Vol. 273, Issue 6, R2112-R2116, December 1997
Physiological regulation of hypothalamic neuropeptide Y
release in lean and obese rats
A.
Stricker-Krongrad,
R.
Kozak,
C.
Burlet,
J. P.
Nicolas, and
B.
Beck
Institut National de la Santé et de la Recherche
Médicale U308 Mécanismes de Régulation du
Comportement Alimentaire, 54000 Nancy, France
 |
ABSTRACT |
The
paraventricular nucleus (PVN) of the hypothalamus is an important site
for the regulation of feeding behavior. Neuropeptide Y (NPY) injected
into this nucleus strongly stimulates food intake. In the current
study, we measured NPY release in the PVN of unrestrained rats through
the push-pull technique. The rats were placed in their habitual
environment and conditions of life. NPY release was augmented by
>40% (P < 0.01) in Long-Evans
rats deprived of food for 12 h. It returned to the baseline as measured
in ad libitum-fed rats 90 min after food access. Its stimulation by 55 mM KCl in refed animals indicated that the whole stock of NPY was not
used during a short fast. During the light-dark transition, when
feeding behavior is initiated, NPY release in lean Zucker rats showed a
peak 20 min after lights off and then declined. It corresponded well
with the first feeding episodes. In the obese Zucker rats, this peak
was absent. NPY release was totally anarchic but at a high level. The
feeding behavior of the obese rats was not as time delimited as in the
lean rats. This study performed in very physiological conditions
therefore indicates that NPY release could drive feeding behavior in
the normal life. Its dysregulation in obese rats could participate in
overeating and absence of feeding rhythm measured in these rats and
speed up the development of their obesity.
push-pull technique; paraventricular nucleus; spontaneous feeding
behavior; fasting; Zucker rat
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INTRODUCTION |
THE HYPOTHALAMIC paraventricular nucleus (PVN) is an
important site where autonomic and neuroendocrine regulatory
information is integrated (33). It is involved in the regulation of
feeding behavior (16, 20) and contains numerous peptides that mediate food intake (23). Among them, neuropeptide Y (NPY) is found in
abundance in fibers (14). These fibers mainly originate in the arcuate
nucleus (ARC) (2) and in the brain stem (27). The PVN plays a critical
role in the effect of NPY on feeding behavior. This has been
demonstrated by several approaches. First, NPY injection in this
nucleus strongly stimulates food intake (12, 29). Sensitivity to
injection of exogenous NPY is enhanced when the NPY concentrations in
the PVN are diminished either by the neurotoxic effect of monosodium
glutamate on the arcuate neurons (31) or by transections of the neural
connections between the brain stem and PVN (24). On the other hand, the
orexigenic effects of NPY can be blocked by direct injection of
antibodies to NPY into the PVN (28). Second, fasting and refeeding
modulate NPY concentrations in the PVN (6, 25). These concentrations
also vary according to the light-dark cycle. A peak is observed at the
beginning of the dark phase (17), and it is well known that this
particular period is characterized by the ingestion of the first meals
by the rat. Finally, by use of push-pull or microdialysis techniques,
several researchers have shown that NPY is released in the PVN in the
basal state (19, 30) and in food-deprived animals (19). This release
can be stimulated in vivo by a potassium-induced depolarization (30).
NPY in the PVN is also involved in abnormal feeding behavior as
observed in the anorexic tumor-bearing rats and in the hyperphagic obese Zucker rats. Diminished and augmented concentrations are respectively measured in the two models (4, 11, 22). The hyperphagia in
obese Zucker rats is also characterized by an absence of regulation by
the feeding state and a decreased sensitivity to NPY injection (5, 32).
The dynamic release of NPY is diminished in tumor-bearing rats (11),
but in hyperphagic Zucker rats, contradictory results were reported. In
vitro, basal NPY efflux from the PVN of obese rats was not different
from that measured in lean rats (18). In vivo, however, release was
significantly augmented (13).
Therefore, in view of this information, the goal of the present
experiment was to ascertain the role of NPY in the PVN in the normal
and perturbed feeding behavior in very physiological conditions. For
this purpose, we first confirmed that NPY is released in greater
quantity after a short fast, and we then described the total anarchy in
the NPY release during the light-dark transition in the obese Zucker
rat.
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MATERIALS AND METHODS |
Experiment 1.
Male Long-Evans (CERJ, Le Genest-Saint-Isle, France) weighing
250-300 g were used for this study. They were housed in plastic cages in the vivarium with a 12:12-h light-dark cycle (lights on
0700-1900). They were fed on a standard laboratory diet (A04, UAR,
Villemoisson sur Orge, France) ad libitum and had tap water to drink.
