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NEUROENDOCRINOLOGY |
Department of Pharmacology, University of Melbourne, Melbourne, Victoria 3010, Australia
Address all correspondence and requests for reprints to: Dr. Margaret Morris, Department of Pharmacology, University of Melbourne, Melbourne, Victoria 3010, Australia. E-mail: mjmorris{at}unimelb.edu.au
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Abstract |
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NPY and MCH stimulated food intake relative to vehicle (4 h intake, 5.9 ± 0.7 and 3.6 ± 0.2 g, respectively; P < 0.0001). BIBO 3304 and GR231118 significantly inhibited MCH- induced feeding by 73% (P < 0.01) and 86% (P < 0.01), respectively, at 2 h. Coadministration of NPY and MCH did not increase food intake above that in response to NPY alone; however, prior administration of BIBO 3304 resulted in a less marked inhibition of feeding (P < 0.05, 30 min only).
Inhibition of MCH-induced feeding by two structurally different NPY Y1-receptor antagonists provides strong evidence that the orexigenic action of MCH involves the Y1-receptor.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NPY is the most potent endogenous stimulator of feeding known, with the intracerebroventricular (icv) administration of nanomole quantities eliciting eating in satiated rats (2). Furthermore, chronic administration of NPY causes hyperphagia and an increase in body weight, resulting in obesity (3). NPY mRNA is markedly increased in the hypothalamus of genetically obese animals (4). Thus, the factors regulating this potent feeding stimulator may have important implications in the therapeutic management of obesity.
NPY-containing fibers are widely distributed throughout the CNS, and within the hypothalamus NPY is particularly abundant in the paraventricular nucleus (PVN) (5), an area important in the control of eating behavior that receives a dense NPY-containing projection from the arcuate nucleus (6). Studies in vivo have demonstrated that NPY release in the PVN is strongly associated with increased appetite (7), and central administration of NPY increases c-fos expression in this region (8).
NPY exerts effects through G protein-coupled receptors (GPCR), of which five subtypes have been cloned (9). NPY Y1, Y2, and Y5 receptors are expressed in hypothalamic areas implicated in the feeding actions of NPY (10). Early studies showed the Y1-agonist [Leu31,Pro34]NPY stimulates food intake (11), whereas a Y1-selective antagonist reduces food intake evoked by both NPY and food deprivation (12). The more recently characterized Y5 receptor is also implicated in feeding behavior, as the Y5-selective agonist PYY-(3–36), stimulates feeding in rats (13). More modest effects on food intake were observed in response to stimulation of the Y2-receptor by the Y2 selective agonist NPY-(13–36) (14).
The NPY knockout mouse, however, has been shown to have a normal body
weight and a normal hyperphagic response to fasting (15),
suggesting that other neuropeptides are able to compensate for this
loss. As previously noted there are many hypothalamic neuropeptides
involved in feeding. Of particular interest to the current study is the
orexigenic neuropeptide MCH, which was first noted for its ability to
induce melanosome aggregation in teleost fish, thus antagonizing the
melanin-dispersing action of 
MSH (16). MCH was isolated
from the rat hypothalamus (17) and identified as a cyclic
19-amino acid neuropeptide in both human and rat (18).
MCH-like immunoreactive (-ir) perikarya were found to be abundant in the lateral hypothalamic area (LHA), subzona incerta, and perifornical area, with fibers distributed widely throughout the rat brain (19). MCH-ir was also found in the PVN, arcuate nucleus, and median eminence (20). A similar regional distribution of MCH peptide was described in human brain, with highest concentrations in the hypothalamus (21). The LHA is another nucleus within the hypothalamus that is important in the regulation of feeding, and lesions to this area result in profound hypophagia (22). Cells in this region contain orexin, in addition to MCH, in separate populations of neurons (for review, see Ref. 23). Both of these neuropeptides have been shown to stimulate feeding.
