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: 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: see text] 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.