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Division of Biology of Growth and Reproduction, Department of
Pediatrics, University of Geneva School of Medicine (P.D.R., P.B.,
D.D.P., M.L.A.), 1211 Geneva 14, Switzerland; Ferring Research Ltd.
(P.D.R., P.B., D.D.P., A.H., J.-L.J.), Chilworth, United Kingdom SO17
7NP; Instituto Tecnológico e Nuclear (P.D.R.), 2685 Sacavem,
Portugal; and Douglass Hospital Research Center, Department of
Psychiatry, McGill University (Y.D., R.Q.), Verdun, Québec,
Canada H4H 1R3
1
Address all correspondence and requests for reprints to: Dr. M. L. Aubert, Hopital des Enfants, Hôpitaux Universitaires de Genève, 6 rue Willy-Donzé, 1211 Geneva 14, Switzerland. E-mail: aubert{at}cmu unige.ch.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The highest concentrations of NPY in the brain are found within several hypothalamic nuclei that regulate a variety of neuroendocrine and autonomic functions (9), and one of the first reported actions of NPY actually involved studies of the endocrine and eating behavior responses to human PP (hPP) and NPY (10, 11, 12, 13, 14, 15). In these original studies, it was shown that central administration of NPY stimulated food consumption (12, 13, 14, 15), inhibited sexual behavior (14), and modulated the activity of the gonadotropic axis (10, 11, 15). In contrast to the straightforward action of NPY on feeding behavior, the regulation of the gonadotropic axis by this neuropeptide is rather complex. It was shown that NPY can stimulate LH release in sex steroid-primed ovariectomized rats after central administration (10, 15). In contrast, in castrated animals, central administration of NPY produced a striking inhibition of LH release, as seen in rats (10, 16, 17), rabbits (18), and nonhuman primates (19). Furthermore, in both male and female intact rats, chronic intracerebroventricular (icv) infusion of NPY led to a profound inhibition of the gonadotropic axis (20, 21) and prolongation of sexual immaturity (22). Based on the observation that this dual action of NPY on the gonadotropic axis could be reproduced by the Y1 agonist [Leu31,Pro34]NPY, but not by the Y2 agonist NPY13–36, both the stimulatory and inhibitory actions of NPY were postulated to be mediated by the NPY Y1 receptor subtype (21, 23). However, after the cloning and pharmacological characterization of the Y4 and Y5 receptors, it clearly appeared that [Leu31,Pro34]NPY is a nonselective Y1, Y4, and Y5 agonist (24, 25, 26). This observation led us to reevaluate the pharmacological profile of the NPY receptor subtype involved in the inhibitory action of NPY on the gonadotropic axis in the castrated rat. For this purpose, we evaluated the effects of NPY analogs displaying different selectivities toward the five NPY receptor subtypes on LH secretion in the castrated rat: [Leu31,Pro34]NPY, a nonselective Y1, Y4, and Y5 agonist; C2-NPY, a selective Y2 agonist; PYY, that has very low affinity for the Y3 receptor; rat PP (rPP), a selective Y4 agonist; hPP, a nonselective Y4 and Y5 agonist; PYY3–36, a nonselective Y2 and Y5 agonist; and finally, [D-Trp32]NPY, a weak, but selective, Y5 ligand (25, 27, 28, 29). We also examined the effect of a selective Y5 antagonist (30). Finally, because several reports have led to the proposal that feeding behavior and activity of the gonadotropic axis are linked, and that NPY may be pivotal in this relationship (21, 31), we also evaluated the effects of these analogs and the Y5 antagonist on food intake. Together with literature data and binding studies performed in the rat brain, these in vivo results have indicated that both inhibition of the gonadotropic axis and stimulation of food intake by NPY are predominantly mediated by the Y5 receptor subtype.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials
Porcine (p) NPY, hPYY3–36, rPP, hPP,
p[Leu31,Pro34]NPY, C2NPY, and pPYY were
purchased from Neosystem (Strasbourg, France).