Several observations pointed to a role for MCH in stimulating feeding,
including antagonistic effects on the actions of MSH, a potent
anorexigenic peptide (24), and elevated levels of MCH mRNA
in the hypothalamus of genetically obese ob/ob mice
(25). Low doses of MCH administered icv stimulate feeding
(25, 26). Furthermore, MCH mRNA was increased by fasting
in both normal and obese animals (25). Recently, mice
carrying a targeted deletion of the MCH gene were reported to have
reduced body weight and hypoadiposity due to hypophagia and an
inappropriately increased metabolic rate (27). Hence, MCH
appears to play a pivotal role in the stimulation of appetite.
Controversy surrounding the nature of the receptor responsible for the actions of MCH was recently resolved with the demonstration that the somatostatin-like receptor-1 (SLC-1), an orphan GPCR, is a specific MCH receptor (28). Consistent with the wide distribution of MCH-ir terminals in the CNS, SLC-1 mRNA and protein were located in the rat cerebral cortex, caudate-putamen, hippocampal formation, amygdala, hypothalamus, and thalamus (29). Binding studies show a similar distribution of MCH-binding sites in the human brain, with the highest concentration in the hypothalamus (30).
Both NPY- and MCH-containing fibers project to areas of the hypothalamus that regulate appetite. Although the orexigenic peptides NPY and MCH operate in regionally discrete pathways, recent anatomical studies provide evidence for a link between them. Reciprocal projections exist between the arcuate nucleus and the LHA (31), and NPY-ir fibers were shown to directly innervate MCH fibers in the LHA (32). The observation that the feeding effects of the LHA peptide orexin were influenced by an antagonist to NPY (33) further suggests that important interactions may arise between different orexigenic peptides in these regions. However, the extent to which NPY and MCH interact to regulate feeding remains unclear. Therefore, this study examined whether the selective NPY Y1 receptor antagonists BIBO 3304 and GR231118 can inhibit feeding induced by MCH in the rat in vivo. We hypothesized that if the feeding response elicited by MCH involved NPY, then a Y1-antagonist might modulate MCH-induced food intake.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Intracerebroventricular cannulation and injections
Rats were anesthetized with pentobarbitone sodium (60 mg/kg BW,
ip; Nembutal), administered the analgesic buprenorphine (0.15 mg/kg,
sc; Temgesic), and placed in a stereotaxic frame (Narishige SR-6N,
Tokyo, Japan). A permanent 9-mm, 22-gauge stainless steel cannula
(Plastics One, Roanoke, VA) was inserted into the right lateral
ventricle (0.8 mm posterior to bregma, 1.5 mm lateral to the midline,
and 3.5 mm below the surface of the brain (34). The
cannula was secured with dental cement (Paladur, Wehrheim, Germany) and
jeweler’s screws. A 28-gauge stainless steel dummy cannula (Plastics
One) was inserted to occlude the guide cannula when not in use. After
surgery rats were housed in individual cages with high top lids to
allow social interaction. To minimize nonspecific stress all rats were
handled daily and acclimatized to experimental conditions for 7 d
before the commencement of the study. All substances were administered
in a volume of 2 µl using a 10-µl Hamilton syringe (Hamilton, Reno,
NV) attached to polyethylene tubing (id, 0.28 mm; od, 0.61 mm) and a
stainless steel injection cannula (Plastics One) extending 0.5 mm
beyond the guide cannula. At the end of the study period, animals were
killed by decapitation after an anesthetic overdose. Cannula placement
was verified after removal of the brain and visual inspection of
coronal brain slices.
Effects of NPY and/or MCH on food intake in the presence and
absence of NPY Y1-receptor antagonists
In an initial study, food intake in response to daytime icv
administration of vehicle, 1 nmol NPY, 2 nmol MCH, or the
coadministration of 1 nmol NPY and 2 nmol MCH was examined in a group
of icv cannulated rats (n = 9) at the beginning of the light
phase. NPY and MCH were dissolved in 0.9% saline. On the day of an
experiment, rats were acclimatized in the experimental room for 1
h with ad libitum access to food and
water. A 28-gauge injection cannula was used to deliver all substances
in a volume of 2 µl over a period of 10 sec. Each experiment
consisted of two injections administered 10 min apart. When the effect
of one agonist alone was being investigated, animals received a prior
dose of the appropriate vehicle. Preweighed food was then placed in the
cage, and food intake was measured at 0.5, 1, 2, and 4 h
postinjection. All combinations of injections were performed in a
randomized order and took place between 0930 and 1030 h. Each
combination of injections was repeated in the same animal where
possible, with a minimum of 48 h between experiments.
