Neuropeptide Y Stimulates Feeding but Inhibits Sexual Behavior in Rats*

The effects of neuropeptide Y (NPY), a tyrosine-rich peptide found in the rat brain, on feeding and sexual behavior were studied in male and female rats. Intraventricular (ivt) injections of NPY during the final hours of the light period induced feeding in a dose-related manner. While the lowest dose tested (0.02 nM) was without effect, higher doses (0.12, 0.47, 2.3 nM) uniformly elicited feeding with a latency of about 15 min in male rats. With the most effective dose, 0.47 nM, the increased food intake was due to an increased local eating rate. In contrast, the pattern of feeding behavior after a related peptide, rat pancreatic polypeptide (rPP), was quite different and less impressive. During the first hour, only one ivt dose of rPP (0.45 nM) evoked an increase in food intake, due to an increased time spent eating. Further, the effects of NPY on food intake were greater during the nocturnal period. Interestingly, increased food intake in nocturnal tests (4 h) was due solely to augmented intake during the first 60 min after ivt administration. In mating tests, initiated 2 h after the onset of darkness and 10 min after ivt administration of peptide, all but the lowest dose of NPY (0.01 nM) drastically suppressed ejaculatory behavior. Most rats treated with higher doses of NPY (0.02, 0.12, or 0.47 nM) mounted and intromitted only a few times before the cessation of sexual activity, and elongated latencies to the initial mount and intromission were observed. In contrast to the dramatic NPY-induced suppression of ejaculatory behavior, rPP (0.11 and 0.45 nM) was without effect on copulatory behavior. To substantiate further that the impairment of sexual behavior seen in NPY-treated rats was not due to an attenuated sexual ability, an additional experiment was performed. Penile reflexes, including erection, were monitored 10 min after ivt injection of NPY (0.12 nM), rPP (0.11 nM), or saline. No effect of NPY or rPP was observed on the proportion of rats showing erection or latency to initial erection, or in the number of erections per test. In fact, a slight facilitation of penile dorsiflexion responses was seen after NPY. These findings suggest that NPY selectively depresses sexual motivation in the male rat. In ovariectomized female rats responding to estrogen plus progesterone with a good level of sexual receptivity (lordosis quotient > 70), ivt saline and 0.01 nM NPY were without effect on sexual behavior. However, higher doses of NPY (0.12 and 0.47 nM) promptly suppressed sexual behavior in tests initiated 10 min after treatment. A significant 50% decrement in receptivity and a virtual elimination of proceptive behavior were observed. Further, although a low level of mounting (one to five mounts in 15 min) was seen in both the saline (33% mounting) and the 0.01 nM NPY (38% mounting) treated groups, none was observed in animals treated with the higher NPY doses. These observations indicate that NPY may also suppress female sexual behavior.     

Bimodal effect of neuropeptide Y on feeding, and its antagonism by receptor blocking agents in rats.

Satiated rats received intracerebroventricular (icv.) injections of several doses of neuropeptide Y (NPY) and the food intake was measured in the following 4 h. The peptide exerted a dose-dependent biphasic effect; the 100 dose significantly suppressed the food intake, but doses of 1 microgram and 5 micrograms stimulated feeding. After the injection of 2 microliters NPY-antiserum (icv., 1:50 dilution), the cumulative food intake decreased significantly in the first 24 h. From the drugs tested the alpha-1-antagonist prazosine (4 micrograms icv.) and the opiate antagonist naloxone (NX, 0.5 micrograms, icv.) selectively inhibited the feeding-stimulatory effect a high icv. dose of NPY. The alpha-2-antagonist yohimbine (4 micrograms icv.) and the non-selective beta-antagonist propranolol (5 micrograms icv.) did not influence either effect of NPY on feeding. The results suggest the involvement of alpha-1-adrenergic and opiate receptors in the food intake-stimulatory effect of a large icv. dose of NPY. The food intake-inhibitory effect of a low icv. peptide dose was not selectively antagonized by the receptor blocking agents used.     

