{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T12:50:37Z","timestamp":1780059037672,"version":"3.54.0"},"reference-count":43,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["grants: 37392 and 37858"],"award-info":[{"award-number":["grants: 37392 and 37858"]}],"id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["DOL342964"],"award-info":[{"award-number":["DOL342964"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The endocannabinoidome (expanded endocannabinoid system, eCBome)-gut microbiome (mBIome) axis plays a fundamental role in the control of energy intake and processing. The liver-expressed antimicrobial peptide 2 (LEAP2) is a recently identified molecule acting as an antagonist of the ghrelin receptor and hence a potential effector of energy metabolism, also at the level of the gastrointestinal system. Here we investigated the role of the eCBome-gut mBIome axis in the control of the expression of LEAP2 in the liver and, particularly, the intestine. We confirm that the small intestine is a strong contributor to the circulating levels of LEAP2 in mice, and show that: (1) intestinal Leap2 expression is profoundly altered in the liver and small intestine of 13 week-old germ-free (GF) male mice, which also exhibit strong alterations in eCBome signaling; fecal microbiota transfer (FMT) from conventionally raised to GF mice completely restored normal Leap2 expression after 7 days from this procedure; in 13 week-old female GF mice no significant change was observed; (2) Leap2 expression in organoids prepared from the mouse duodenum is elevated by the endocannabinoid noladin ether, whereas in human Caco-2\/15 epithelial intestinal cells it is elevated by PPAR\u03b3 activation by rosiglitazone; (3) Leap2 expression is elevated in the ileum of mice with either high-fat diet\u2014or genetic leptin signaling deficiency\u2014(i.e., ob\/ob and db\/db mice) induced obesity. Based on these results, we propose that LEAP2 originating from the small intestine may represent a player in eCBome- and\/or gut mBIome-mediated effects on food intake and energy metabolism.<\/jats:p>","DOI":"10.3390\/molecules27010001","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T04:35:57Z","timestamp":1640061357000},"page":"1","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome"],"prefix":"10.3390","volume":"27","author":[{"given":"M\u00e9lissa","family":"Shen","sequence":"first","affiliation":[{"name":"Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Manca","sequence":"additional","affiliation":[{"name":"Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"},{"name":"Unit\u00e9 Mixte Internationale en Recherche Chimique et Biomol\u00e9culaire du Microbiome et son Impact sur la Sant\u00e9 M\u00e9tabolique et la Nutrition, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-5500","authenticated-orcid":false,"given":"Francesco","family":"Suriano","sequence":"additional","affiliation":[{"name":"Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Universit\u00e9 Catholique de Louvain, 1200 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayudu","family":"Nallabelli","sequence":"additional","affiliation":[{"name":"Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Pechereau","sequence":"additional","affiliation":[{"name":"Centre Nutrition, Sant\u00e9 et Soci\u00e9t\u00e9 (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), \u00c9cole de Nutrition (FSAA), Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9n\u00e9dicte","family":"Allam-Ndoul","sequence":"additional","affiliation":[{"name":"Centre Nutrition, Sant\u00e9 et Soci\u00e9t\u00e9 (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), \u00c9cole de Nutrition (FSAA), Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4480-8370","authenticated-orcid":false,"given":"Fabio Arturo","family":"Iannotti","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5944-7200","authenticated-orcid":false,"given":"Nicolas","family":"Flamand","sequence":"additional","affiliation":[{"name":"Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4078-1908","authenticated-orcid":false,"given":"Alain","family":"Veilleux","sequence":"additional","affiliation":[{"name":"Centre Nutrition, Sant\u00e9 et Soci\u00e9t\u00e9 (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), \u00c9cole de Nutrition (FSAA), Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2040-2448","authenticated-orcid":false,"given":"Patrice D.","family":"Cani","sequence":"additional","affiliation":[{"name":"Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Universit\u00e9 Catholique de Louvain, 1200 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5635-1545","authenticated-orcid":false,"given":"Cristoforo","family":"Silvestri","sequence":"additional","affiliation":[{"name":"Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"},{"name":"Centre Nutrition, Sant\u00e9 et Soci\u00e9t\u00e9 (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), \u00c9cole de Nutrition (FSAA), Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Di Marzo","sequence":"additional","affiliation":[{"name":"Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"},{"name":"Unit\u00e9 Mixte Internationale en Recherche Chimique et Biomol\u00e9culaire du Microbiome et son Impact sur la Sant\u00e9 M\u00e9tabolique et la Nutrition, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"},{"name":"Centre Nutrition, Sant\u00e9 et Soci\u00e9t\u00e9 (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), \u00c9cole de Nutrition (FSAA), Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"},{"name":"Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy"},{"name":"Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Universit\u00e9 Laval, Quebec City, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1110\/ps.0213603","article-title":"Isolation and biochemical characterization of LEAP-2, a novel blood peptide expressed in the liver","volume":"12","author":"Krause","year":"2003","journal-title":"Protein Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.cellimm.2009.11.010","article-title":"Expression and functional analyses of liver expressed antimicrobial peptide-2 (LEAP-2) variant forms in human tissues","volume":"261","author":"Howard","year":"2010","journal-title":"Cell. 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