In a second group of animals, the effects of the synthetic Y1-selective receptor antagonist BIBO 3304 on food intake in response to 1 nmol NPY, 2 nmol MCH, and the coadministration of 1 nmol NPY and 2 nmol MCH were examined. BIBO 3304 (20 nmol) was dissolved in dimethylsulfoxide (25% in saline). To make within-group comparisons, responses to the combinations of injections used in the previous study were repeated in these animals with the appropriate vehicle. Food intake was then measured at 0.5, 1, 2, and 4 h. Again, all combinations of injections were performed in a randomized order.
Using a similar protocol, responses to the Y1-selective peptide antagonist GR231118, whose structure is based on the C-terminal end of the NPY molecule (12), were investigated in a new experimental series. In addition to its Y1 antagonist properties, this agent has some Y4 agonist activity (35). GR231118 (5 nmol dissolved in 0.9% saline) was administered before 1 nmol NPY or 2 nmol MCH, and the effects on food intake were examined. Again, feeding responses to NPY, MCH, and the appropriate vehicle were measured in this group of animals.
Drugs
MCH (human/rat) was purchased from Auspep (Melbourne,
Australia). Prof. James Angus (Department of Pharmacology,
University of Melbourne) donated NPY (porcine) and GR231118. BIBO 3304
was a gift from Boehringer Ingelheim GmbH (Biberach,
Germany). Pentobarbitone sodium and buprenorphine were purchased
from Rhone Merieux (Pinkenba, Australia) and Reckitt and Colman (Hull,
UK), respectively.
Statistical analysis
Food intake is expressed as the mean ± SEM.
Results from the feeding studies were analyzed by one-way ANOVA with
repeated measures, followed by the post-hoc least
significant difference test for pairwise comparisons where required.
P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Vehicle-treated rats
consumed 0.9 ± 0.2 g (n = 8) over this period. The
injection of either NPY or MCH significantly stimulated food intake
relative to vehicle at all time points examined (Fig. 1; n = 9;
P < 0.001). Food intake in response to NPY
administration occurred with a rapid onset, such that rats had eaten
3.6 ± 0.4 g in the first 30 min, with 5.9 ± 0.7 g
eaten over the 4-h period. Administration of a near-maximal dose of MCH
(26) resulted in a 4-h food intake of 3.6 ± 0.2
g. Thus, the stimulation of food intake by MCH was significantly less
than that observed after NPY at all time points examined
(P < 0.001; Fig. 1).
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; n = 9;
P < 0.01). This inhibition occurred immediately, with
a reduction in food intake from 1.6 ± 0.2 to 0.5 ± 0.2
g (n = 9, P < 0.01) at 30 min. Inhibition of
MCH-induced feeding was sustained throughout the experiment, reaching a
maximum of 73% at 2 h post injection when corrected for food
intake after vehicle administration [vehicle + MCH, 3.1 ±
0.3 g (n = 9); BIBO 3304 + MCH, 1.3 ± 0.3 g
(n = 9); vehicle + vehicle, 0.7 ± 0.2 g (n = 8);
P < 0.01; Fig. 2A]. After BIBO 3304 administration,
MCH-induced food intake was not significantly different from that in
the vehicle group for the first 2 h of the experiment (Fig. 2A).
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; n = 8;
P < 0.001). This inhibition was rapid in onset, as
NPY-induced food intake was reduced from 3.6 ± 0.4 to 1.3 ±
0.4 g at 30 min, representing a 71% reduction. BIBO 3304 provided
a sustained inhibition of feeding in response to NPY for the duration
of the experiment, with a 63% reduction still evident after 4 h
(Fig. 2B; n = 8; P < 0.001). This dose of BIBO
3304 did not completely abolish NPY-induced feeding (Fig. 2B).
