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Endocrinology Vol. 140, No. 10 4494-4500
Copyright © 1999 by The Endocrine Society

ARTICLES

Inhibition of Neuropeptide Y (NPY)-Induced Feeding and c-Fos Response in Magnocellular Paraventricular Nucleus by a NPY Receptor Antagonist: A Site of NPY Action1

Makoto Yokosuka2, Pushpa S. Kalra and Satya P. Kalra

Departments of Neuroscience (S.P.K.) and Physiology (P.S.K.), University of Florida Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32610

Address all correspondence and requests for reprints to: Satya P. Kalra, Ph.D., Department of Neuroscience, University of Florida Brain Institute, University of Florida College of Medicine, 100 South Newell Drive, Box 100244, Gainesville, Florida 32610-0244. E-mail: skalra{at}ufbi.ufl.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Neuropeptide Y (NPY) is one of the important endogenous orexigenic peptides. In these studies we employed c-Fos immunostaining and a selective NPY Y1 receptor antagonist to identify the site of action of NPY in the hypothalamus. The results showed that intracerebroventricular administration of NPY stimulated feeding and increased immunostaining of c-Fos, a product of the immediate early gene c-fos, in several hypothalamic sites, including the dorsomedial nucleus, the supraoptic nucleus, and the two subdivisions of the paraventricular nucleus (PVN), the parvocellular PVN, and magnocellular PVN (mPVN). Intracerebroventricular administration of 1229U91, a selective NPY Y1 receptor antagonist, affected neither food intake nor c-Fos-like immunoreactivity (FLI) in these hypothalamic sites. Coadministration of NPY and NPY Y1 receptor antagonist inhibited NPY-induced food intake by 48%, but failed to affect NPY-induced FLI in the supraoptic nucleus, dorsomedial nucleus, and parvocellular PVN. However, this combined treatment decreased FLI by 46% in the mPVN (P < 0.05). These results showed that whereas NPY can stimulate FLI in several hypothalamic sites, the selective NPY Y1 antagonist suppressed NPY-induced FLI only in the mPVN. Thus, these findings lend credence to the view that a subpopulation of Y1 receptor-containing neurons in the mPVN in part mediate stimulation of feeding by NPY.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THERE HAS BEEN a recent upsurge in our understanding of the neural pathways regulating appetite in the rodent primarily due to the identification and characterization of the actions of a large number of orexigenic and anorexigenic neurotransmitters/neuromodulators in the hypothalamus (1, 2). Among the orexigenic messenger molecules, neuropeptide Y (NPY) is now recognized as an important endogenous appetite transducer. NPY-producing neurons that participate in the daily management of feeding behavior are localized in the arcuate nucleus (ARC) of the hypothalamus and in the brainstem (3, 4, 5). Whereas experimental evidence shows that each of these two subpopulations contributes toward the regulation of daily energy intake in different ways (6, 7, 8, 9, 10), the precise location in the brain where NPY released from the projections of these neurons acts to stimulate feeding is ill defined. Administration of NPY into the lateral, third, or fourth cerebroventricle stimulated a robust feeding response (11, 12, 13). As NPY can gain entry into the extracellular fluid from the cerebrospinal fluid and is transported to neural sites in the vicinity (14, 15), it is possible that the site of NPY action may lie in the neuroaxis surrounding the cerebroventricular system (11). Indeed, microinjection of NPY into various hypothalamic and extrahypothalamic sites was found to stimulate feeding in sated rats (16, 17). Within the hypothalamus, microinjection of NPY into the paraventricular nucleus (PVN), medial preoptic area, ventromedial nucleus (VMN), dorsomedial nucleus (DMN), and perifornical hypothalamus stimulated robust feeding. As these neural sites are innervated by NPY cells located in the ARC and brainstem, and both NPY Y1 (18, 19, 20) and Y5 receptor subtypes, putative receptors mediating feeding (21, 22, 23), are localized in these sites, it is quite possible that the field of NPY action is widespread in the hypothalamus (1, 2).

