Ontology highlight
ABSTRACT: Background
Orphanin FQ (aka nociceptin; N/OFQ) binds to its nociceptin opioid peptide (NOP) receptor expressed in proopiomelanocortin (POMC) neurons within the arcuate nucleus (ARC), a critical anorexigenic component of the hypothalamic energy balance circuitry. It inhibits POMC neurons by modifying neuronal excitability both pre- and postsynaptically. We tested the hypothesis that N/OFQ inhibits neurotransmission at synapses involving steroidogenic factor (SF)-1 neurons in the ventromedial nucleus (VMN) and ARC POMC neurons in a sex- and diet-dependent fashion.Methods
Electrophysiological recordings were done in intact male and in cycling and ovariectomized female NR5A1-Cre and eGFP-POMC mice. Energy homeostasis was assessed in wildtype animals following intra-ARC injections of N/OFQ or its saline vehicle.Results
N/OFQ (1??M) decreased light-evoked excitatory postsynaptic current (leEPSC) amplitude more so in males than in diestrus or proestrus females, which was further accentuated in high-fat diet (HFD)-fed males. N/OFQ elicited a more robust outward current and increase in conductance in males than in diestrus, proestrus, and estrus females. These pleiotropic actions of N/OFQ were abrogated by the NOP receptor antagonist BAN ORL-24 (10??M). In ovariectomized female eGFP-POMC mice, 17?-estradiol (E2; 100?nM) attenuated the N/OFQ-induced postsynaptic response. SF-1 neurons from NR5A1-Cre mice also displayed a robust N/OFQ-induced outward current and increase in conductance that was sexually differentiated and suppressed by E2. Finally, intra-ARC injections of N/OFQ increased energy intake and decreased energy expenditure, which was further potentiated by exposure to HFD and diminished by estradiol benzoate (20??g/kg; s.c.).Conclusion
These findings show that males are more responsive to the pleiotropic actions of N/OFQ at anorexigenic VMN SF-1/ARC POMC synapses, and this responsiveness can be further enhanced under conditions of diet-induced obesity/insulin resistance.
SUBMITTER: Hernandez J
PROVIDER: S-EPMC6373052 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Biology of sex differences 20190212 1
<h4>Background</h4>Orphanin FQ (aka nociceptin; N/OFQ) binds to its nociceptin opioid peptide (NOP) receptor expressed in proopiomelanocortin (POMC) neurons within the arcuate nucleus (ARC), a critical anorexigenic component of the hypothalamic energy balance circuitry. It inhibits POMC neurons by modifying neuronal excitability both pre- and postsynaptically. We tested the hypothesis that N/OFQ inhibits neurotransmission at synapses involving steroidogenic factor (SF)-1 neurons in the ventromed ...[more]