Effect of GR231118 on MCH-induced feeding
In a separate group of rats, the effect of 5 nmol GR231118, which
is structurally unrelated to BIBO 3304, on MCH- induced feeding was
investigated (Fig. 3A). Prior
administration of GR231118 significantly reduced food intake in
response to 2 nmol MCH at all time points examined (n = 8,
P < 0.01). The inhibition was rapid in onset, and food
intake was reduced by 86% at 2 h [vehicle + MCH, 2.7 ±
0.4 g (n = 10); GR231118 + MCH, 0.7 ± 0.1 g
(n = 8); vehicle + vehicle, 0.4 ± 0.1 g (n = 11);
P < 0.01]. After 4 h MCH-induced food intake
remained inhibited by 50% in the presence of GR231118. As observed for
BIBO 3304, in response to GR231118, MCH-induced food intake was not
significantly different from that in the vehicle group for the first
2 h of the experiment (Fig. 3A).
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; n = 4; P < 0.001). The
administration of GR231118 abolished the feeding response to 1 nmol NPY
for the first 2 h of the experiment. Moreover, administration of
GR231118 led to a sustained reduction of NPY-induced food intake, such
that a 77% inhibition was still evident at 4 h [vehicle + NPY,
6.8 ± 0.9 g (n = 8); GR231118 + NPY, 2.0 ±
1.1 g (n = 4); vehicle + vehicle, 0.6 ± 0.2 g
(n = 11); P < 0.001; Fig. 3B].
Effect of BIBO 3304 on NPY and MCH coadministration
To investigate possible additive effects, responses to icv
coadministration of 1 nmol NPY and 2 nmol MCH on food intake were
compared with those to 1 nmol NPY alone. Feeding induced by the
coadministration of both agonists closely resembled the feeding
response to 1 nmol NPY. At 4 h food intake reached 6.3 ±
0.7 g (n = 8) in response to coadministration of the agonists
compared with 5.9 ± 0.7 g (n = 9) after 1 nmol NPY.
In a separate group of animals, the effects of 20 nmol BIBO 3304, a
dose that had previously inhibited both NPY and MCH-induced food
intake, on the feeding response to coadministration of 1 nmol NPY and 2
nmol MCH were examined (Fig. 4). Prior
administration of BIBO 3304 significantly reduced food intake in
response to coadministration of both agonists at 30 min from 3.1
± 0.7 g (n = 13) to 1.6 ± 0.5 g (n = 8;
P < 0.05); however, food intake was no longer
different at 1 h. Although food intake in response to combined NPY
and MCH administration remained slightly lower in the presence of BIBO
3304, there was no significant difference at any other time point
examined. Food intake at 4 h was 6.5 ± 0.9 g (n =
13) and 6.3 ± 0.8 g (n = 8) in the absence and presence
of antagonist, respectively. Food intake in response to the
coadministration of 1 nmol NPY and 2 nmol MCH was not different from
that in response to the administration of 1 nmol NPY alone, which is
consistent with the results from the earlier series.
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Activation of the Y1-receptor by MCH
To test the hypothesis that MCH can stimulate feeding by directly
activating the Y1-receptor, the effect of MCH was
examined in a well characterized Y1-receptor
system, the rat mesenteric artery. Mesenteric artery tone was examined
using a Mulvaney myograph as previously described (36). In
four experiments, constrictor responses to
[Leu31,Pro34]NPY were
evaluated over a concentration range of
10-10–10-6
M. Robust constrictor responses to
[Leu31,Pro34]NPY were
observed, resulting in an EC50 value of 8.1, and
BIBO 3304 inhibited this constrictor activity in a dose-dependent
manner. However, no evidence of constrictor activity in response to MCH
from 3 x 10-9 to 3 x
10-5 M was found in vessels from the
same animals. Moreover, in the presence of 10-5
M MCH,
[Leu31,Pro34]NPY was
still able to elicit a normal constrictor response.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study has shown, for the first time, that food intake
induced by MCH is significantly inhibited by BIBO 3304. BIBO 3304 is a
recently available synthetic nonpeptide molecule that competes with
high affinity (IC50, 0.2 nM) for the
rat Y1-receptor and displays micromolar affinity
for the Y2-, Y4-, and
Y5-receptors (37). These results
suggest that the feeding response elicited by MCH is mediated in part
through activation of the Y1-receptor. This could
be achieved via an indirect mechanism by which MCH causes NPY release
and thus stimulates food intake, or perhaps through a direct activation
of the Y1-receptor by MCH itself (see Fig. 5). As reported previously after PVN
administration (38), in this study icv BIBO 3304
significantly inhibited the feeding induced by central administration
of NPY. We also demonstrated that the administration of BIBO 3304 alone
did not affect daytime feeding relative to vehicle. Therefore, it is
unlikely that the reduction in MCH-induced food intake was due to
nonspecific side-effects of BIBO 3304.
