Neuropeptide Y-Mediated Inhibition of Proopiomelanocortin Neurons in the Arcuate Nucleus Shows Enhanced Desensitization in ob/ob Mice

Abstract

NPY and alphaMSH are expressed in distinct neurons in the arcuate nucleus of the hypothalamus, where alphaMSH decreases and NPY increases food intake and body weight. Here we use patch-clamp electrophysiology from GFP-labeled POMC and NPY neurons to demonstrate that NPY strongly hyperpolarized POMC neurons through the Y1R-mediated activation of GIRK channels, while the alphaMSH analog, MTII, had no effect on activity of NPY neurons. While initially NPY had similar effects on POMC neurons derived from ob/ob mice, further studies revealed a significant increase in desensitization of the NPY-induced currents in POMC neurons from ob/ob mice. This increase in desensitization was specific to NPY, as GABA(B) and microOR agonists showed unaltered desensitization in POMC neurons from ob/ob mice. These data reveal an intricate and asymmetric interplay between NPY and POMC neurons in the hypothalamus and have important implications for the delineation of the neural circuits that regulate feeding behavior.

Mechanisms of Neuropeptide Y, Peptide YY, and Pancreatic Polypeptide Inhibition of Identified Green Fluorescent Protein-Expressing GABA Neurons in the Hypothalamic Neuroendocrine Arcuate Nucleus

“…Previous studies have suggested that postsynaptic NPY actions may be attributable to Y 1 receptor activation (Rhim et al, 1997;Sun et al, 2001b;Sun et al, 2003;Fu et al, 2004;Roseberry et al, 2004). Our results were consistent with this.…”

“…5A, trace 1 (Doods et al, 1996;Sun et al, 2003) (Doods et al, 1999), did not block the hyperpolarization induced by 100 nM [Pro 34 ]NPY 1-36 (n ϭ 6) (Fig. 5C In other hypothalamic neurons, postsynaptic NPY actions have been shown to depend mainly on the activation of Y 1 receptor (Rhim et al, 1997;Fu et al, 2004;Roseberry et al, 2004). In hypothalamic slices incubated with 1 M BIBP3226, NPY still hyperpolarized ARC GABA neurons by 5.2 Ϯ 1.4 mV (n ϭ 5; p Ͻ 0.05) (data not shown), suggesting that another NPY receptor, in addition to Y 1 , is involved in the postsynaptic actions of this peptide.…”

“…3) showed that inhibitory NPY actions in GAD67 neurons involved a decrease in whole-cell input resistance consistent with channel opening. If these inhibitory effects were mediated by the activation of NPYsensitive inwardly rectifying potassium channels (Sun et al, 2001a;Fu et al, 2004;Roseberry et al, 2004), a suppression of its actions in the presence of external barium would be expected (Sodickson and Bean, 1996). To evaluate this, we performed experiments in the presence of 0.8 mM barium in the external solution and found that NPY (1 M) had little hyperpolarizing effect under these conditions (change in the membrane potential, 1.22 Ϯ 0.66 mV; n ϭ 6; p Ͼ 0.05).…”

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

“…These numbers were nonetheless within the range of that recently shown to be sufficient to stimulate food intake (∼300 neurons and above) (39). By contrast, labeling of POMC neurons was more surprising given that ghrelin is generally acknowledged to indirectly target this population via GHS-R-1a-expressing presynaptic NPY neurons (25,40). Together with ex vivo studies demonstrating direct effects of ghrelin on POMC neuron electrical activity (25), our results clearly suggest that POMC neurons may be a direct target for ghrelin in vivo.…”

Common neuropeptide Y2 receptor gene variant is protective against obesity among Swedish men

“…25 It is expressed mainly in orexigenic NPY/AGRP neurons 15 which, in direct synaptic contact with anorectic POMC/CART neurons in the arcuate nucleus, 30 integrates gut hormone signals such as PYY . 31,32 Hence, Y2R mediates negative regulation of NPY signaling, and indirectly upregulation of POMC/CART, through PYY and NPY. 7 Peripheral administration of PYY in rodents reduces NPY mRNA levels and increases the POMC mRNA levels in the arcuate nucleus, as well as reduces food intake, but has no effect in fasted Y2R knockout mice.…”