{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T19:37:02Z","timestamp":1772221022711,"version":"3.50.1"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Enteropeptidase (EP; enterokinase) is a serine protease that regulates intestinal protein digestion by converting trypsinogen into active trypsin, and thus initiates activation of the pancreatic zymogen cascade. Chronic inhibition of EP and trypsin (EP\/T) with camostat (Foipan, FOY-305) or its active metabolite (FOY-251) causes weight loss in obese mice by reducing intestinal protein absorption and suppression of food intake, however, the mechanisms leading to appetite suppression are not well understood. We tested the hypothesis that cholecystokinin (CCK) signaling mediates the anorectic effects of EP\/T inhibition using a CCK1R inhibitor (loxiglumide) or CCK1R knockout (KO) mice. Acute treatment with loxiglumide was able to partially reverse FOY-251-induced gallbladder contraction and delayed gastric emptying in mice. Chronic co-administration of loxiglumide reversed FOY-251 mediated effects on food intake and metabolism in diet-induced obese (DIO) mice. Chronic dosing of FOY-251 caused similar reductions in food intake but greater weight loss in CCK1R KO mice compared to wildtype (WT) mice, primarily due to fat mass loss. Pair fed (PF) groups revealed food intake-dependent and -independent mechanisms of weight loss by FOY-251. Notably, FOY-251 treatment induced sustained weight loss, whereas body weight loss rebounded in PF animals. In CCKR1 KO mice, FOY-251 caused greater weight loss, and increased protein calorie loss relative to that in WT mice, while having no effect on glycemic control or FGF21. Hence, CCK1R-dependent and -independent mechanisms modulate the metabolic effects of EP\/T inhibition and may play a role in maintaining weight loss by this mechanism.<\/jats:p>","DOI":"10.1371\/journal.pone.0312927","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T13:30:55Z","timestamp":1748957455000},"page":"e0312927","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Role of CCK1 receptor in metabolic benefits of intestinal enteropeptidase inhibition in mice"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4232-0197","authenticated-orcid":true,"given":"Kamal","family":"Albarazanji","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4464-1929","authenticated-orcid":true,"given":"Simon Amadeus","family":"Hinke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cassandre","family":"Cavanaugh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Beck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neetu","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raul C.","family":"Camacho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Leonard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1348-3999","authenticated-orcid":true,"given":"Andrea R.","family":"Nawrocki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"issue":"11","key":"pone.0312927.ref001","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1161\/CIRCRESAHA.115.306825","article-title":"Epidemiology of obesity and diabetes and their cardiovascular complications","volume":"118","author":"S Bhupathiraju","year":"2016","journal-title":"Circ Res"},{"issue":"10","key":"pone.0312927.ref002","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.tem.2020.06.002","article-title":"Role of Energy Excretion in Human Body Weight Regulation","volume":"31","author":"J Lund","year":"2020","journal-title":"Trends Endocrinol Metab"},{"issue":"3","key":"pone.0312927.ref003","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s40265-019-1057-0","article-title":"Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity","volume":"79","author":"MJ Pereira","year":"2019","journal-title":"Drugs"},{"issue":"11","key":"pone.0312927.ref004","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0049612","article-title":"Enteropeptidase: a gene associated with a starvation human phenotype and a novel target for obesity treatment","volume":"7","author":"S Braud","year":"2012","journal-title":"PLoS One"},{"issue":"12","key":"pone.0312927.ref005","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.4155\/fmc.10.263","article-title":"\u201cEnergy expenditure genes\u201d or \u201cenergy absorption genes\u201d: a new target for the treatment of obesity and Type II diabetes","volume":"2","author":"S Braud","year":"2010","journal-title":"Future Med