[D-Trp32]NPY was obtained from Bachem California, Inc. (Torrance, CA).
[Leu31,Pro34]PYY was synthesized in Douglas
Hospital Research Center (Verdun, Canada). The Y5 antagonist,
trans-naphthalene-1-sulfonic
acid-{4-{[4-(3-dimethylamino-propylamino)-quinazolin-2-ylamino]-methyl}-cyclohexylmethyl}-amide
(30), was synthesized in the Medicinal Chemistry Department of Ferring
Research Ltd. (Chilworth, UK). This compound has a structure very
similar to that of CGP71683A, a Y5 antagonist described by the same
investigators and presented at the Fourth International Neuropeptide Y
Conference (London, UK) in October 1997. BIBP3226 was provided by Karl
Thomae GmbH (Biberach an der Riss, Germany).
125I for binding was obtained from ICN Pharmaceuticals Canada Ltd. (Montreal, Canada), and bacitracin was purchased from Sigma Chemical Co. (St. Louis, MO). Schleicher and Schuell no. 32 glass filters were obtained from Xymotech (Montreal, Canada). 125I was incorporated into the tyrosine residue of [Leu31,Pro34]PYY using the chloramine-T method as previously described (32), and the specific activity was assumed to be a theoretical value (2000 Ci/mmol).
Surgical procedure
Castration and implantation of intracerebroventricular
cannula. Rats were weighed and anesthetized with ketamine/xylazine
(3 and 7 mg/kg, ip, respectively). An incision of the skin was made in
the middle of the scrotum, and the testicles and epididymis were
exposed. The testicles were separated from the epididymis and cut-off
after ligation of the artery. Cannulas, aimed at the right lateral
ventricle, were placed 1 mm posterior and 2 mm lateral to bregma and
extended 2 mm below the outer surface of the skull. Rats were allowed
to recover for 7 days, as described previously (20).
Implantation of jugular catheter. Under the same anesthetic, the ventral side of the throat was shaved, and an incision was made down the center of the throat. The right jugular vein was exposed and cannulated using polythene tubing (OD, 1.0 mm) connected to a medical grade silicone tubing (OD, 0.94 mm; silicone side in the jugular vein). The tubing was secured, and the polythene side was externalized through an incision made on the dorsal side of the neck. The catheter was rinsed with 300 µl Ringer’s solution containing 0.1% heparin. Rats were allowed to recover for at least 24 h in individual cages, with food and water available ad libitum.
Experimental procedure
All experiments were carried out between 14–18 h. Before the
start of the experiments, rats were weighed and placed in individual
cages with a preweighed amount of food. The different analogs,
dissolved in sterile distilled water, were injected (icv) in a volume
of 5 µl. The Y5 antagonist, dissolved in sterile distilled water
slightly acidified by acetic acid 2% (15% of the total volume, pH
6.5), was injected (icv) 15 min before NPY. Blood samples (200–250
µl) were removed immediately before and 15, 30, 60, 90, and 120 min
after central injections. Each blood sample was replaced with an
equivalent volume of Ringer’s solution containing 0.1% heparin.
Plasma was extracted and stored at -20 C until determination of LH by
RIA. Food intake was measured after 2 h. At the end of the study,
the rats were anesthetized, and an icv injection of 5 µl methylene
blue dye was made. Animals were then killed by decapitation, and the
brain was inspected for uniform and complete spread of the dye in the
lateral ventricle. Data from any subject with inadequate spread of the
marker were discarded.
Determination of plasma LH levels
LH was determined by RIA using reagents prepared by Dr. A.
F. Parlow and provided by the NIDDK (Bethesda, MD), with the exception
of the second antiserum. NIDDK antirat LH S11 serum was used. Values
were expressed in terms of the RP-1 reference standard. For each
experiment, all plasma samples (vehicle control and tested analog) were
measured in the same RIA.