After at least 2 wk of habituation, the rats were anesthetized by
intraperitoneal injection of chloral hydrate-ketamine (Ketalar, Parke-Davis, France; 150 mg/kg body wt). They were stereotaxically implanted with a push-pull cannula (external cannula 500 µm, internal cannula 100 µm with 250-µm protusion) with a guide cannula placed above the right PVN. After 1 wk of recovery, they were perfused with
artificial cerebrospinal fluid (CSF) in our climatized push-pull room
for 8 h in the light period. The rate of perfusion was 13 µl/min. The
perfusion generally started 1 h after lights on. Thirty-minute samples
were collected into polypropylene tubes containing 10 µl of aprotinin
(Iniprol, Laboratoires Choay, France) and kept on ice. The samples were
lyophilized and stored at 
40°C before assay for NPY.
The rats were divided into two groups. The first group was perfused in
standard free-moving conditions with food and water available during
the entire session. The second group was food deprived for 12 h, i.e.,
corresponding to the dark period preceding the perfusion period. Water
remained available. Ninety minutes after the beginning of the perfusion
session, the rats were given access to food. A subgroup of this second
group (n = 3) was perfused with
hyperosmotic CSF (55 mM KCl) for 30 min starting 3 h after the
beginning of the session and then reperfused with normal CSF until the
end of the session.
Animal behaviors were recorded during the entire perfusion time by one
experimenter. Each of the mutually nonexclusive following behaviors was
recorded: moving, sleeping, resting, and eating.
At the end of the perfusion periods, the rats were killed by
decapitation, and brains were removed for histological control. Animals
with misplacement of the cannula or tissue damage were discarded from
the study.
Experiment 2.
Six-month-old lean (Fa/) and
obese (fa/fa)
Zucker rats born in our laboratory were used. Obese rats were
significantly heavier than the lean ones (542.0 ± 5.0 vs. 390.5 ± 5.6 g; P < 0.0001). They were
adapted to an inverse light-dark cycle (lights off at 1500). They were
fed on a standard laboratory diet (A04, UAR) ad libitum and had tap
water to drink.
They were cannulated as previously described for the Long-Evans rats.
They were allowed at least 1 wk of recovery.
The day before perfusion, they were transferred from the vivarium to
our temperature-regulated push-pull room. On the perfusion day, the
push-pull cannula was installed 3 h before lights off. This was
followed by a period of equilibration of 2 h with perfusion of
artificial CSF. Samples were then obtained every 20 min for a period of
3 h starting 1 h before lights off. The perfusion rate was the same as
for the Long-Evans rats (13 µl/min). When the lights went off, a red
light went on to allow the experimenter to control the perfusion and to
write down the animal behavior. Previous measurement showed that this
does not modify the feeding behavior of the rats. Cumulative time spent
eating was measured during each sampling period.
As for the Long-Evans, the Zucker rats were decapitated for the control
of the cannula placement. The main reason for discarding animals was
rupture of the third ventricle indicated during perfusion by an
unbalanced flow (too much efflux) and laterality. Eleven lean and nine
obese rats were finally used for NPY measurement and data analysis.
Trunk blood was sampled for the determination of the plasma glucose and
triglycerides to characterize the lean
Fa/ and obese fa/fa rats.
Assays.
Plasma glucose and triglycerides were measured by enzymatic techniques
using commercially available kits (Boehringer-Mannheim, Meylan,
France). NPY was measured with a specific radioimmunoassay developed in
our laboratory as previously described (4). In the present experiment,
maximal binding was 45.0 ± 2.5%. A 50% decrease of the bound
activity was obtained with a concentration of 0.41 ± 0.05 ng/ml of NPY. Assay sensitivity was 5 pg/tube. Nonspecific binding was
6.0 ± 0.4%. For the assay, the lyophilized samples were
reconstituted with 0.04 M phosphate buffer (pH 7.4) containing bovine
serum albumin (fraction V, Sigma Chemicals, La Verpillière,
France), aprotinin (4,000 IU/ml), and sodium azide (Merck, Darmstadt,
Germany).
Statistical analysis.
Results were compared by two-way analysis of variance and Friedman's
and Student's t-tests. Only
P < 0.05 was considered significant.
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RESULTS |
Experiment 1.
NPY release in the two groups of rats is shown in Fig.
1. In standard free-moving conditions, the
mean NPY content in the samples of the first group of rats was 31.5 ± 2.3 pg/tube. Before food access, the NPY content in the samples
of the food-deprived rats averaged 46.0 ± 5.5 pg/tube and was
significantly higher than the ad libitum-fed rats
(P < 0.01). After refeeding, NPY content progressively decreased. This decrease became significant 60 and 90 min after food availability (33.2 ± 2.6 vs. 46.0 ± 5.5 pg/tube; P < 0.05). After 90 min, it
did not change significantly until the end of the perfusion and was not
significantly different from that of the ad libitum-fed rats.
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Fig. 1.