Chem"},{"issue":"7599","key":"pone.0312927.ref006","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/S0140-6736(69)92071-6","article-title":"Intestinal enterokinase deficiency","volume":"1","author":"B Hadorn","year":"1969","journal-title":"Lancet"},{"issue":"2","key":"pone.0312927.ref007","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/0006-3002(56)90329-8","article-title":"The action of enterokinase on trypsinogen","volume":"20","author":"I YAMASHINA","year":"1956","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"pone.0312927.ref008","first-page":"242","article-title":"Enteropeptidase, a type II transmembrane serine protease","volume":"1","author":"XL Zheng","year":"2009","journal-title":"Front Biosci (Elite Ed)"},{"issue":"5","key":"pone.0312927.ref009","doi-asserted-by":"crossref","DOI":"10.1152\/ajpgi.00404.2018","article-title":"Intestinal serine protease inhibition increases FGF21 and improves metabolism in obese mice","volume":"316","author":"K Albarazanji","year":"2019","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"10","key":"pone.0312927.ref010","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1111\/dom.13799","article-title":"SCO-792, an enteropeptidase inhibitor, improves disease status of diabetes and obesity in mice","volume":"21","author":"H Yashiro","year":"2019","journal-title":"Diabetes Obes Metab"},{"issue":"7","key":"pone.0312927.ref011","doi-asserted-by":"crossref","first-page":"843","DOI":"10.3109\/00365528509088832","article-title":"Comparative study of the effects of equal amounts of fat, protein, and starch on plasma cholecystokinin in man","volume":"20","author":"WP Hopman","year":"1985","journal-title":"Scand J Gastroenterol"},{"key":"pone.0312927.ref012","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0014-2999(89)90528-1","article-title":"Evidence that decreased feeding induced by systemic injection of cholecystokinin is mediated by CCK-A receptors","volume":"173","author":"CT Dourish","year":"1989","journal-title":"Eur J Pharmacol"},{"issue":"4","key":"pone.0312927.ref013","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1136\/gut.35.4.501","article-title":"Effect of a low dose of intraduodenal fat on satiety in humans: studies using the type A cholecystokinin receptor antagonist loxiglumide","volume":"35","author":"RJ Lieverse","year":"1994","journal-title":"Gut"},{"key":"pone.0312927.ref014","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/B978-0-12-386933-3.00008-X","article-title":"The role of cholecystokinin receptors in the short-term control of food intake","volume":"114","author":"AI Sayegh","year":"2013","journal-title":"Prog Mol Biol Transl Sci"},{"key":"pone.0312927.ref015","article-title":"Gastric branch vagotomy blocks nutrient and cholecystokinin-induced suppression of gastric emptying","volume":"264","author":"GJ Schwartz","year":"1993","journal-title":"Am J Physiol"},{"issue":"4511","key":"pone.0312927.ref016","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1126\/science.7268408","article-title":"Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat","volume":"213","author":"GP Smith","year":"1981","journal-title":"Science"},{"key":"pone.0312927.ref017","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/j.1749-6632.1994.tb44068.x","article-title":"Effect of cholecystokinin on gastric motility in humans","volume":"713","author":"C Beglinger","year":"1994","journal-title":"Ann N Y Acad Sci"},{"issue":"3","key":"pone.0312927.ref018","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/eci.12400","article-title":"Endogenous elevation of plasma cholecystokinin does not prevent gallstones","volume":"45","author":"RA Shahid","year":"2015","journal-title":"Eur J Clin Invest"},{"issue":"5","key":"pone.0312927.ref019","doi-asserted-by":"crossref","first-page":"585","DOI":"10.2170\/jjphysiol.51.585","article-title":"Importance of CCK-A receptor for gallbladder contraction and pancreatic secretion: a study in CCK-A receptor knockout mice","volume":"51","author":"S Suzuki","year":"2001","journal-title":"Jpn J Physiol"},{"issue":"4","key":"pone.0312927.ref020","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/0031-9384(83)90071-9","article-title":"Trypsin inhibitor effects on food intake and weight gain in Zucker rats","volume":"31","author":"CL McLaughlin","year":"1983","journal-title":"Physiol Behav"},{"issue":"5","key":"pone.0312927.ref021","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1093\/jn\/118.5.645","article-title":"Effects of