On the other hand, when changes in NPY levels in various hypothalamic sites were correlated with the shifts in energy balance, only PVN NPY levels increased during fasting and were reinstated after refeeding (24). Subsequently, it was also shown that in fasted rats NPY release increased only in the PVN extracellular compartment (25). In rats maintained on scheduled feeding regimens, NPY release in the PVN increased before feeding, and as these rats consumed food, the release rate steadily subsided (25). Although these findings identified the PVN as a possible site of NPY release associated with induction of appetite due to energy imbalance, it remained possible that NPY released under these conditions could act both locally in the PVN and in the neighboring sites where NPY-containing nerve terminals and NPY receptors overlap (3, 4, 5, 18, 19, 20, 21, 22, 23).

An examination of c-Fos protein, a product of the immediate early gene transcription factor, c-fos, indicated that intraventricular administration of NPY into the third or fourth cerebroventricle increased c-Fos-like immunoreactivity (FLI) in several neural sites in the hindbrain and forebrain (12, 13). However, in a few nuclei, including the magnocellular division of the paraventricular nucleus (mPVN) and DMN, the intensity of staining and the number of c-Fos-expressing cells rose significantly in association with feeding. That these two hypothalamic sites may be involved in the regulation of feeding was also indicated when NPY-induced feeding was suppressed by pretreatment with leptin (26). Leptin, an adipocyte hormone (27, 28, 29), has been shown to inhibit feeding by diminishing the orexigenic effects of several neuropeptides, including NPY (27, 28, 29, 30, 31, 32, 33, 34). We found that leptin, although ineffective on its own, significantly suppressed NPY-induced FLI in the mPVN along with a marked reduction in food intake. On the other hand, FLI was augmented in the DMN of these leptin- and NPY-treated rats (26). This observation together with the reported morphological link between the mPVN and DMN (35, 36) supported the possibility that NPY and leptin may interact in these two nuclei to suppress feeding. Based on these varied lines of evidence, we reasoned that a subpopulation of NPY-responsive neurons selectively involved in stimulation of feeding may reside in the mPVN and that blockade of NPY action by a suitable NPY receptor antagonist (NPY-A) may diminish FLI in the mPVN along with suppression of feeding. To test this hypothesis, in the current investigation we employed a selective NPY Y1 receptor antagonist 1229U91 (37, 38), shown previously to inhibit both NPY-induced and spontaneous feeding in normal and hyperphagic rats (7, 39).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal treatments and tissue preparation
Male Sprague Dawley rats (225–250 g; Zivic-Miller Laboratories, Inc., Zelienople, PA) were housed individually in stainless steel cages in an air-conditioned room (23 C) with a controlled light-dark cycle (lights on, 0500–1900 h) and with free access to Purina rat chow and water (Ralston Purina Co., St. Louis, MO). The protocols used in this study were approved by the institutional animal care and use committee. Rats were anesthetized with xylazine and ketamine and implanted with permanent stainless steel cannulas into the right lateral ventricle of the brain according to the rat stereotaxic atlas (26, 40). During a 10-day period of recovery, rats were handled daily to minimize stress-related effects of the injection procedures. In studies reported previously (12, 13) we observed that the intensity and number of neurons showing FLI remained stable for up to 3–4 h after the icv injection of NPY. Therefore, the following experiment was designed to evaluate the effects of NPY and Y1 receptor antagonist for a 2-h period. On the day of the experiment, 1 h before the icv injection, food was withdrawn, but water was available ad libitum. One hour later, 12 rats were injected intercerebroventricularly (icv) with porcine NPY (1 nmol/3 µl in saline; Peninsula Laboratories, Inc., Palo Alto, CA), followed immediately by either the Y1 receptor antagonist 1229U91 (5 µg/3 µl in saline; n = 6) or 3 µl saline (n = 6) between 0930–1030 h. Another group of 12 rats received saline alone, immediately followed by either 1229U91 or saline between 0930–1030 h. The doses selected for NPY and 1229U91 injections were based on previous studies (7, 39). Immediately after the injections, preweighed rat chow was placed in the cages. The amount of food consumed during the next 2 h was measured to the nearest 0.1 g. At the end of this period, rats were deeply anesthetized by an injection of sodium pentobarbital (40 mg/kg, ip) between 1130–1230 h, perfused transcardially with 0.1 M PBS (pH 7.4), followed by a cold fixative solution (4% paraformaldehyde in 0.1 M phosphate buffer. Brains were removed and postfixed overnight at 4 C in the same fixative solution and then transferred to 30% sucrose in 0.1 M phosphate buffer. Brains were stored at -80 C until further processing for immunocytochemical localization of c-Fos protein.

