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It hydrolyzes carboxylester, thioester, and amide bonds in many exogenous and endogenous compounds, including lipids. CES2 therefore not only plays an important role in the metabolism of many (pro-)drugs, toxins and pesticides, directly influencing pharmacology and toxicology in humans, but it is also involved in energy homeostasis, affecting lipid and glucose metabolism. In this study we investigated the pharmacological and physiological functions of CES2. We constructed <jats:italic>Ces2<\/jats:italic> cluster knockout mice lacking all eight <jats:italic>Ces2<\/jats:italic> genes (<jats:italic>Ces2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2013\/\u2013<\/jats:italic>\n            <\/jats:sup> strain) as well as humanized hepatic or intestinal CES2 transgenic strains in this <jats:italic>Ces2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2013\/\u2013<\/jats:italic>\n            <\/jats:sup> background. We showed that oral availability and tissue disposition of capecitabine were drastically increased in <jats:italic>Ces2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2013\/\u2013<\/jats:italic>\n            <\/jats:sup> mice, and tissue-specifically decreased by intestinal and hepatic human CES2 (hCES2) activity. The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in <jats:italic>Ces2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2013\/\u2013<\/jats:italic>\n            <\/jats:sup> mice, but only marginally rescued by hCES2 expression. On the other hand, <jats:italic>Ces2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2013\/\u2013<\/jats:italic>\n            <\/jats:sup> mice exhibited fatty liver, adipositis, hypercholesterolemia and diminished glucose tolerance and insulin sensitivity, but without body mass changes. Paradoxically, hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size, adipose tissue mass and overall body weight, suggesting a \u201chealthy\u201d obesity phenotype. In contrast, intestinal hCES2 expression efficiently rescued all phenotypes, and even improved some parameters, including body weight, relative to the wild-type baseline values. Our results suggest that the induction of intestinal hCES2 may combat most, if not all, of the adverse effects of metabolic syndrome. These CES2 mouse models will provide powerful preclinical tools to enhance drug development, increase physiological insights, and explore potential solutions for metabolic syndrome-associated disorders.<\/jats:p>","DOI":"10.1038\/s41401-024-01407-4","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T11:04:28Z","timestamp":1730718268000},"page":"777-793","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice"],"prefix":"10.1038","volume":"46","author":[{"given":"Yao-geng","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-pei","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joke","family":"Beukers-Korver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Rosing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-long","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Els","family":"Wagenaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Lebre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-ying","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Pritchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahmen","family":"Bin Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Huijbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos H.","family":"Beijnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred H.","family":"Schinkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,4]]},"reference":[{"key":"1407_CR1","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.apsb.2018.05.005","volume":"8","author":"D Wang","year":"2018","unstructured":"Wang D, Zou L, Jin Q, Hou J, Ge G, Yang L. 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