Regulation of food intake by neuropeptide Y in goldfish

In mammals, neuropeptide Y (NPY) is a potent orexigenic factor. In the present study, third brain ventricle (intracerebroventricular) injection of goldfish NPY (gNPY) caused a dose-dependent increase in food intake in goldfish, and intracerebroventricular administration of NPY Y1-receptor antagonist BIBP-3226 decreased food intake; the actions of gNPY were blocked by simultaneous injection of BIBP-3226. Goldfish maintained on a daily scheduled feeding regimen display an increase in NPY mRNA levels in the telencephalon-preoptic area and hypothalamus shortly before feeding; however, a decrease occured in optic tectum-thalamus. In both fed and unfed fish, brain NPY mRNA levels decreased after scheduled feeding. Restriction in daily food ration intake for 1 wk or food deprivation for 72 h resulted in increased brain NPY mRNA levels. Results from these studies demonstrate that NPY is a physiological brain signal involved in feeding behavior in goldfish, mediating its effects, at least in part, through Y1-like receptors in the brain.     

Attenuated feeding responses to circadian and palatability cues in mice lacking neuropeptide Y

Neuropeptide Y (NPY) is a potent orexigenic peptide that is implicated in the feeding response to a variety of stimuli. The current studies employed mice lacking NPY (Npy−/−) and their wild-type (Npy+/+) littermates to investigate the role of this peptide in the feeding response to circadian and palatability cues. To investigate the response to a circadian stimulus, we assessed food intake during the 4-h period following dark onset, a time of day characterized by maximal rates of food consumption. Compared to Npy+/+ controls, intake of Npy−/− mice was reduced by 33% during this period (0.6 ± 0.1 g versus 0.9 ± 0.1 g; p ≤ 0.05). In contrast, intake did not differ between genotypes when measured over a 24-h period (3.7 ± 0.2 g versus 3.5 ± 0.3 g; p = ns). Furthermore, reduced dark cycle 4 h food intake in Npy−/− mice was not evident after a 24-h fast (1.4 ± 0.1 g for both genotypes; p = ns), despite a pronounced delay in the initiation of feeding (636 ± 133 s versus 162 ± 29 s; p ≤ 0.05). To investigate the role of NPY in the feeding response to palatability cues, mice were presented with a highly palatable diet (HP) for 1 h each day (in addition to having ad libitum access to chow) for 18 days. Npy+/+ mice rapidly increased daily HP intake such that by the end of the first week, they derived a substantial fraction of daily energy from this source (41 ± 3%). By comparison, HP intake was markedly reduced in Npy−/− mice during the first week (24 ± 7% of daily energy intake, p ≤ 0.05 versus Npy+/+), although it eventually increased (by Day 9) to values comparable to those of Npy+/+ controls. These experiments suggest that NPY contributes to the mechanism whereby food intake increases in response to circadian and palatability cues and that mechanisms driving food intake in response to these stimuli differ from those activated by energy restriction.     

Neuropeptide-Y in the paraventricular nucleus increases ethanol self-administration

The paraventricular nucleus (PVN) of the hypothalamus is known to modulate feeding, obesity, and ethanol intake. Neuropeptide-Y (NPY), which is released endogenously by neurons projecting from the arcuate nucleus to the PVN, is one of the most potent stimulants of feeding behavior known. The role of NPY in the PVN on ethanol self-administration is unknown. To address this issue, rats were trained to self-administer ethanol via a sucrose fading procedure and injector guide cannulae aimed at the PVN were surgically implanted. Microinjections of NPY and NPY antagonists in the PVN were conducted prior to ethanol self-administration sessions. All doses of NPY significantly increased ethanol self-administration and preference, and decreased water intake. The NPY antagonist D-NPY partially reduced ethanol self-administration and completely blocked the effects of an intermediate dose of NPY (10 fmol) on ethanol intake, preference, and water intake. The competitive non-peptide Y1 receptor antagonist BIBP 3226 did not significantly alter ethanol self-administration or water intake when administered alone in the PVN but it completely blocked the effect of NPY (10 fmol) on ethanol intake. NPY infused in the PVN had no effect on ethanol self-administration when tested in rats that did not have a long history of ethanol self-administration. The doses of NPY tested produced no effect on food intake or body weight measured during the 24-h period after infusion in either ethanol-experienced or ethanol-inexperienced rats. These results indicate that elevation of NPY levels in the PVN potently increases ethanol self-administration and that this effect is mediated through NPY Y1 receptors.     