Immunocytochemistry for FLI
Serial frontal sections (45 µm) of the frozen brain were cut on a cryostat; sections were oriented according to the rat stereotaxic atlas (40). Every fourth section was selected for immunocytochemistry of FLI according to a procedure described previously (26). Endogenous peroxidase activity was blocked by incubation with 3% hydrogen peroxide, and nonspecific binding was blocked with 1% BSA in PBST (0.3% Triton X-100 in 50 mM PBS, pH 7.4) containing 5% normal goat serum and 0.05% sodium azide. Sections were incubated with the Fos antibody (rabbit polyclonal IgG, Ab-5 lot 60950101, Oncogene Science, Inc., Cambridge, MA; diluted 1:45,000 with BSA-PBST) for 72 h at 4 C. The second antibody was biotinylated goat antirabbit IgG (2.0 µl/ml; Vector Laboratories, Inc., Burlingame, CA) followed by avidin-biotin complex solution (4.5 µl each/ml; Vector Laboratories, Inc., Burlingame, CA). Color was developed with the chromogen solution, consisting of nickel chloride (0.25 mg/ml), diaminobenzidine (0.2 mg/ml), and 0.0025% hydrogen peroxide in 0.175 M sodium acetate buffer, pH 7.4, for 8 min. After a wash with 10 mM PBS, sections were mounted onto gelatin-coated glass slides and examined under a light microscope for location of c-Fos-positive sites. Adjoining sections were stained with cresyl violet for identification of brain areas.

Quantification of FLI-positive cells
Brain sections among animals were carefully matched under a microscope according to the appearance of brain structures in sections stained with cresyl violet and by immunocytochemistry. The number of FLI-positive cells was counted in the hypothalamic site of interest with the image analysis system (M4-Image Analysis, Imaging Research, Inc., Ontario, Canada), as previously described (26). For each region of interest, two sections from each rat corresponding to the plates in the rat brain atlas (40) were selected as follows: 1) the supraoptic nucleus (SON) corresponding to Fig. 24 in Ref. 40 ; 2) mPVN and parvocellular subdivision of the PVN (pPVN) corresponding to Fig. 25; and 3) DMN corresponding to Fig. 31 in Ref. 40 . Images from the selected sections were captured using a camera linked to a computer. The sites of interest matching the corresponding picture taken from the cresyl violet-stained section were outlined, and the number of FLI-positive cells in the site of interest was counted in two sections.

Statistical analyses
The food intake and FLI data were analyzed using one-way ANOVA with treatment as the independent variable, followed post-hoc by Newman-Keuls multiple comparison test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of NPY and NPY-A alone or together on food intake
Little feeding was noted in control sated rats receiving saline alone between 0930–1030 h (Fig. 1Go). Similarly, NPY-A on its own did not elicit feeding in sated rats, indicating that it has no NPY agonist activity. In several additional studies, we have affirmed this finding (unpublished). Also, small amounts of food intake, as normally observed during experimentation, were not affected by NPY-A administration. It suggested that this spontaneous feeding may be due to stimulation by orexigenic signals other than NPY. As expected (11, 12, 13), administration of NPY elicited a robust feeding response, which was markedly attenuated by the concurrent administration of NPY-A (Fig. 1Go); these rats consumed 48% less food than those receiving only the NPY treatment (P < 0.05).



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  		Figure 1. Effects of NPY and the NPY Y1 receptor antagonist, 1229U91, on food intake. The histogram in this figure and that in Fig. 2Go represent the mean ±SE (n = 6 rats/group). Dissimilar superscripts denote significant differences from each other (P < 0.05).

 
Effects of NPY and NPY-A alone or together on FLI in hypothalamic sites
In general, the topography of hypothalamic sites displaying increased FLI in response to NPY was similar to that reported previously (12, 13). In this study, the effects of NPY-A administration on NPY-induced FLI were examined in those hypothalamic sites shown previously to be associated with a feeding response (2, 16). The results summarized in Figs. 2–5GoGoGoGo show that NPY alone significantly enhanced FLI in the SON (Fig. 3Go), DMN (Fig. 4Go), and pPVN and mPVN (Fig. 5Go). On the other hand, NPY-A was completely ineffective in altering NPY-induced FLI in any of these four hypothalamic sites ( Figs. 2–5GoGoGoGo). Administration of NPY-A along with NPY caused no shift in the number of NPY-activated FLI neurons in the SON (Figs. 2Go and 3Go), DMN (Figs. 2Go and 4Go), and pPVN (Figs. 2Go and 5Go). In contrast, whereas NPY-A on its own was ineffective, it significantly reduced the c-Fos response to NPY in the mPVN (Figs. 2Go and 5Go). The NPY-induced c-Fos response was attenuated by 46% by NPY-A (Fig. 2Go). This reduction closely paralleled the 48% decrease in food intake (Fig. 1Go).