camostat, a synthetic protease inhibitor, on endocrine and exocrine pancreas of the rat","volume":"118","author":"MK M\u00fcller","year":"1988","journal-title":"J Nutr"},{"issue":"6","key":"pone.0312927.ref022","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1097\/00006676-198611000-00008","article-title":"Endogenous CCK release and pancreatic growth in rats after feeding a proteinase inhibitor (camostate)","volume":"1","author":"B G\u00f6ke","year":"1986","journal-title":"Pancreas"},{"issue":"1","key":"pone.0312927.ref023","first-page":"54","article-title":"Preventive and therapeutic effects of the protease inhibitor camostat on pancreatic fibrosis and atrophy in cck-1 receptor-deficient rats","volume":"30","author":"D Jia","year":"2005","journal-title":"Pancreas"},{"issue":"2","key":"pone.0312927.ref024","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1093\/jn\/133.2.352","article-title":"Soybean beta-conglycinin peptone suppresses food intake and gastric emptying by increasing plasma cholecystokinin levels in rats","volume":"133","author":"T Nishi","year":"2003","journal-title":"J Nutr"},{"issue":"12","key":"pone.0312927.ref025","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1016\/S0196-9781(00)00329-6","article-title":"Does increased endogenous CCK interact with serotonin to reduce food intake in rats?","volume":"21","author":"JP Voigt","year":"2000","journal-title":"Peptides"},{"issue":"7","key":"pone.0312927.ref026","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.slasd.2022.07.001","article-title":"Screening for positive allosteric modulators of cholecystokinin type 1 receptor potentially useful for management of obesity","volume":"27","author":"DG Dengler","year":"2022","journal-title":"SLAS Discov"},{"issue":"22","key":"pone.0312927.ref027","doi-asserted-by":"crossref","first-page":"6797","DOI":"10.1016\/j.bmcl.2010.08.115","article-title":"Discovery of N-benzyl-2-[(4S)-4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6-yl]-N-isopropylacetamide, an orally active, gut-selective CCK1 receptor agonist for the potential treatment of obesity","volume":"20","author":"R Elliott","year":"2010","journal-title":"Bioorg Med Chem Lett"},{"issue":"2","key":"pone.0312927.ref028","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/sj.clpt.6100272","article-title":"Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients","volume":"83","author":"J Jordan","year":"2008","journal-title":"Clin Pharmacol Ther"},{"issue":"9","key":"pone.0312927.ref029","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.tem.2016.04.002","article-title":"Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target","volume":"27","author":"LJ Miller","year":"2016","journal-title":"Trends Endocrinol Metab"},{"issue":"1","key":"pone.0312927.ref030","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3109\/00498259409043223","article-title":"Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration","volume":"24","author":"I Midgley","year":"1994","journal-title":"Xenobiotica"},{"key":"pone.0312927.ref031","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.clinbiochem.2021.07.007","article-title":"Determination of camostat and its metabolites in human plasma - Preservation of samples and quantification by a validated UHPLC-MS\/MS method","volume":"96","author":"LK S\u00f8rensen","year":"2021","journal-title":"Clin Biochem"},{"issue":"9","key":"pone.0312927.ref032","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.1210\/en.2005-0473","article-title":"Peripheral exendin-4 and peptide YY(3-36) synergistically reduce food intake through different mechanisms in mice","volume":"146","author":"T Talsania","year":"2005","journal-title":"Endocrinology"},{"issue":"4","key":"pone.0312927.ref033","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/hep.1840160414","article-title":"Effect of loxiglumide and atropine on erythromycin-induced reduction in gallbladder volume in human subjects","volume":"16","author":"MC Jebbink","year":"1992","journal-title":"Hepatology"},{"issue":"3","key":"pone.0312927.ref034","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1007\/BF02934496","article-title":"Effect of oral protease inhibitor administration on gallbladder motility in patients with mild chronic pancreatitis","volume":"32","author":"M Sugiyama","year":"1997","journal-title":"J Gastroenterol"},{"key":"pone.0312927.ref035","article-title":"Action of the cholecystokinin antagonist L364,718 on gastric emptying