Does neuropeptide Y contribute to the anorectic action of amylin?

Neuropeptide Y (NPY) is a potent feeding stimulant acting at the level of the hypothalamus. Amylin, a peptide co-released with insulin from pancreatic beta cells, inhibits feeding following peripheral or central administration. However, the mechanism by which amylin exerts its anorectic effect is controversial. This study investigated the acute effect of amylin on food intake induced by NPY, and the effect of chronic amylin administration on food intake and body weight in male Sprague Dawley rats previously implanted with intracerebroventricular (icv) cannulae. Rats received 1 nmol NPY, followed by amylin (0.05, 0.1, 0.5 nmol) or 2 microl saline. Increasing doses of amylin resulted in a dose-dependent inhibition of NPY-induced feeding by 31%, 74% and 99%, respectively (P < 0.05). To determine the chronic effects of i.c.v. amylin administration on feeding, rats received 0.5 nmol amylin or saline daily, 30 min before dark phase, over 6 days. Amylin significantly reduced food intake at 1, 4, 16 and 24 hours; after 6 days, amylin-treated rats showed a significant reduction in body weight, having lost 17.3 +/- 6.1 g, while control animals gained 7.7 +/- 5.1 g (P < 0.05). Brain NPY concentrations were not elevated, despite the reduced food intake, suggesting amylin may regulate NPY production or release. Thus, amylin potently inhibits NPY-induced feeding and attenuates normal 24 hour food intake, leading to weight loss.     

Regulation of food intake in the goldfish by interaction between ghrelin and orexin

Intracerebroventricular (ICV) administration of ghrelin, orexin and neuropeptide Y (NPY) stimulates food intake in goldfish. Orexin and NPY interact with each other in the regulation of feeding, while ghrelin-induced feeding has also shown to be mediated by NPY in the goldfish model. To investigate the interaction between ghrelin and orexin, we examined the effects of a selective orexin receptor-1 antagonist, SB334867, and a growth hormone secretagogue-receptor antagonist, [D-Lys(3)]-GHRP-6, on ghrelin- and orexin-A-induced feeding. Ghrelin-induced food intake was completely inhibited for 1h following ICV preinjection of SB334867, while [D-Lys(3)]-GHRP-6 attenuated orexin-A stimulated feeding. Furthermore, ICV administration of ghrelin or orexin-A at a dose sufficient to stimulate food intake increased the expression of each other's mRNA in the diencephalon. These results indicate that, in goldfish, ghrelin and orexin-A have interacting orexigenic effects in the central nervous system. This is the first report that orexin-A-induced feeding is mediated by the ghrelin signaling in any animal model.     

Continuous intraventricular infusion of neuropeptide Y evokes episodic food intake in satiated female rats: effects of adrenalectomy and cholecystokinin

