{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:36:40Z","timestamp":1785404200627,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,26]]},"group-title":"Animal Behavior and Cognition","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 MH132504"],"award-info":[{"award-number":["R01 MH132504"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R00 DA049862"],"award-info":[{"award-number":["R00 DA049862"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["P30 DK020579"],"award-info":[{"award-number":["P30 DK020579"]}]},{"name":"McDonnell Center for Systems Neuroscience","award":["GF0010881"],"award-info":[{"award-number":["GF0010881"]}]},{"name":"McDonnell Center for Cellular and Molecular Neurobiology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,26]]},"abstract":"Abstract<\/jats:title>\n \n The mu opioid receptor system has long been recognized for its role in regulating ingestive behaviors and food palatability. However, beyond their robust expression in the brain, opioid receptors are also found throughout the body, including the stomach, intestines, and pancreas. Previous studies suggest that opioids may directly regulate glycemia through actions in the endocrine pancreas, but whether these metabolic effects are linked to their influence on ingestive behavior remains unclear. Here, we used metabolic, ingestive, and genetic approaches to determine how the mu opioid receptor (MOPR) regulates in vivo phenotypes via its actions in endocrine pancreas. Glucose and insulin tolerance tests in male\n Oprm1<\/jats:italic>\n KO mice had enhanced glucose tolerance and insulin sensitivity. Conditional deletion of MOPRs in alpha cells had no effect. To test if loss of MOPRs influence overt ingestive behaviors, we measured 24-hour ad libitum food consumption using Feeding Experimental Devices (FEDs) in wild type,\n Oprm1<\/jats:italic>\n knockout (MOPR-deficient) and\n GCG<\/jats:italic>\n -Cre x\n Oprm1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n mice (10-12 weeks old). We found that\n Oprm1<\/jats:italic>\n KO male, but not female, mice exhibited increased mass and food intake, and dysregulated ingestive microstructures relative to wild type controls. Conditional deletion of MOPRs in alpha cells only recapitulated some of the phenotypes related to ingestive microstructure. These findings suggest that MOPR regulation of ingestive behaviors extends beyond typical neural circuits of reward to include peripheral metabolic organ mechanisms.\n <\/jats:p>\n \n Highlights<\/jats:title>\n \n \n -<\/jats:label>\n \n Male\n Oprm1<\/jats:italic>\n knockout mice show increased body mass and food intake\n <\/jats:p>\n <\/jats:list-item>\n \n -<\/jats:label>\n \n Male, but not female,\n Oprm1<\/jats:italic>\n knockout mice have enhanced glucose tolerance and insulin sensitivity\n <\/jats:p>\n <\/jats:list-item>\n \n -<\/jats:label>\n MOPR deletion in pancreatic alpha cells did not alter glucose metabolism<\/jats:p>\n <\/jats:list-item>\n \n -<\/jats:label>\n MOPR deletion in alpha cells increased meal frequency but reduced meal size in males<\/jats:p>\n <\/jats:list-item>\n \n -<\/jats:label>\n MOPR deletion in alpha cells only reduced meal size in females<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>","DOI":"10.64898\/2026.05.21.726374","type":"posted-content","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T17:30:17Z","timestamp":1779816617000},"source":"Crossref","is-referenced-by-count":0,"title":["Pancreatic mu opioid receptors regulate metabolism and ingestive behaviors"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6775-5238","authenticated-orcid":false,"given":"Diego A.","family":"De Gregorio","sequence":"first","affiliation":[{"name":"Biophotonics Research Center, Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, Missouri, 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8036-1313","authenticated-orcid":false,"given":"Daniel C.","family":"Castro","sequence":"additional","affiliation":[{"name":"Biophotonics Research Center, Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, Missouri, 63110"},{"name":"Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri, 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.21.726374","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T11:20:19Z","timestamp":1779967219000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.21.726374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.05.21.726374","relation":{},"subject":[],"published":{"date-parts":[[2026,5,26]]},"subtype":"preprint"}}