in the rat","volume":"255","author":"T Green","year":"1988","journal-title":"Am J Physiol"},{"issue":"3","key":"pone.0312927.ref036","doi-asserted-by":"crossref","DOI":"10.1152\/ajpregu.00490.2006","article-title":"Endogenous cholecystokinin reduces food intake and increases Fos-like immunoreactivity in the dorsal vagal complex but not in the myenteric plexus by CCK1 receptor in the adult rat","volume":"292","author":"CN Sullivan","year":"2007","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"5","key":"pone.0312927.ref037","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1053\/j.gastro.2010.01.044","article-title":"Cholecystokinin knockout mice are resistant to high-fat diet-induced obesity","volume":"138","author":"C-M Lo","year":"2010","journal-title":"Gastroenterology"},{"issue":"2","key":"pone.0312927.ref038","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.physbeh.2010.02.023","article-title":"Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin?","volume":"100","author":"JL Trevaskis","year":"2010","journal-title":"Physiol Behav"},{"key":"pone.0312927.ref039","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.appet.2018.05.131","article-title":"A GLP-1:CCK fusion peptide harnesses the synergistic effects on metabolism of CCK-1 and GLP-1 receptor agonism in mice","volume":"127","author":"DC Hornigold","year":"2018","journal-title":"Appetite"},{"issue":"6","key":"pone.0312927.ref040","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.coph.2007.09.011","article-title":"Progress in developing cholecystokinin (CCK)\/gastrin receptor ligands that have therapeutic potential","volume":"7","author":"MJ Berna","year":"2007","journal-title":"Curr Opin Pharmacol"},{"issue":"5","key":"pone.0312927.ref041","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.metabol.2004.12.005","article-title":"Synthetic protease inhibitor camostat prevents and reverses dyslipidemia, insulin secretory defects, and histological abnormalities of the pancreas in genetically obese and diabetic rats","volume":"54","author":"D Jia","year":"2005","journal-title":"Metabolism"},{"key":"pone.0312927.ref042","doi-asserted-by":"crossref","first-page":"105337","DOI":"10.1016\/j.phrs.2020.105337","article-title":"Enteropeptidase inhibition improves obesity by modulating gut microbiota composition and enterobacterial metabolites in diet-induced obese mice","volume":"163","author":"J Sugama","year":"2021","journal-title":"Pharmacol Res"},{"key":"pone.0312927.ref043","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000542758","article-title":"Effects of a protease inhibitor camostat mesilate on gut microbial function in patients with irritable bowel syndrome: a pilot randomized placebo-controlled study","author":"M Kanazawa","year":"2024","journal-title":"Digestion"},{"issue":"1","key":"pone.0312927.ref044","article-title":"Differential body weight and feeding responses to high-fat diets in rats and mice lacking cholecystokinin 1 receptors","volume":"293","author":"S Bi","year":"2007","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"1","key":"pone.0312927.ref045","doi-asserted-by":"crossref","DOI":"10.1152\/ajpendo.00601.2004","article-title":"Effect of murine strain on metabolic pathways of glucose production after brief or prolonged fasting","volume":"289","author":"S Burgess","year":"2005","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"4","key":"pone.0312927.ref046","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1210\/en.2018-00985","article-title":"Tamoxifen Improves Glucose Tolerance in a Delivery-, Sex-, and Strain-Dependent Manner in Mice","volume":"160","author":"AM Ceasrine","year":"2019","journal-title":"Endocrinology"},{"key":"pone.0312927.ref047","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/978-981-10-8684-7_3","article-title":"Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease","volume":"1061","author":"GC Farrell","year":"2018","journal-title":"Adv Exp Med Biol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0312927","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T13:31:06Z","timestamp":1748957466000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0312927"}},"subtitle":[],"editor":[{"given":"Cheorl-Ho","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,3]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0312927","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.10.17.618852","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,3]]}}}