{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T05:55:40Z","timestamp":1768715740924,"version":"3.49.0"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T00:00:00Z","timestamp":1619568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-DK078184"],"award-info":[{"award-number":["R01-DK078184"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P41-EB-015908"],"award-info":[{"award-number":["P41-EB-015908"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["I-1804"],"award-info":[{"award-number":["I-1804"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012892","name":"National High Magnetic Field Laboratory","doi-asserted-by":"publisher","award":["P19414"],"award-info":[{"award-number":["P19414"]}],"id":[{"id":"10.13039\/100012892","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Ketogenesis occurs in liver mitochondria where acetyl-CoA molecules, derived from lipid oxidation, are condensed into acetoacetate (AcAc) and reduced to \u03b2-hydroxybutyrate (BHB). During carbohydrate scarcity, these two ketones are released into circulation at high rates and used as oxidative fuels in peripheral tissues. Despite their physiological relevance and emerging roles in a variety of diseases, endogenous ketone production is rarely measured in vivo using tracer approaches. Accurate determination of this flux requires a two-pool model, simultaneous BHB and AcAc tracers, and special consideration for the stability of the AcAc tracer and analyte. We describe the implementation of a two-pool model using a metabolic flux analysis (MFA) approach that simultaneously regresses liquid chromatography-tandem mass spectrometry (LC-MS\/MS) ketone isotopologues and tracer infusion rates. Additionally, 1H NMR real-time reaction monitoring was used to evaluate AcAc tracer and analyte stability during infusion and sample analysis, which were critical for accurate flux calculations. The approach quantifies AcAc and BHB pool sizes and their rates of appearance, disposal, and exchange. Regression analysis provides confidence intervals and detects potential errors in experimental data. Complications for the physiological interpretation of individual ketone fluxes are discussed.<\/jats:p>","DOI":"10.3390\/metabo11050279","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T22:29:07Z","timestamp":1619648947000},"page":"279","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["In Vivo Estimation of Ketogenesis Using Metabolic Flux Analysis\u2014Technical Aspects and Model Interpretation"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7714-2547","authenticated-orcid":false,"given":"Stanislaw","family":"Deja","sequence":"first","affiliation":[{"name":"Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5058-330X","authenticated-orcid":false,"given":"Blanka","family":"Kucejova","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8042-4206","authenticated-orcid":false,"given":"Xiaorong","family":"Fu","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey D.","family":"Browning","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0871-1494","authenticated-orcid":false,"given":"Jamey D.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA"},{"name":"Department of Molecular Physiology and Bio-physics, Vanderbilt University, Nashville, TN 37235, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shawn","family":"Burgess","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1152\/physrev.1980.60.1.143","article-title":"Physiological roles of ketone bodies as substrates and signals in mammalian tissues","volume":"60","author":"Robinson","year":"1980","journal-title":"Physiol. 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