{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:20:33Z","timestamp":1790058033584,"version":"4.0.1"},"reference-count":42,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T00:00:00Z","timestamp":1721001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,15]]},"abstract":"<jats:p>\n                    The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (\n                    <jats:italic>\n                      Mc3r\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    ), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in\n                    <jats:italic>\n                      Mc3r\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.\n                  <\/jats:p>","DOI":"10.1172\/jci178250","type":"journal-article","created":{"date-parts":[[2024,7,14]],"date-time":"2024-07-14T14:00:36Z","timestamp":1720965636000},"source":"Crossref","is-referenced-by-count":12,"title":["Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice"],"prefix":"10.1172","volume":"134","author":[{"given":"Naima S.","family":"Dahir","sequence":"first","affiliation":[{"name":"Life Sciences Institute,"},{"name":"Department of Molecular and Integrative Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Gui","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"},{"name":"Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Wu","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"},{"name":"Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick R.","family":"Sweeney","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix A.J.","family":"Rouault","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"},{"name":"Department of Molecular and Integrative Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savannah Y.","family":"Williams","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis E.","family":"Gimenez","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomi K.","family":"Sawyer","sequence":"additional","affiliation":[{"name":"Courage Therapeutics, Newton, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen T.","family":"Joy","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna K.","family":"Mapp","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"},{"name":"Department of Chemistry, School of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger D.","family":"Cone","sequence":"additional","affiliation":[{"name":"Life Sciences Institute,"},{"name":"Department of Molecular and Integrative Physiology, and"},{"name":"Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,7,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81865-6"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04088-9"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/2407"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1210\/endo.141.9.7791"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/79254"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2003.tb03188.x"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1201994109"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-2049"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aat0866"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd6434"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/cne.25379"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/35078085"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113188"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.3224"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1021\/jm301253y"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2018.09.009"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206038"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-023-00811-0"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.09.010"},{"issue":"6_suppl","key":"B20","first-page":"8","article-title":"The pharmacokinetic properties of glucagon-like peptide-1 receptor agonists and their mode and mechanism of action in patients with type 2 diabetes","volume":"67","author":"Anderson","year":"2018","journal-title":"J Fam Prac"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ijo.2011.158"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60659-0"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2011.12.022"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15647"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2337\/ds19-0062"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.02.003"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-07-02939.2003"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2010.08.002"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201404508"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.07.008"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2015.00147"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnab025"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nn1455"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3193-18.2019"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4392"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03729-3"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2018.03.007"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18640"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1836-20.2020"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1172\/JCI157515"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62543"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.66173"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/178250\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T23:27:47Z","timestamp":1779233267000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/178250"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,15]]},"references-count":42,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7,15]]},"published-print":{"date-parts":[[2024,7,15]]}},"alternative-id":["10.1172\/JCI178250"],"URL":"https:\/\/doi.org\/10.1172\/jci178250","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,15]]},"article-number":"e178250"}}