Ligand binding assays
Membranes were prepared as previously described (32). Briefly,
rats were killed by decapitation, and their brains rapidly removed and
homogenized in Krebs-Ringer phosphate (KRP) buffer at pH 7.4 of the
following composition: NaCl (120 mM), KCl (4.7
mM), CaCl2 (2.2 mM),
KH2PO4 (1.2 mM), MgSO4
(1.2 mM), dextrose (5.5 mM), and
NaHCO3 (25 mM) using a Brinkmann Instruments, Inc., Polytron (Westbury, NY; at setting 6 for
15–20 sec). Homogenates were centrifuged at 49,000 x
g for 20 min, supernatants were discarded, and pellets were
washed, resuspended, and recentrifuged twice.
All binding assays were initiated by adding 100 µl of membrane
preparations in a final volume of 500 µl KRP containing 0.1%
(wt/vol) BSA, 0.05% (wt/vol) bacitracin, 125I-labeled
[Leu31,Pro34]PYY (25–35 pM), and
various competitors (pNPY, hPYY3–36, hPP, rPP,
[Leu31,Pro34]pNPY, C2-NPY,
[D-Trp32]NPY, and the Y5 antagonist) at
concentrations ranging from 10-12–10-6
M. All binding assays were performed in the absence or
presence of 1 µM BIBP3226 to block the Y1 receptor
subtype. Nonspecific binding was determined in the presence of 1
µM pNPY. After 2 h, the binding reaction was
terminated by rapid filtration through Schleicher and Schuell no. 32
glass filters (previously soaked in 1.0% polyethyleneimine) using a
cell harvester filtering apparatus (Brandel Instruments, Gaithersburg,
MD). Filters were rinsed three times with 3 ml cold KRP, and the
radioactivity remaining on filters was quantified using a 
-counter
with 85% efficiency (Packard Instruments, Downers Grove, IL).
All binding experiments were repeated three times, each in triplicate, and results are expressed as a percentage of the specific binding, representing the mean ± SEM. IC50 values (i.e. concentration of unlabeled peptide required to compete for 50% of specific binding of the radioligand) of the various peptides and Y5 antagonist were calculated from the competition binding assays data using GraphPad software (GraphPad Software, Inc., San Diego, CA).
Statistical analysis
The effect of each NPY analog on plasma concentrations of LH was
analyzed by one-way ANOVA followed by Dunnett’s t test to
examine the differences between each postinjection time point and the
preinjection basal value. The effects of NPY analogs on food intake
were analyzed by a one-way ANOVA followed by Dunnett’s t
test. For the study with the Y5 antagonist, one-way ANOVA followed by
Students-Newman-Keuls test were performed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The lowest NPY dose tested (0.07
nmol) was ineffective. For the other four doses, a significant decrease
(P < 0.05) was first observed after 30 min. Minimum LH
values were reached after 30 min for the 0.23-nmol dose and at later
times with increasing doses. With the highest dose (7 nmol), plasma LH
levels were still decreasing after 120 min.
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]. Two analogs, C2-NPY and rPP, did not
affect plasma LH levels (Fig. 2).
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. All compounds produced a highly
significant, dose-related decrease in plasma LH levels: NPY, F(5, 44) = 25.17 and P < 0.001;
[Leu31,Pro34]NPY, F(3, 38) = 15.7 and
P < 0.001; PYY3–36, F(4, 41) = 23.51
and P < 0.001; hPP, F(4, 46) = 25.71 and
P < 0.001; and [D-Trp32]NPY,
F(3, 23) = 8.05 and P < 0.001. At the 2.3-nmol
dose, NPY, PYY3–36,
[Leu31,Pro34]NPY, and hPP generated similar
highly significant (P < 0.001) levels of LH inhibition
(76.7 ± 3.0%, 71.8 ± 3.0%, 67.3 ± 8.2%, and
64.0 ± 4.5%, respectively). With
[D-Trp32]NPY, 55.0 ± 6.5% of
inhibition was achieved at a dose of 7 nmol only.
