{"doi":"10.1113/jp283378","title":"The vital role of arcuate nociceptin/orphanin FQ neurones in mounting an oestradiol‐dependent adaptive response to negative energy balance via inhibition of nearby proopiomelanocortin neurones","abstract":"Abstract We tested the hypothesis that N/OFQ neurones in the arcuate nucleus (N/OFQ ARC ) inhibit proopiomelanocortin (POMC ARC ) neurones in a diet‐ and hormone‐dependent manner to promote a more extensive rebound hyperphagia upon re‐feeding following an 18 h fast. We utilized intact male or ovariectomized (OVX) female mice subjected to ad libitum ‐feeding or fasting conditions. N/OFQ ARC 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 ad libitum ‐feeding conditions. Stimulation of N/OFQ ARC neurones more robustly inhibited POMC ARC neurones under fasting conditions compared to ad libitum ‐feeding conditions. N/OFQ ARC inhibition of POMC ARC neurones is hormone dependent as chemostimulation of N/OFQ ARC neurones from fasted males and OVX females produced a sizable outward current in POMC ARC neurones. Oestradiol (E 2 ) markedly attenuated the N/OFQ‐induced POMC ARC outward current. Additionally, N/OFQ tonically inhibits POMC ARC neurones to a greater degree under fasting conditions than in ad libitum ‐feeding conditions as evidenced by the abrogation of N/OFQ–nociceptin opioid peptide (NOP) receptor signalling and inhibition of N/OFQ release via chemoinhibition of N/OFQ ARC neurones. Intra‐arcuate nucleus application of N/OFQ further elevated the hyperphagic response and increased meal size during the 6 h re‐feed period, and these effects were mimicked by chemostimulation of N/OFQ ARC neurones in vivo . E 2 attenuated the robust N/OFQ‐induced rebound hyperphagia seen in vehicle‐treated OVX females. These data demonstrate that N/OFQ ARC 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 2 in females. image Key points Nociceptin/orphanin FQ (N/OFQ) promotes increased energy intake and decreased energy expenditure under conditions of positive energy balance in a sex‐ and hormone‐dependent manner. 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‐induced hyperexcitability of N/OFQ neurones. Additionally, N/OFQ promotes a sustained increase in rebound hyperphagia and increase in meal size during the re‐feed period following a fast. 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.","journal":"The Journal of Physiology","year":2022,"id":281716,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.962,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":702652,"name":"Nikki Le","orcid":null,"position":1,"is_corresponding":false},{"id":635165,"name":"Jennifer Hernandez","orcid":"0000-0001-8836-4455","position":2,"is_corresponding":false},{"id":957409,"name":"Veronica Mata‐Pacheco","orcid":null,"position":3,"is_corresponding":false},{"id":701610,"name":"Edward J. Wagner","orcid":"0000-0002-9630-5217","position":4,"is_corresponding":false},{"id":701609,"name":"Sarah Sayers","orcid":"0000-0002-6189-3303","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T00:29:11.698554Z","pmid":"36217719","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}