Agouti-Related Peptide and MC3/4 Receptor Agonists Both Inhibit Excitatory Hypothalamic Ventromedial Nucleus Neurons

Abstract

Anorexigenic melanocortins decrease food intake by activating MC3/MC4 receptors (MC3/4R); the prevailing view is that the orexigenic neuropeptide agouti-related peptide (AgRP) exerts the opposite action by acting as an antagonist at MC3/MC4 receptors. A total of 370 hypothalamic ventromedial nucleus (VMH) glutamatergic neurons was studied using whole-cell recording in hypothalamic slices from a novel mouse expressing green fluorescent protein (GFP) under control of the vesicular glutamate transporter 2 (vGluT2) promoter. Massive numbers of GFP-expressing VMH dendrites extended out of the core of the nucleus into the surrounding cell-poor shell. VMH dendrites received frequent appositions from AgRP-immunoreactive axons in the shell of the nucleus, but not the core, suggesting that AgRP may influence target VMH neurons. ␣-MSH, melanotan II (MTII), and selective MC3R or MC4R agonists were all inhibitory, reducing the spontaneous firing rate and hyperpolarizing vGluT2 neurons. The MC3/4R antagonist SHU9119 was excitatory. Unexpectedly, AgRP did not attenuate MTII actions on these neurons; instead, these two compounds showed an additive inhibitory effect. In the absence of synaptic activity, no hyperpolarization or change in input resistance was evoked by either MTII or AgRP, suggesting indirect actions. Consistent with this view, MTII increased the frequency of spontaneous and miniature IPSCs. In contrast, the mechanism of AgRP inhibition was dependent on presynaptic inhibition of EPSCs mediated by G i /G o -proteins, and was attenuated by pertussis toxin and NF023, inconsistent with mediation by G s -proteins associated with MC receptors. Together, our data suggest that the mechanism of AgRP actions on these excitatory VMH cells appears to be independent of the actions of melanocortins on MC receptors.

Neuropeptide Y Suppresses Anorexigenic Output from the Ventromedial Nucleus of the Hypothalamus

“…Although an action to suppress GABAergic input appears counterintuitive in this model, the basal frequency of GABAergic synaptic events in the VMN was approximately fourfold lower than that for glutamate. Thus, the effect of NPY on excitatory glutamatergic transmission would be expected to predominate; this is consistent with observations by others (Fu and van den Pol, 2008). Glutamatergic inputs to VMN neurons can arise from intra-VMN collateral connections (Canteras et al, 1994); hence any postsynaptic inhibitory actions of NPY on VMN neurons would be abetted by the suppression of collateral excitation.…”

“…There is a high density of agouti-related peptide (AgRP)/ NPY-immunoreactive axons in the VMN shell (Broberger et al, 1998;HaskellLuevano et al, 1999); VMN neurons can have long dendrites that extend out into the VMN shell to form synaptic contacts with NPY nerve terminals (Fu and van den Pol, 2008). However, the VMN core is not devoid of NPY projections (Broberger et al, 1998;Fetissov et al, 2003) and NPY released in the shell would also be expected to diffuse into the core to affect neuronal activity.…”

Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

“…Melanocortin-4 receptors are expressed both pre-and postsynaptically within the PVH (Cowley et al 1999;Kishi et al 2003;Liu et al 2003). Melanocortin agonists have been reported to act presynaptically to increase either inhibitory (IPSC) or excitatory postsynaptic current (EPSC) frequency (Cowley et al 1999;Fu and van den Pol 2008;Wan et al 2008). Thus it is possible that insulin activates POMC neurons to subsequently modulate glutamatergic neurotransmission within the PVH.…”

Melanocortin system in cancer-related cachexia

“…It has been proposed that AgRP acts as an inverse agonists of MC4R [55][56][57], however, although AgRP is a competitive inhibitor of α-MSH and homologous agonists, they do not share perfectly overlapping binding sites within the individual MC receptors, as the hAgRP(109-118) decapeptide results in antagonism at the MC3R while retaining MC1R agonist activity and MC4R antagonist activity [58]. In another study, AgRP did not have the opposite effect as MC3/4R agonists; also, the combined application of an inverse agonist together with the agonist is supposed to cancel the effect of the agonist, but in the experiments by Fu et al [59] AgRP and MC3/4…”