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). The antagonistic action of Y5-ant was
dose related; a significant inhibition was reached with the dose equal
to or greater than 60 µg, and full reversion was achieved at a dosage
of 100 µg (Fig. 5).
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). Both
hPP (known as a mixed Y4-Y5 specific analog) and PYY3–36
(known as a mixed Y2-Y5 specific analog) had a very weak affinity for
Y1-like activity and a strong binding capacity for the Y5-like type of
binding (Table 1). The Y2-selective NPY analog C2-NPY and the
Y4-selective peptide rPP displayed very weak activity for both types of
binding. Finally, the nonpeptidic Y5 receptor antagonist described by
Novartis clearly induced strong inhibition of the Y5-like type of
binding and no inhibition of the Y1-like type of activity in this
competitive binding system (Table 1). In addition, this compound was
found to have no affinity for Y1 receptors in intact human
neuroblastoma SK-N-MC cells (IC50, >1000
nM).
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). The
minimal effective dose was 0.7 nmol for NPY, hPP, and
PYY3–36 and 2.3 nmol for
[Leu31,Pro34]NPY. At the dose of 2.3 nmol,
PYY3–36 and NPY stimulated food intake to a comparable
extent (PYY3–36, 7.0 ± 0.9 g; NPY, 5.7 ±
1.1 g), whereas [Leu31,Pro34]NPY and hPP
were less efficient ([Leu31,Pro34]NPY,
3.1 ± 1.2 g; hPP, 1.9 ± 0.6 g).
[D-Trp32]NPY at the doses tested (0.7–7
nmol) was unable to stimulate food intake.
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).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The panel of NPY agonists used in this study was chosen because their specificities toward the different Y receptors are well documented by numerous studies published over several years (for review, see Refs. 6, 7). Recently, their specificities were further established by functional studies of the specific Y receptor, expressed in stable cell lines such as, for example, the analysis proposed by Gerald et al. (25). Also, the specificities of several NPY agonists or antagonists for the Y1 and Y5 receptor subtypes in rat brain were reevaluated recently by two of us, using a paradigm of binding competition of [125I][Leu31,Pro34]PYY to rat brain membrane homogenates in the absence or presence of 1 mM BIBP3226, a highly specific Y1 receptor antagonist (35), that allows clear discrimination between Y1 and Y5 receptor binding specificities (29).
In the present study we confirmed the clear dose-dependent inhibitory action of centrally administered NPY on LH secretion in the male castrated rat, first described by Kalra and Crowley in the eighties (15). The involvement of the Y2 receptor subtype for this NPY action on LH secretion was eliminated in another study published by Kalra et al. in 1992 (23) and by us, as chronic administration of NPY13–36 had no effect on the pituitary-testicular axis of male rats (21). Consistent with this, C2-NPY, a specific Y2 analog, had no effect on LH secretion in the castrated rat in the present study. Receptor subtype Y4 could be eliminated as well, as the specific Y4 receptor agonist rPP was inactive. Furthermore, PYY, which binds only poorly to the Y3 receptor subtype (28), was as active as NPY to inhibit LH secretion, making it unlikely that the Y3 receptor subtype could be involved. At this point, only receptor subtypes Y1 and Y5 were still candidates for the mediation of the action of NPY on LH secretion. Three analogs were particularly useful to demonstrate that NPY action on LH secretion in the castrated rat is predominantly mediated by the Y5 receptor subtype: PYY3–36, a