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The extent of inhibition of MCH-induced food intake by both BIBO 3304 and GR231118 was similar, with 73% and 86% inhibition at 2 h, respectively. The slight difference in the degree of inhibition by the two antagonists may arise from variation between the two groups of animals used. Although the administration of a higher dose of BIBO 3304 (40 nmol) was investigated, the presence of adverse reactions precluded further investigation. The time course of the inhibitory effects of BIBO 3304 and GR231118 on MCH was similar, with a more marked effect over the first 2 h.
This study also investigated the effects of coadministration of NPY and MCH on food intake. If these agonists stimulate feeding through independent mechanisms operating in parallel, one might have expected an additive effect of the food intake achieved in response to each agonist alone. However, coadministration of NPY and MCH did not increase food intake above that achieved by NPY alone. These results may not be surprising if the dose of NPY approached that maximally effective in stimulating food intake. The doses of NPY and MCH chosen gave very reproducible effects, and we know from parallel studies using NPY and a different mediator (Hansen, M. J., and M. J. Morris, unpublished observations) that it is possible to elicit 9–10 g food intake under identical conditions. Therefore, we believe that if these mediators were acting in an entirely independent manner, a larger response would have been observed. Further work is needed to test this, particularly the effect of BIBO 3304 on feeding responses to lower doses of NPY and MCH coadministration. In support of an interaction, our results demonstrating that 20 nmol BIBO 3304 was less able to inhibit food intake in response to the combination of agonists than to NPY alone suggest that antagonism of the Y1-receptor is less effective in the presence of MCH. This may arise due to competition by MCH at the Y1-receptor. Alternatively, MCH may stimulate NPY release, leading to an increased amount of NPY at the Y1-receptor. This possibility could be tested using techniques to measure in vivo NPY release. Finally, the relatively weaker antagonism of agonist-induced feeding by BIBO 3304 in the presence of both MCH and NPY may reflect the summation of non-Y1-receptor-mediated effects of both agonists (via Y5-receptor/SLC-1 receptor).
The fact that two selective Y1-receptor antagonists are able to block feeding induced by MCH also suggests that MCH may act in part directly at the Y1-receptor. Another possibility is that MCH may act via SLC-1 receptors on Y1-receptor-expressing neurons, altering neuronal responsivity. To our knowledge, the ability of MCH to bind the Y1-receptor has not been previously examined; however, the observed lack of constrictor activity of MCH in a well characterized Y1-receptor model in mesenteric blood vessels suggests that this is unlikely to be the case. We found no response to MCH in mesenteric arteries that contracted to [Leu31,Pro34]NPY, nor did MCH affect the ability of [Leu31,Pro34]NPY to cause contraction, suggesting that MCH does not compete at the Y1-receptor, at least in this preparation. If MCH does activate the Y1-receptor, it might be expected that the feeding response to MCH in the Y1 knockout would be attenuated. The Y5-receptor may make some contribution to the feeding action of MCH, but this question was not examined in the present study. The possibility that SLC-1 might be another NPY receptor appears unlikely, as the peptides screened for identification of the cognate ligand for SLC-1 were obtained from whole rat brain extracts, and only MCH and a truncated version of MCH yielded high agonist activity (44). An SLC-1 receptor antagonist would further help to characterize the mechanism of action of MCH.
