Nociceptin/orphanin FQ modulates energy homeostasis through inhibition of neurotransmission at VMN SF-1/ARC POMC synapses in a sex- and diet-dependent manner

Abstract

BackgroundOrphanin 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.MethodsElectrophysiological 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.ResultsN/OFQ (1 μM) 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 μM). In ovariectomized female eGFP-POMC mice, 17β-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 μg/kg; s.c.).ConclusionThese 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.Electronic supplementary materialThe online version of this article (10.1186/s13293-019-0220-3) contains supplementary material, which is available to authorized users.

Extrahypothalamic GABAergic nociceptin–expressing neurons regulate AgRP neuron activity to control feeding behavior

“…The findings of an anorexigenic effect on activation of nociceptin-expressing neurons might seem at odds with the previous literature that describes an increase in feeding when pharmacological doses of nociceptin are delivered either intracerebroventricularly or into specific brain regions such as the arcuate nucleus (20, 28, 51). It has been suggested that this orexigenic effect occurs via inhibition of arcuate POMC and VMH neurons (26, 28, 29). However, injection of neuropeptides is unlikely to resemble the spatial and temporal pattern of physiological release but will instead likely induce long-lasting binding to nociceptin receptors throughout the arcuate nucleus, VMH, and other regions.…”

“…These data therefore suggested the possibility that nociceptin, released from aBNST neurons (that perhaps coexpress GABA), inhibits arcuate AgRP/NPY neurons to suppress feeding. However, nociceptin-expressing cells are also found in the ventromedial hypothalamus (VMH), and injection of nociceptin agonists to this brain region increases feeding (28, 29). Therefore, we next investigated whether VMH neurons, which may express and release endogenous nociceptin in the arcuate nucleus, directly synapse with arcuate NPY neurons.…”

Pituitary Adenylate Cyclase-Activating Polypeptide Excites Proopiomelanocortin Neurons: Implications for the Regulation of Energy Homeostasis

“…These data demonstrate that E 2 enhances excitatory neurotransmission at VMN PACAP/ARC POMC synapses via activation of G q -coupled mERs. We and others have shown previously that long-term exposure to HFD produces central insulin resistance that is sexually differentiated and associated with attenuated anorexigenic signaling within VMN SF-1/ARC POMC synapses [37][38][39]. We therefore wanted to examine whether a similar duration of HFD exposure could dampen anorexigenic transmission at VMN PACAP/ARC POMC synapses.…”

Role of nociceptin/orphanin FQ and nociceptin opioid peptide receptor in depression and antidepressant effects of nociceptin opioid peptide receptor antagonists

“…The role of GIRK for hyperpolarization effect of N/OFQ is further supported by findings that N/OFQ-induced outward potassium currents in the arcuate nucleus and ventromedial nucleus of the hypothalamus are suppressed by tertiapin [35] and SKH23390 [36], both of which are known as selective GIRK inhibitors. Outward K + currents through GIRK have been demonstrated in many brain areas including ventromedial nucleus of hypothalamic nucleus [36], arcuate nucleus [3738], perifornical and lateral areas of tuberal hypothalamus [39], hippocampal pyramidal neurons [33], lateral and central amygdala [34], thalamic reticular nucleus (NRT), and ventrobasal complex [40]. GIRK activation by N/OFQ in these brain areas hyperpolarizes neurons and thus inhibits neuronal excitability.…”