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  		Figure 2. Effects of NPY and 1229U91 on the number of c-Fos-positive cells in the DMN, pPVN, and mPVN. Dissimilar superscripts denote significant differences from each other (P < 0.05).

 


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  		Figure 3. Photomicrograph showing FLI in the SON of rats treated with saline alone (A; SAL+SAL), NPY alone (B; SAL+NPY), the NPY antagonist U1229491 (NPY-A+SAL), or NPY antagonist plus NPY (NPY-A+NPY). OC, Optic chiasm. Bar, 100 µm.

 


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  		Figure 4. Photomicrograph showing FLI in the DMN in response to four treatments as indicated in Fig. 3Go. V3, Third ventricle; Pe, paraventricular nucleus; DMNc, compact part of DMN; DMNv, ventral part of DMN. Bar, 100 µm.

 


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  		Figure 5. Photomicrograph showing FLI in the pPVN and mPVN in response to four treatments as indicated in Fig. 3Go. Bar, 100 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
NPY administration stimulated FLI in neurons located in the SON, DMN, and the two subdivisions of the PVN, the mPVN and pPVN. These findings complement several previous reports (12, 13, 26). Further, NPY-A administration alone was ineffective in stimulating FLI at any of these hypothalamic sites. Administration of NPY-A together with NPY also failed to affect the NPY-induced FLI in SON, DMN, and pPVN. In contrast, NPY-A attenuated by 46% the FLI-response produced by NPY in the mPVN, and these rats ate 48% less than those receiving NPY alone. These results imply that a subpopulation of neurons in the mPVN containing NPY receptors stimulate feeding upon activation by NPY; blockade of these receptors by the selective Y1 receptor antagonist, 1229U91, suppresses the feeding response. Alternatively, NPY may engage Y1 receptors located on neurons outside the mPVN that directly or indirectly activate those neurons in the mPVN that display increased FLI in association with feeding. Also, it is possible that NPY may suppress the inhibitory interneurons to result in activation of FLI in the mPVN.

Intraventricular administration of NPY has also been shown to modify the secretion of pituitary hormones (reviewed in Ref. 41). Therefore, it is possible that a proportion of the mPVN neurons activated by NPY may be associated with neuroendocrine function. A large population of oxytocin- and vasopressin-producing magnocellular neurons reside in the mPVN. As NPY stimulates oxytocin and vasopressin release (42, 43, 44), it is quite possible that the pattern of changes observed in the mPVN FLI may be related to activation of NPY receptors on these neurons (42, 43). However, this is unlikely because the NPY-A failed to alter NPY-induced FLI in the SON, which, like the mPVN, contains oxytocin- and vasopressin-producing neurons. The other possibility, that some other unidentified neurotransmitter/neuromodulator-producing neurons in the mPVN may be the targets of NPY and NPY-A interaction, cannot be completely ruled out, because the function of the mPVN neurons exhibiting significant shifts in FLI in response to NPY and NPY-A is unknown.