MCH displays nanomolar affinity for its receptor, SLC-1 (28). As MCH-induced food intake is inhibited by two Y1-receptor antagonists, the possibility that MCH acts via its receptor to cause NPY release and thereby stimulate food intake seems quite feasible. The anatomical distribution of fibers further supports this hypothesis. MCH-ir fibers, SLC-1 mRNA, and immunoreactivity are found in hypothalamic areas that are implicated in NPY-induced feeding, including the PVN (29, 31). MCH-ir terminals are also found in the arcuate nucleus (31), a site of a major arcuo-PVN NPY-ergic projection. The site of any putative MCH-induced NPY release cannot be determined from the results of this study using exogenous icv administration of these orexigenic peptides.
From the results of the present study, we cannot exclude the
possibility that GR231118 and BIBO 3304 are both antagonists at the
SLC-1 receptor (Fig. 5), although the similar degree of inhibition of
NPY and MCH effects observed by these well characterized molecules
support a Y1 receptor mechanism. Interestingly,
recent reports detail the existence of a second GPCR for MCH, MCH-R2
(45, 46), in areas implicated in the regulation of body
weight (46).
The role of MCH in the regulation of food intake and its influence on other feeding mediators is particularly intriguing, as cell-specific lesions to the LHA produce hypophagia (23, 47). MCH cell bodies are localized in the LHA, and in separate, but spatially overlapping, cell bodies within the LHA are the orexins, newly recognized peptides that also stimulate food intake upon icv administration (48). The feeding effects of orexin were recently shown to involve NPY receptors, suggesting an interaction between these two mediators (33). Targeted deletion of the MCH gene results in decreased food intake and body weight (27), closely resembling the phenotype of rats with LHA lesions, whereas targeted deletion of the orexin gene induces narcolepsy (49). The recent observation that transgenic mice that overexpress MCH are hyperphagic and display an obese phenotype (50) confirms the fundamental role MCH plays in the regulation of food intake.
This study demonstrates that two structurally distinct, Y1-selective antagonists are able to significantly inhibit the feeding response evoked by MCH. With the overlapping distribution of MCH- and NPY-containing fibers and receptors, this new evidence supports the hypothesis that the responses of these two important orexigenic peptides are integrated. Although it is generally considered that arcuate NPY cells may make contact with LHA MCH-ir neurons (23), leading to MCH release, one interpretation of our finding is that MCH may elicit hyperphagia in part by stimulating NPY release subsequent to activation of the SLC-1 receptor. It is also possible that MCH is able to stimulate food intake by directly acting at the Y1-receptor, although our in vitro findings do not support this possibility. Although further work is needed to delineate the mechanism by which MCH may interact with NPY to stimulate food intake, the present study provides evidence that the feeding response elicited by MCH is mediated through activation of the NPY Y1-receptor, probably by regulating NPY release.
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Acknowledgments |
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Footnotes |
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Abbreviations: CNS, Central nervous system; GPCR, G protein- coupled receptors; icv, intracerebroventricular; -ir, immunoreactive; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; PVN, paraventricular nucleus; SLC-1, somatostatin-like receptor-1.
Received May 8, 2001.
Accepted for publication September 10, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), 2 nmol MCH (
), or vehicle (
), on food intake over
4 h in male Sprague Dawley rats (n = 8/group). Data are
expressed as the mean ± SEM and were analyzed using
repeated measures ANOVA followed by the post-hoc least
significant difference test. 
, P < 0.001,
significantly different from both NPY and MCH. *, P
< 0.001, significantly different from MCH.
) of 20 nmol BIBO 3304 on daytime food
intake in male Sprague Dawley rats (n = 9/group). B, Effect of icv
administration of 1 nmol NPY on daytime food intake in the absence
(
) of 20 nmol BIBO 3304 in male Sprague Dawley
rats (n = 8/group). Data are expressed as the mean ±
SEM and were analyzed using repeated measures ANOVA,
followed by the post-hoc least significant difference
test. *, P < 0.01, significant effect of BIBO 3304
on MCH. #, P < 0.001, significant effect of BIBO
3304 on NPY. 
) or the coadministration of 1 nmol NPY and 2 nmol MCH in the
absence (
) of 20 nmol BIBO 3304 in male Sprague
Dawley rats (n = 8, 13, and 8, respectively). Food intake was
measured over a 4-h period. Data are expressed as the mean ±
SEM and were analyzed using repeated measures ANOVA,
followed by the post-hoc least significant difference
test. 