In these studies the pattern of feeding behavior during continuous intraventricular (IVT) infusion of NPY for 4 hr in the satiated female rat was monitored. Whereas saline infusion was ineffective, each of the three doses of NPY (117, 470 or 1175 pmol/hr) increased feeding during the entire 4 hr infusion and 2 hr postinfusion period. The cumulative food intake at the end of 4 hr of NPY infusion was enhanced in a dose-related fashion between 0, 117 and 470 pmol/hr; at 1175 pmol/hr food intake plateaued. In addition, the latency to initiate feeding response decreased in a dose-related fashion and feeding occurred in discrete (35-45) episodes during the 4 hr infusion period. Further, the total time feeding and local eating rate (g/min) increased significantly in response to the higher rates of NPY infusion. Concurrent infusion of cholecystokinin (CCK) at either equimolar or 2.5 x NPY dose, affected neither the NPY-induced cumulative food intake nor any other parameter of feeding behavior. On the other hand, cumulative food intake was significantly decreased in adrenalectomized rats in response to NPY infusion (470 pmol/hr); a response due primarily to a marked suppression in some, and almost complete cessation of food consumption in other rats during the second 2 hr period of NPY infusion. These studies show that continuous central infusion of NPY can produce sustained, intermittent feeding behavior and adrenalectomy significantly curtailed the duration of NPY effectiveness.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification, tissue distribution and evaluation of brain neuropeptide Y gene expression in the Brazilian flounder Paralichthys orbignyanus

Neuropeptide Y (NPY) is one of the most potent stimulants of food intake in vertebrates, mammals and fish. However, the present knowledge about feeding behaviour in fish is still limited and based on studies in a few species. The Brazilian flounder Paralichthys orbignyanus is being considered for aquaculture, and it is important to understand the mechanisms regulating feeding in order to improve its performance in captivity. The objectives of this study were to clone NPY cDNA, evaluate the mRNA levels in different tissues of flounder, and also evaluate brain NPY expression to associate food intake with NPY expression levels. A 597 bp NPY cDNA was cloned from Brazilian flounder brain. NPY expression was detected in all the peripheral tissues analysed. No significant differences were observed in brain NPY gene expression over 24 h after food intake at a temperature of 15 ± 3°C. No correlation was observed among plasma glucose, total protein, cholesterol, triglycerides and NPY expression levels during this 24 h period. On the other hand, mRNA levels were increased after two weeks of fasting at elevated temperatures. Our results suggest that NPY mRNA levels in Brazilian flounder are affected by temperature.     

Orexigenic effect of the melanocortin MC4 receptor antagonist HS014 is inhibited only partially by neuropeptide Y Y1 receptor selective antagonists

Neuropeptide Y (NPY) and melanocortin (MC) peptides have opposite effects on food intake: NPY-like peptides and MC receptor antagonists stimulate feeding and increase body weight, whereas melanocortins and NPY antagonists inhibit food intake. In this study we tested whether the orexigenic effect of the selective MC4 receptor antagonist HS014 (1 nmol) could be inhibited by three different NPY antagonists, (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]D-argininam ide (BIBP3226), (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2(diphenyl acetyl)-argininamidetrifluoroacetate (BIBO3304), and decapeptide [D-Tyr(27,36)D-Thr32]NPY(27-36), after icv administration in freely feeding male rats. All three NPY receptor antagonists inhibited the orexigenic effects of HS014 partially and with markedly different potency. [D-Tyr(27,36)D-Thr32]NPY(27-36) was active only in subconvulsive dose. The NPY Y1 selective antagonist BIBP3226 was more effective in inhibiting the effect of HS014 than BIBO3304 despite in vitro data indicating that BIBP3226 is about 10 times less potent than BIBO3304 at NPY Y1 receptor. An enantiomer of BIBO3304, BIBO3457, failed to inhibit HS014-induced feeding, indicating that the effects of BIBO3304 were stereoselective. These results suggest that stimulation of food intake caused by weakening of melanocortinergic tone at the MC4 receptor is partially but not exclusively related to NPY Y1 receptor activation.     

