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.

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. 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.