{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T11:13:20Z","timestamp":1780658000680,"version":"3.54.1"},"reference-count":58,"publisher":"American Society for Clinical Investigation","issue":"12","license":[{"start":{"date-parts":[[2019,6,20]],"date-time":"2019-06-20T00:00:00Z","timestamp":1560988800000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Council","award":["MR\/P011705\/1"],"award-info":[{"award-number":["MR\/P011705\/1"]}]},{"name":"Medical Research Council","award":["MC_UP_A090_1006"],"award-info":[{"award-number":["MC_UP_A090_1006"]}]},{"name":"Medical Research Council","award":["MR\/P01836X\/1"],"award-info":[{"award-number":["MR\/P01836X\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,6,20]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Dietary changes have led to the growing prevalence of type 2 diabetes and nonalcoholic fatty liver disease. A hallmark of both disorders is hepatic lipid accumulation, derived in part from increased de novo lipogenesis. Despite the popularity of high-protein diets for weight loss, the effect of dietary protein on de novo lipogenesis is poorly studied. We aimed to characterize the effect of dietary protein on de novo lipid synthesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We use a 3-way crossover interventional study in healthy males to determine the effect of high-protein feeding on de novo lipogenesis, combined with in vitro models to determine the lipogenic effects of specific amino acids. The primary outcome was a change in de novo lipogenesis\u2013associated triglycerides in response to protein feeding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      We demonstrate that high-protein feeding, rich in glutamate, increases de novo lipogenesis\u2013associated triglycerides in plasma (1.5-fold compared with control;\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.0001) and liver-derived very low-density lipoprotein particles (1.8-fold;\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.0001) in samples from human subjects (\n                      <jats:italic>n<\/jats:italic>\n                      = 9 per group). In hepatocytes, we show that glutamate-derived carbon is incorporated into triglycerides via palmitate. In addition, supplementation with glutamate, glutamine, and leucine, but not lysine, increased triglyceride synthesis and decreased glucose uptake. Glutamate, glutamine, and leucine increased activation of protein kinase B, suggesting that induction of de novo lipogenesis occurs via the insulin signaling cascade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>These findings provide mechanistic insight into how select amino acids induce de novo lipogenesis and insulin resistance, suggesting that high-protein feeding to tackle diabetes and obesity requires greater consideration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>The research was supported by UK Medical Research Council grants MR\/P011705\/1, MC_UP_A090_1006 and MR\/P01836X\/1. JLG is supported by the Imperial Biomedical Research Centre, National Institute for Health Research (NIHR).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.124819","type":"journal-article","created":{"date-parts":[[2019,5,30]],"date-time":"2019-05-30T12:01:31Z","timestamp":1559217691000},"source":"Crossref","is-referenced-by-count":49,"title":["A randomized 3-way crossover study indicates that high-protein feeding induces de novo lipogenesis in healthy humans"],"prefix":"10.1172","volume":"4","author":[{"given":"Evelina","family":"Charidemou","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Ashmore","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8765-2033","authenticated-orcid":true,"given":"Xuefei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben D.","family":"McNally","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"West","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke\u2019s Hospital, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1802-357X","authenticated-orcid":true,"given":"Sonia","family":"Liggi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Harvey","sequence":"additional","affiliation":[{"name":"Medical Research Council \u2014 Elsie Widdowson Laboratory, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Orford","sequence":"additional","affiliation":[{"name":"Medical Research Council \u2014 Elsie Widdowson Laboratory, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1336-7744","authenticated-orcid":true,"given":"Julian L.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom."},{"name":"Computational and Systems Medicine, Surgery and Cancer, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1210\/jc.2008-1595","article-title":"Obesity and the metabolic syndrome in developing countries","volume":"93","author":"Misra","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/84.2.289"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v4.i7.209"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23621"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/77.1.43"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/73.2.253"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81993"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.04.022"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-018-1439-8"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/81.1.35"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118645"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1355"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2014.03.006"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0145850"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0706517104"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047303"},{"key":"B17","article-title":"Sex-specific differences in lipid and glucose metabolism","volume":"5","author":"Varlamov","year":"2014","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.5812\/ijem.4783"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.002500"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44442"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/87.4.817"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1021\/bi00516a008"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1968.tb00376.x"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204681200"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.06.002"},{"issue":"41","key":"B26","doi-asserted-by":"crossref","first-page":"38052","DOI":"10.1074\/jbc.M106703200","article-title":"Amino acid and insulin signaling via the mTOR\/p70 S6 kinase pathway: a negative feedback mechanism leading to insulin resistance in skeletal muscle cells","volume":"276","author":"Tremblay","year":"2001","journal-title":"J Biol Chem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1177\/1535370216633312"},{"issue":"5","key":"B28","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.bbadis.2013.02.003","article-title":"Prevention and reversal of hepatic steatosis with a high-protein diet in mice","volume":"1832","author":"Garcia-Caraballo","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/nu8090571"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2015.93"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1039\/b816965a"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22887"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.06.034"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.166991"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.2.1092"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.111138698"},{"issue":"3","key":"B37","doi-asserted-by":"crossref","first-page":"393","DOI":"10.2337\/diab.46.3.393","article-title":"Long-chain fatty acids inhibit acetyl-CoA carboxylase gene expression in the pancreatic \u03b2-cell line INS-1","volume":"46","author":"Brun","year":"1997","journal-title":"Diabetes"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181393"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0b013e32832b3f4c"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2011.328"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32914"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1172\/JCI19992"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.07.116"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2015.1123355"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80595-4"},{"key":"B46","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.2337\/diabetes.52.5.1073","article-title":"Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38","volume":"52","author":"Au","year":"2003","journal-title":"Diabetes"},{"issue":"1","key":"B47","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissue","volume":"226","author":"Folch","year":"1957","journal-title":"J Biol Chem"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1021\/ac103093w"},{"key":"B49","doi-asserted-by":"crossref","first-page":"13.24.1","DOI":"10.1002\/0471250953.bi1324s46","article-title":"Employing ProteoWizard to convert raw mass spectrometry data","volume":"46","author":"Holman","year":"2014","journal-title":"Curr Protoc Bioinformatics"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btn323"},{"key":"B51","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing. 2017. http:\/\/www.r-project.org\/ Accessed May 14, 2019"},{"key":"B52","doi-asserted-by":"crossref","DOI":"10.1186\/s12859-015-0562-8","article-title":"IPO: a tool for automated optimization of XCMS parameters","volume":"16","author":"Libiseller","year":"2015","journal-title":"BMC Bioinformatics"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1021\/ac051437y"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1021\/ac202450g"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-018-1349-5"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2011.335"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-4-23"},{"key":"B58","unstructured":"Warnes GR, et al. gplots: Various R Programming Tools for Plotting Data. R package Version 3.0.1. https:\/\/rdrr.io\/cran\/gplots\/ 2016. Accessed May 14, 2019"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/124819\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:28:02Z","timestamp":1779193682000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/124819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,30]]},"references-count":58,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,6,20]]},"published-print":{"date-parts":[[2019,6,20]]}},"alternative-id":["10.1172\/jci.insight.124819"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.124819","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,30]]},"article-number":"e124819"}}