To date, six NPY receptor subtypes have been cloned (1, 45). Of these, two receptor subtypes, Y1 and Y5, have been implicated in mediation of NPY-induced food intake (19, 36, 37, 39, 45, 46, 47, 48), and these receptors are localized in various hypothalamic sites, including the PVN, and in extrahypothalamic sites in the rat brain (18, 19, 20, 21, 22, 23). The NPY-induced FLI topography corresponded with the sites containing Y1 and Y5 receptors in the hypothalamus. Our results invoke Y1 receptors as partial mediators of NPY-induced feeding. Based on the differential binding affinities of NPY and related peptides in in vitro and in vivo functional assays, 1229U91 is believed to be a selective receptor antagonist for Y1 receptors and an agonist for Y4 receptors and binds with extremely low affinity to the Y2 and Y5 subtypes (37, 38, 49). Although the Y2 receptors are not involved in stimulation of feeding, the Y4 agonists, human and rat pancreatic peptide, stimulate feeding at a relatively lower level (11, 50, 51). However, as 1229U91 failed to stimulate feeding on its own in this study and previous reports (37, 38, 39), it is unlikely that the agonist action of 1229U91 at Y4 receptors was a factor in inhibition of FLI in the mPVN. Based on the extremely low affinity of 1229U91 for Y5 receptors, reported only in in vitro functional assays (37, 38, 49), it is reasonable to assume that a major portion of the food intake stimulated by NPY is mediated through the Y1 receptors, possibly located in a subpopulation of neurons either in the mPVN or elsewhere in the hypothalamus. Although mice lacking NPY feed normally (52), Marsh et al. (53) showed that in Y5-deficient mice, NPY-A completely blocked the NPY-induced feeding, thereby affirming Y1 receptor involvement. In Y1-deficient mice, NPY-induced feeding was reduced somewhat compared with that in wild-type mice (54). These findings together with the current observation that NPY antagonist failed to completely suppress feeding stimulated by NPY, and Y5-deficient mice displayed significantly reduced feeding induced by NPY (53) do not rule out the concomitant involvement of Y5 receptors in the mPVN and elsewhere. This possibility will be tested when selective Y5 receptor antagonists are available.

In this context, our previous report (26) related to the neural substrates of leptin and NPY interaction is of considerable interest for two reasons. First, leptin has been shown to inhibit spontaneous and NPY-induced food intake (32, 33, 34). Leptin pretreatment inhibited NPY-induced FLI selectively in the mPVN, a response quite similar to that induced by NPY-A (26). This concordant diminution of the FLI response clearly implies that the subpopulations of mPVN neurons engaged in stimulation of feeding are the targets not only of NPY, but of leptin as well. New studies employing Y1 and Y5 receptor antagonists are warranted to determine whether Y1 and leptin receptors are coexpressed in the mPVN neurons or whether distinct interconnected subpopulations constitute the orexigenic network in the mPVN. Second, we reported that leptin and NPY, each on its own, elicited FLI responses in several hypothalamic sites. In addition, leptin administration followed by NPY produced an additive FLI response in the DMN (26). Thus, it is possible that the DMN is linked not only morphologically (35, 36), but also functionally, with the mPVN. As NPY-A failed to affect FLI in the DMN on its own or cause a change in the NPY-induced FLI response, we suspect that a subpopulation of neurons in the DMN, unlike that in the mPVN, expresses leptin receptors exclusively and thus is unlikely to be disrupted by NPY-A. The role of this subpopulation of neurons exclusively responding to leptin in the control of feeding behavior, if any, remains to be ascertained. In this regard, it is interesting to note that NPY gene expression in the DMN is augmented in rats displaying hyperphagia after disruption either of signaling in the VMN with colchicine (55) or of melanocortin signaling in agouti-yellow mice (56).

Another intriguing observation that emanates from our studies is that NPY stimulated FLI in a number of neural sites, and yet Y1 receptor antagonist inhibited the response only in the mPVN. Based on the fact that NPY is a pleiotropic peptide, it is reasonable to suggest that the action of NPY at these sites may involve receptors other than Y1 to mediate varied neuroendocrine and other behavioral functions (1, 20, 41, 42).

In summary, the results of these studies show that whereas NPY stimulated c-Fos in several hypothalamic nuclei, the selective NPY-Y1 receptor antagonist, 1229U91, suppressed NPY-induced FLI only in the mPVN, a response associated with inhibition of food intake. Cumulatively, these and our earlier findings with leptin lend credence to the existence of a subpopulation of NPY Y1 receptor-producing neurons in the mPVN that mediates stimulation of feeding by NPY.


   Acknowledgments
 
Thanks are due to Mrs. Dawn Stewart for secretarial assistance. We thank Dr. A. J. Daniels, Department of Metabolic Diseases, GlaxoWellcome, for the supply of the NPY Y1 receptor antagonist, 1229U91.


   Footnotes
 
1 This work was supported by NIH Grant DK-37273. Presented at the 28th Annual Meeting of the Society for Neuroscience, Los Angeles, CA, November 7–12, 1998. Back

2 Current address: Department of Anatomy, St. Marianna University School of Medicine, 2–16-1 Sugao Miyamae-Ku, Kawasaki 216, Japan. Back

Received January 8, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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