Neuropeptide Y receptor(s) mediating feeding in the rat: characterization with antagonists

The present study evaluated the effect of the neuropeptide Y (NPY) Y1 receptor antagonists BIBO 3304 and SR 120562A and of the Y5 receptor antagonists JCF 104, JCF 109, and CGP 71683A on feeding induced either by NPY or food deprivation. In a preliminary experiment, NPY was injected into the third cerebroventricle (3V) at doses of 0.07, 0.15, 0.3, or 0.6 nmol/rat. The dose of 0.3 nmol/rat, which produced a cumulative 2-h food intake of 11.2 +/- 1.9 g/kg body weight, was chosen for the following experiments. The antagonists were injected in the 3V 1 min before NPY. The Y1 receptor antagonist BIBO 3304 significantly inhibited NPY-induced feeding at doses of 1 or 10 nmol/rat. The Y1 receptor antagonist SR 120562A, at the dose of 10 but not of 1 nmol/rat, significantly reduced the hyperphagic effect of NPY, 0.3 nmol/rat. The Y5 receptor antagonists JCF 104 and JCF 109 (1 or 10 nmol/rat) and CGP 71683A (10 or 100 nmol/rat) did not significantly modify the effect of NPY, 0.3 nmol/rat. However, JCF 104 (10 nmol/rat) and CGP 71683A (100 nmol/rat), but not JCF 109 (10 nmol/rat), significantly reduced food intake during the interval from 2 to 4 h after injection of a higher dose, 0.6 nmol/rat, of NPY. Feeding induced by 16 h of food deprivation was significantly reduced by the Y1 receptor antagonist BIBO 3304 (10 nmol/rat), but it was not significantly modified by the same dose of SR 120562A or JCF 104. These findings support the idea that the hyperphagic effect of NPY is mainly mediated by Y1 receptors. The results obtained with JCF 104 and CGP 71683A suggest that Y5 receptors may have a modulatory role in the maintenance of feeding induced by rather high doses of NPY after the main initial feeding response.     

Neuropeptide Y-induced feeding is dependent on GABAA receptors in neonatal chicks

In mammals and birds, neuropeptide Y (NPY) and gamma-aminobutyric acid (GABA) are found in brain areas known to be involved in the control of ingestive behavior and act to increase voluntary food intake. In rats, significant evidence suggest a functional and behavioral interaction between NPY and GABA mediated transmission in various brain regions, including the arcuate and paraventricular nuclei of the hypothalamus which can be important in the regulation of feeding behavior. In the present study, the effect of intracerebroventricular (ICV) administration of NPY and GABA receptor antagonists on food intake was examined in neonatal chicks. The ICV injection of NPY strongly stimulated food intake while co-administration of NPY and picrotoxin, a GABA_A antagonist, (but not CGP54626, a GABA_B antagonist) weakened food intake induced by NPY. These results suggest that central NPY stimulates food intake in neonatal chicks by interaction with the GABAergic system via GABA_A receptors.     

Agouti-related protein in the hypothalamic paraventricular nucleus: effect on feeding

Agouti-related protein (Agrp) is an endogenous melanocortin-4 receptor antagonist implicated in the regulation of food intake. Effects of Agrp on feeding under varying conditions were investigated. Agrp (10 to 100 pmol) was injected into the hypothalamic paraventricular nucleus of satiated (a.m. and p.m. injections) and food-deprived rats, or was co-administered with 117 pmol Neuropeptide Y (NPY). Agrp significantly stimulated light-phase feeding by 24 h post-injection. However, Agrp stimulated dark-phase and deprivation-induced feeding by 4 and 2 h, respectively. Animals receiving NPY and Agrp consumed more than animals receiving either peptide alone, the effect remaining by 24 h.     

