{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T18:14:06Z","timestamp":1784052846331,"version":"3.55.0"},"reference-count":72,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"946","funder":[{"name":"NIH","award":["NIH R01DK-129919"],"award-info":[{"award-number":["NIH R01DK-129919"]}]},{"name":"NIH","award":["NIH R01DK-120309"],"award-info":[{"award-number":["NIH R01DK-120309"]}]},{"name":"NIH","award":["NIH R01ES030197"],"award-info":[{"award-number":["NIH R01ES030197"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2026,7,14]]},"abstract":"<jats:p>Triglycerides can be formed by fatty acid esterification of glycerol 3-phosphate (G3P) and by de novo lipogenesis (DNL). We identified G3P as a stimulus that activated mTORC1, a nutrient-sensing protein complex that promotes DNL in the liver. We found that the major source of G3P in primary mouse hepatocytes was glycerol kinase (GK), which generates G3P from glycerol. Mice with a liver-specific GK deficiency showed reductions not only in hepatic triglyceride production and storage but also in mTORC1-dependent DNL. Sequentially blocking hepatic pathways for G3P metabolism and analysis of hepatocytes and mice deficient in glycerol phosphate dehydrogenases, alternative enzymatic sources for G3P, showed that mTORC1 activation positively correlated with G3P amounts and was not mediated by a G3P precursor or other glycerol metabolites. G3P generated by wild-type GK in glycerol-treated cells induced mTORC1 activation through GATOR2, a complex that also activates mTORC1 in response to amino acids. In contrast, GK with inactivating mutations found in GK deficiency did not induce activation of mTORC1 in response to glycerol. These results show that by coordinating the production of substrates needed for esterification, G3P stimulates hepatic DNL through mTORC1 activation. In obesity, higher glycerol levels and enhanced GK-mediated metabolism drive hepatic TG accumulation, contributing to metabolic dysfunction\u2013associated fatty liver disease.<\/jats:p>","DOI":"10.1126\/scisignal.aeb7989","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T17:58:16Z","timestamp":1784051896000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Glycerol 3-phosphate activates lipid metabolism through GATOR2-dependent regulation of mTORC1"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5670-0406","authenticated-orcid":true,"given":"Hyokjoon","family":"Kwon","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingqiong","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0098-1560","authenticated-orcid":true,"given":"Mijung","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8152-5367","authenticated-orcid":true,"given":"Huiting","family":"Xu","sequence":"additional","affiliation":[{"name":"AskPharma, Princeton, NJ 08540, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Chi","sequence":"additional","affiliation":[{"name":"College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8391-8583","authenticated-orcid":true,"given":"Sally","family":"Radovick","sequence":"additional","affiliation":[{"name":"Clinical and Translational Research Institute, University of Arizona Health Sciences, Tucson, AZ 85704, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7598-5022","authenticated-orcid":true,"given":"Haiwei","family":"Gu","sequence":"additional","affiliation":[{"name":"College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7038-5848","authenticated-orcid":true,"given":"Ling","family":"He","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0595-421X","authenticated-orcid":true,"given":"Fredric E.","family":"Wondisford","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01301-6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00003-1"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0b013e328337b0c4"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20210071"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2017.91"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.12.009"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77812"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2018.10.016"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc20-1644"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1423952112"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23621"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI134165"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.11.049"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0199-y"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90570-3"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-019-0038-7"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.04.013"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.03.015"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.07.007"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.01.024"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.11.049"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0250-5"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg6621"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.046"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899548"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00732-4"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1066015"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.03.028"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2023.01.004"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2018.tb00008.x"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0609140103"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.8.1317"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.46.070177.004001"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm780"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.12.067"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-024-01222-1"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.11.005"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102708"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.011033"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.11.1803"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.10.004"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.043"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.12.017"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.034397"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf8271"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.287953.116"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.06.055"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1157535"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2004.06.007"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2005.12.074"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)83796-6"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.315180"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.12.019"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1514375113"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202401311"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004390100545"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi8009407"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8430315"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.013"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.12.011"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0800"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1682-x"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0166"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201800945RR"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(77)91437-1"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232044"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004112"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.09.017"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.7b00396"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.9b03107"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108572"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.aeb7989","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T17:58:19Z","timestamp":1784051899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.aeb7989"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":72,"journal-issue":{"issue":"946","published-print":{"date-parts":[[2026,7,14]]}},"alternative-id":["10.1126\/scisignal.aeb7989"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.aeb7989","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]},"assertion":[{"value":"2025-08-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-05","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeb7989"}}