mixed Y2 and Y5 agonist; hPP, a mixed Y4 and Y5 agonist; and [D-Trp32]NPY, a weak but selective Y5 ligand (25, 27, 28, 29). Those three analogs were found to inhibit LH secretion with potency and efficacy similar to those of NPY despite very weak affinity for the Y1 receptor subtype. Taken together, the data obtained with PYY3–36, hPP, and [D-Trp32]NPY indicated that the Y5, rather than the Y1, receptor subtype is involved in mediation of the inhibitory action of NPY on LH secretion in the castrated rat. These data make it very unlikely that the Y1 receptor subtype is still involved, although this possibility cannot be completely eliminated at this point. For such a demonstration, a pure Y1 receptor agonist or a powerful, selective, and nontoxic Y1 receptor antagonist is still needed. There are unfortunately no Y1 antagonists that could be used for such a demonstration. It is known that the nonpeptidic BIBP3226 (35) and the more recently available BIBO3304 (36) are specific Y1 antagonists, but their use in in vivo models is limited due to their neurotoxicity. In a preliminary experiment performed in our laboratory, BIBO3304 (10 µg/rat), coinjected centrally (icv) with NPY (3 µg/rat), was unable to inhibit the inhibitory effect of NPY on LH secretion (data not shown). When tested at a larger concentration (30 µg/rat), BIBO3304 clearly induced neurotoxic manifestations, thus preempting the use of this antagonist at meaningful concentrations. 1229U91 (GW1229) is another Y1 antagonist that could have been used in our model (37). However, this peptidic NPY analog is known to display high binding affinity in vitro for both Y1 and Y4 receptors and weak affinity for Y2 and Y5 receptor subtypes (38). It is therefore very difficult to make any meaningful demonstration of Y1 specificity by using such a compound.
We synthesized a Y5 antagonist that was described as having an IC50 of 2.3 nM for the cloned Y5 receptor (30). In our hands, this nonpeptidic receptor antagonist was found to be highly specific to displace the 125I-labeled [Leu31,Pro34]PYY/BIBP3226-insensitive sites in the rat brain and to display no binding to Y1 receptors of neuroblastoma SK-N-MC cells, thus confirming its Y5 specificity. This Y5 receptor antagonist, when administered icv, with no apparent toxicity problem, fully reversed, in a dose-dependent manner, the inhibitory action of NPY on LH secretion. This finding strongly reinforces the concept that the Y5 receptor subtype is mainly, if not exclusively, involved in the NPY inhibitory action on LH secretion.
The Y5 receptor subtype was originally described as a receptor subtype mediating the orexigenic effect of NPY (25). Our data with Y5 agonists and a specific Y5 antagonist confirmed that the Y5 receptor subtype is involved in the stimulation of food intake by exogenous NPY. The dose-response studies indicated that the Y5 agonist PYY3–36 was as potent as NPY, confirming the work of Gerald et al. (25). Another Y5 agonist, hPP, was found to be as potent as [Leu31,Pro34]NPY in stimulating food intake. Finally, the Y5 antagonist that was used in the present study clearly blocked NPY-induced stimulation of food intake in the castrated rat. [D-Trp32]NPY, a weak but specific Y5 ligand (25, 27, 29), that was found to be an agonist in our LH assay was unable to significantly induce food intake at 7 nmol, the highest dose used in the present study. In another study, central administration of [D-Trp32]NPY at a dose of 2 nmol stimulated food intake in rats (25). On the other hand, several groups have reported an antagonistic action of [D-Trp32]NPY on NPY-induced foodintake (27, 39).