Importance of Orexigenic Counter‐Regulation for Multiple Targeted Feeding Inhibition

Objective: Central feeding regulation involves both anorectic and orexigenic pathways. This study examined whether targeting both systems could enhance feeding inhibition induced by anorectic neuropeptides. Research Methods and Procedures: Experiments were carried out in 24‐hour fasted rats. Intracerebroventricular (ICV) injections were accomplished through stereotaxically implanted cannulae aimed at the lateral cerebral ventricle. Food intake of standard rat chow pellets was subsequently recorded for 2 hours. Results: Blockade of orexigenic central opioids and neuropeptide Y (NPY) by ICV naloxone (25 μg) or the NPY receptor antagonist [d‐Trp³²]NPY (NPY‐Ant; 10 μg) powerfully augmented the feeding suppression induced by ICV glucagon‐like peptide 1 (7‐36)‐amide (GLP‐1; 10 μg) or xenin‐25 (xenin; 15 μg) in 24‐hour fasted rats. Most importantly, in combination with naloxone or NPY‐Ant, even a low and ineffective dose of GLP‐1 (5 μg) caused a 40% reduction of food intake, which was augmented further when both antagonists were given in combination with GLP‐1. The combination of GLP‐1 (5 μg) and xenin (10 μg) at individually ineffective doses caused a 46% reduction of food intake, which was abolished at a 10‐fold lower dose. This ineffective dose, however, reduced food intake by 72% when administered in combination with naloxone and NPY‐Ant. Discussion: Targeting up to four pathways of feeding regulation in the central nervous system by blockade of endogenous feeding stimuli and simultaneous administration of anorectic neuropeptides potentiated reduction of food intake. This raises a promising perspective for treatment of obesity.     

Effects of neuropeptide Y on food intake and brain biogenic amines in the rainbow trout (Oncorhynchus mykiss)

Neuropeptide Y (NPY) is one of the most potent stimulants of food intake in mammals, but very little is known about NPY actions in fish. The present study investigated the role of NPY in food intake in the rainbow trout (Oncorhynchus mykiss). Food intake was monitored at different times after intracerebroventricular administration of porcine NPY (4 or 8 microg). Both doses significantly increased food intake at 2 and 3 h, and this effect was dose-dependent. However, 50 h after administration of NPY, food intake was significantly lower than in control fish, and cumulative food intake had returned to levels similar to those seen in the control group. The NPY antagonist (D-Tyr27,36, D-Thr32)-NPY (10 microg) inhibited food intake 2 h after icv administration, but did not block the orexigenic effect of NPY when administered jointly with 4 microg NPY. To identify the NPY receptor subtypes involved in the effects of NPY on food intake, we studied the effects of the Y1 receptor agonist (Leu31, Pro34)-NPY (4 microg), the Y2 receptor agonist NPY(3-36) (4 microg), and the highly specific Y5 receptor agonist (cPP(1-7), NPY19-23, Ala31, Aib32, Gln34)-hPP (4 microg). Short-term (2 h) food intake was moderately stimulated by the Y1 agonist, more strongly stimulated by the Y2 agonist, and unaffected by the Y5 agonist. We found that administration of NPY (8 microg icv) had no effect on aminergic systems in several brain regions 2 and 50 h after NPY administration. These results indicate that NPY stimulates feeding in the rainbow trout, and suggest that this effect is cooperatively mediated by Y2- and Y1-like NPY receptors, not by Y5-like receptors.     

Naloxone blockade of growth hormone-releasing factor-induced feeding

The opiate antagonist naloxone was used to examine the possibility that endogenous opioid function is involved in the expression of the increased feeding observed following intracerebroventricular (i.c.v.) administration of rat hypothalamic growth hormone-releasing factor (GRF). It was found that systemically administered naloxone (0.125, 0.25 and 0.50 mg/kg) significantly suppressed the increased food intake observed following i.c.v. GRF (4.0 pmol) treatment. Though potent enough to eliminate ingestive effects of GRF, baseline food intake was unaffected by 0.125 mg/kg naloxone. Examination of 0.4, 4.0 and 40.0 pmol i.c.v. administered GRF-(3-40), a structurally related but physiologically inactive peptide, revealed no effect on food intake. The present results suggest involvement of endogenous opioid function in GRF-stimulated feeding.     

