{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T22:12:02Z","timestamp":1783980722296,"version":"3.55.0"},"reference-count":57,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005277","name":"Presbyterian Historical Society","doi-asserted-by":"publisher","award":["DA024314"],"award-info":[{"award-number":["DA024314"]}],"id":[{"id":"10.13039\/100005277","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>We tested the hypothesis that N\/OFQ neurones in the arcuate nucleus (N\/OFQ<jats:sup>ARC<\/jats:sup>) inhibit proopiomelanocortin (POMC<jats:sup>ARC<\/jats:sup>) neurones in a diet\u2010 and hormone\u2010dependent manner to promote a more extensive rebound hyperphagia upon re\u2010feeding following an 18\u00a0h fast. We utilized intact male or ovariectomized (OVX) female mice subjected to <jats:italic>ad libitum<\/jats:italic>\u2010feeding or fasting conditions. N\/OFQ<jats:sup>ARC<\/jats:sup> neurones under negative energy balance conditions displayed heightened sensitivity as evidenced by a decreased rheobase threshold, increased firing frequency, and increased burst duration and frequency compared to <jats:italic>ad libitum<\/jats:italic>\u2010feeding conditions. Stimulation of N\/OFQ<jats:sup>ARC<\/jats:sup> neurones more robustly inhibited POMC<jats:sup>ARC<\/jats:sup> neurones under fasting conditions compared to <jats:italic>ad libitum<\/jats:italic>\u2010feeding conditions. N\/OFQ<jats:sup>ARC<\/jats:sup> inhibition of POMC<jats:sup>ARC<\/jats:sup> neurones is hormone dependent as chemostimulation of N\/OFQ<jats:sup>ARC<\/jats:sup> neurones from fasted males and OVX females produced a sizable outward current in POMC<jats:sup>ARC<\/jats:sup> neurones. Oestradiol (E<jats:sub>2<\/jats:sub>) markedly attenuated the N\/OFQ\u2010induced POMC<jats:sup>ARC<\/jats:sup> outward current. Additionally, N\/OFQ tonically inhibits POMC<jats:sup>ARC<\/jats:sup> neurones to a greater degree under fasting conditions than in <jats:italic>ad libitum<\/jats:italic>\u2010feeding conditions as evidenced by the abrogation of N\/OFQ\u2013nociceptin opioid peptide (NOP) receptor signalling and inhibition of N\/OFQ release via chemoinhibition of N\/OFQ<jats:sup>ARC<\/jats:sup> neurones. Intra\u2010arcuate nucleus application of N\/OFQ further elevated the hyperphagic response and increased meal size during the 6 h re\u2010feed period, and these effects were mimicked by chemostimulation of N\/OFQ<jats:sup>ARC<\/jats:sup> neurones <jats:italic>in vivo<\/jats:italic>. E<jats:sub>2<\/jats:sub> attenuated the robust N\/OFQ\u2010induced rebound hyperphagia seen in vehicle\u2010treated OVX females. These data demonstrate that N\/OFQ<jats:sup>ARC<\/jats:sup> neurones play a vital role in mitigating the impact of negative energy balance by inhibiting the excitability of anorexigenic neural substrates, an effect that is diminished by E<jats:sub>2<\/jats:sub> in females.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15303-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Nociceptin\/orphanin FQ (N\/OFQ) promotes increased energy intake and decreased energy expenditure under conditions of positive energy balance in a sex\u2010 and hormone\u2010dependent manner.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Here it is shown that under conditions of negative energy balance, i.e. fasting, N\/OFQ inhibits anorexigenic proopiomelanocortin (POMC) neurones to a greater degree compared to homeostatic conditions due to fasting\u2010induced hyperexcitability of N\/OFQ neurones.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Additionally, N\/OFQ promotes a sustained increase in rebound hyperphagia and increase in meal size during the re\u2010feed period following a fast.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results promote greater understanding of how energy balance influences the anorexigenic circuitry of the hypothalamus, and aid in understanding the neurophysiological pathways implicated in eating disorders promoting cachexia.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283378","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T06:55:50Z","timestamp":1665471350000},"page":"4939-4961","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The vital role of arcuate nociceptin\/orphanin FQ neurones in mounting an oestradiol\u2010dependent adaptive response to negative energy balance via inhibition of nearby proopiomelanocortin neurones"],"prefix":"10.1113","volume":"600","author":[{"given":"Sarah","family":"Sayers","sequence":"first","affiliation":[{"name":"Graduate College of Biomedical Sciences Western University of Health Sciences  Pomona CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki","family":"Le","sequence":"additional","affiliation":[{"name":"Graduate College of Biomedical Sciences Western University of Health Sciences  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