The comparison of dose-response curves for inhibition of LH secretion and stimulation of food intake indicates that the rank ordering of peptide activity for inhibition of LH secretion, NPY = PYY3–36 = hPP = [Leu31,Pro34]NPY > [D-Trp32]NPY, paralleled the rank ordering of peptide activity for stimulation of food intake, NPY = PYY3–36 > hPP = [Leu31,Pro34]NPY >> [D-Trp32]NPY. Together with the antagonist study, this observation suggests that the same subtype is mediating both effects of NPY. However, the different sensitivity to [D-Trp32]NPY we have evidenced also suggests the possible existence of minor differences between the Y5 subtypes mediating those two actions, for example, differences in receptor density or different second messengers. The identity of the major NPY receptor(s) mediating the stimulation of food intake is still uncertain, and recent data have indicated that both Y5 and Y1 could be involved (36, 36, 40, 41, 42, 43), or possibly that mediation is through the Y5 subtype with participation of the Y1 subtype. Wyss et al. recently demonstrated that correlation between in vivo ED50 for stimulation of food intake by NPY and in vitro IC50 for the binding to receptors expressed on cell lines is strong for the Y5, weak for the Y1, and nonsignificant for the Y2 and Y4 subtypes (40). Repeated icv injections of Y5 antisense oligodeoxynucleotides prevented both NPY-induced and fasting-induced food intake in rats (41). NPY Y1 receptor-deficient mice have normal food intake and exhibit modest obesity and hyperinsulinemia (43). Finally, Wieland et al. demonstrated that the Y1 receptor subtype is still involved in the stimulation of food intake by injecting the Y1 antagonist BIBO3304 (30 µg/rat) locally at the level of the paraventricular nucleus that in these conditions could inhibit both the feeding response induced by 1 µg NPY as well as the hyperphagia induced by a 24-h fast (36). Obviously, more work is necessary to delineate the Y receptor subtype(s) for the action of NPY on feeding, but this was not the primary aim of the current study.
Much work is also still needed to understand the role of NPY in the modulation of gonadotropin secretion in physiological conditions, its role as an excitatory signal to LH release (31), and its role to clarify the involvement of NPY action on that axis in several pathophysiological situations. The demonstration that null mutation of the NPY gene produced transgenic mice that were almost normal, with normal fertility, clearly cast some doubts on the relevance of the described specific stimulatory and inhibitory actions of NPY, in particular on reproduction (44, 45). It is quite likely, however, that the important redundancy of peptides from the PP family and NPY receptor subtypes made possible a rapid reprogramming of the actions normally assigned to NPY, and then knockout mice appear normal at birth and in adulthood. Recently, similar findings were published with gene deletion of the Y1 receptor subtype (43, 46) and the Y5 receptor subtype (47) with, as an outcome, fertile mice. One important limitation of these studies is that NPY or specific NPY receptor are lost from conception, allowing the development of compensatory systems that could take the place of the missing NPY receptor. Development of useful inducible promoters will be an important advance for these transgene techniques.
The elegant studies by Kalra et al. have indicated that NPY is involved in the modulation of LH release at the time of the ovulatory peak, stressing the participation of NPY in the triggering of a large secretion of LH (31). As important is the observation that NPY can inhibit LH/FSH secretion, at least when administered exogenously (21, 34). There are several presumptions that endogenously produced NPY can also modulate gonadotropin secretion in pathological conditions (33, 48). Gene expression for NPY and the synthesis and release of this peptide are enhanced in several pathological situations associated with hypogonadism, such as malnutrition (49), obesity (50), and diabetes (51, 52). Increased NPY output in the hypothalamus, such as that seen in diabetic rats that drives robust food intake (52), could also fulfill an inhibitory action on LH secretion. The recent demonstration that leptin administration to ob/ob mice reestablished LH secretion and fertility with a concomitant decrease in gene expression for NPY in the hypothalamus at least indicates that such a specific inhibitory action of NPY on gonadotropin secretion is possible (53).
In conclusion, our results indicate that the Y5 receptor subtype is involved in the inhibitory control of the gonadotropic axis by NPY and confirm other work that have considered this subtype as a mediator of NPY action on food consumption.
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Acknowledgments |
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Footnotes |
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Received November 2, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-adrenoceptor blockade. Acta Physiol
Scand 116:393–402[Medline]
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,
Significantly different from vehicle-injected rats; *, significantly
different from NPY-injected rats, as determined by Student-Newman-Keuls
test (P < 0.05).