Feeding after fourth ventricular administration of neuropeptide Y receptor agonists in rats

Neuropeptide Y (NPY) and peptide YY (PYY) stimulate food intake after injection into the fourth cerebral ventricle, suggesting that NPY receptors in the hindbrain are targets for the stimulatory effect of these peptides on food intake. However, the NPY/PYY receptor subtype mediating the feeding response in the hindbrain is not known. To approach to this question we compared dose-effect of several NPY receptor agonists to stimulate food intake in freely-feeding rats 60- and 120-min after injection into the fourth cerebral ventricle. At the 120-min time point, PYY was 2- to 10-times as potent as NPY over the dose-response range and stimulated twice the total intake at the maximally effective dose (2-fold greater efficacy). NPY was 2-times as potent as the Y1, Y5 receptor agonist, [Leu(31)Pro(34)]NPY but acted with comparable efficacy. The Y5-, Y2-differentiating receptor agonist, NPY 2-36, was comparable in potency to PYY at low doses but equal in efficacy NPY and [Leu(31)Pro(34)]NPY. The Y2 receptor agonist, NPY 13-36, produced only a marginal effect on total food intake. The profile of agonist potency after fourth cerebral ventricle administration is similar to the profile obtained when these or related agonists are injected in the region of the hypothalamus. Agonists at both Y1 and Y5 receptors stimulated food intake with a rank order of potency that does not conclusively favor the exclusive involvement of a single known NPY receptor subtype. Thus it is possible that the ingestive effects of NPY and PYY are mediated by multiple or novel receptor subtypes in the hindbrain. And the relatively greater potency and efficacy of PYY raises the possibility that a novel PYY-preferring receptor in the hindbrain is involved in the stimulation of food intake.     

Trp3, Arg5]-ghrelin(1-5) stimulates growth hormone secretion and food intake via growth hormone secretagogue (GHS) receptor

Ghrelin, a 28 amino acid peptide identified as an endogenous ligand for growth hormone secretagogue (GHS) receptor, stimulates food intake and growth hormone (GH) secretion. We designed low molecular weight peptides with affinity for the GHS receptor based on the primary structure of ghrelin. We found that [Trp3, Arg5]-ghrelin(1-5) (GSWFR), a novel pentapeptide composed of all L-amino acids, had affinity for the GHS receptor (IC50 = 10 microM). GSWFR stimulated GH secretion after intravenous or oral administration. Centrally administered GSWFR increased food intake in non-fasted mice. The orexigenic action of GSWFR was inhibited by a GHS receptor antagonist, [D-Lys3]-GH-releasing peptide-6, suggesting that GSWFR stimulated food intake through the GHS receptor. The orexigenic action of GSWFR was also inhibited by a neuropeptide Y (NPY) Y1 receptor antagonist, BIBO3304. These results suggest that the GSWFR-induced feeding is mediated by the NPY Y1 receptor.     

Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus

Neuropeptide Y (NPY), a peptide contained within numerous presynaptic terminals in the hypothalamic paraventricular nucleus (PVN), was injected directly into the PVN of satiated, brain-cannulated rats, and food and water intake were measured 0.5, 1, 2 and 4 hrs postinjection. Neuropeptide Y (24 and 78 pmoles/0.3 microliter isotonic saline) caused a dose-dependent increase in food intake, as well as a small, dose-dependent increase in water intake. This effect on feeding occurred even when food was not presented until 4 hrs postinjection. To determine the behavioral specificity of this effect, the impact of PVN injection of NPY (78 pmoles) on various behaviors was observed. With food available, only feeding and drinking behavior were affected. No change in other behaviors, including grooming, rearing, sleeping, resting or different levels of activity, was observed. With food absent, NPY still elicited drinking, suggesting that this is a primary effect, rather than secondary to the feeding. In addition to drinking, NPY reliably increased activity while decreasing sleep and grooming. These results suggest an important role for hypothalamic NPY, or a structurally-related peptide, in the regulation of feeding and drinking behavior.