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M113.037309"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00332.2001"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11559"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4791.964"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0931"},{"key":"e_1_2_10_28_1","article-title":"Supersaturated Solutions of Fat Stains in Dilute Isopropanol for Demonstration of Acute Fatty Degeneration Not Shown by Herxheimer's Technique","volume":"36","author":"Lillie R. 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