Neuropeptide Y (NPY) release in paraventricular nucleus (PVN: mean ± SE) in 12-h food-deprived (FD) and refed Long-Evans rats ( ). A
subgroup was infused with 55 mM KCl after refeeding ( ). Baseline
release was measured in ad libitum (ad lib)-fed rats ( ). For
statistics, see RESULTS.
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The perfusion with hyperosmotic CSF induced a significant increase of
NPY release compared with the prepotassium levels in the same rats
(64.2 ± 3.6 vs. 24.2 ± 1.7 pg/tube;
P < 0.01), or with the mean levels
observed in the ad libitum-fed rats (P < 0.01). It rapidly returned to basal level.
The behaviors of the different groups of rats are shown in Figs.
2 and 3. A significant
increase in eating is measured immediately after the food access in the
food-deprived rats. Before food access, the food-deprived rats are
characterized by an augmentation in the time spent moving
(P < 0.05). Potassium infusion
induced a new episode of food intake (Fig. 3).
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Fig. 2.
Associated behaviors (mean ± SE) observed during push-pull session
in FD, refed (RF), and refed + potassium-stimulated (RF + KCl)
Long-Evans rats. * P < 0.05 vs. FD; ** P < 0.01 vs. FD;
° P < 0.05 vs. RF.
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Fig. 3.
Time spent eating (mean ± SE) during each sampling period of
push-pull perfusion in refed Long-Evans rats and after stimulation with
hyperosmotic KCl () and in ad libitum-fed rats (). , RF rats
without KCl stimulation.
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Experiment 2.
At the end of the experiment, all rats had gained weight. Final body
weight of lean rats was 412.3 ± 4.5 g, and that of the obese rats
was 627.8 ± 26.5 g. Obese rats were hyperglycemic [7.80 ± 0.26 (fa/fa) vs. 6.68 ± 0.26 (Fa/) mM;
P < 0.01] and
hypertriglyceridemic [3.31 ± 0.26 (fa/fa) vs. 0.56 ± 0.03 (Fa/) mM;
P < 0.001].
Feeding behavior of the Zucker rats is shown in Fig.
4. In the lean rats, there were two
clear-cut meals (P = 0.003) observed 20 and 100 min after lights off. The profile of the feeding behavior in
the obese rats looked like that of the lean rats, but due the large
variations observed between animals, typical meals could not be
detected (P = 0.55). Obese rats had a
tendency to spend more time for eating.
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Fig. 4.
Time spent eating (mean ± SE) during each sampling period of
push-pull perfusion in lean (A) and
obese (B) Zucker rats. Vertical bar,
light-dark transition.
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NPY release in both groups is shown in Fig.
5. In lean rats, NPY release progressively
increased during the last hour of the light period and peaked 20 min
after the beginning of the dark period (11.5 ± 1.4 vs. 6.2 ± 1.0 pg/tube; P < 0.013). It then regularly decreased until the end of the perfusion period. This phenomenon was not observed in the obese rats, and the profile was very
irregular without any significant variation during the entire
perfusion. However, the levels of release were augmented at least by
50% at the beginning (P = 0.012) and
end (P = 0.034) of the perfusion
period in obese compared with lean rats. These levels were equivalent
to the peak of release in the lean rats.
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Fig. 5.
NPY release in PVN in lean ( ) and obese () Zucker rats during
light-dark transition.
°° P < 0.01 vs.
samples of beginning and end of push-pull session. Significant
difference between 2 groups of rats:
* P < 0.05;
** P < 0.01.
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DISCUSSION |
In this study, we investigated the dynamic release of NPY in the
hypothalamus of rats through the push-pull technique. NPY is actually
considered to be the most potent stimulator of food intake and
therefore to play a major role in the regulation of feeding behavior
(reviewed in Ref. 29). Most of the information concerning the role and
regulation of NPY arises from measurements of its brain concentrations
in different feeding conditions. It was thus shown that its
concentration increases in the ARC and PVN in food-deprived animals. It
is normalized by food ingestion (6, 25) and can be modulated by diet
composition at short and long term (7, 8). It presents a nycthemeral
rhythm in the ARC and PVN (17). Its increased levels could also
participate in the development of hyperphagia and obesity in the Zucker
fa/fa rat (3, 4, 9). Measurements of
NPY mRNA expression in the ARC are generally in good agreement with the
peptide content (26). However, these two measures of content and
expression only reflect a timely situation and cannot give the entire
picture of what really happens during feeding. The measurement of the release will give an idea of the functional variations of NPY because
it can be measured in undisturbed, free-moving rats placed in their
habitual environment. The PVN was the hypothalamic site chosen for the
placement of the push-pull cannula because of its particular
sensitivity to NPY injection and its general involvement in numerous
feeding conditions (reviewed in Ref. 29). Several previous studies have
already shown that NPY is released in the basal fed state in this
nucleus (19, 30). We confirmed these data in the present study.
Moreover, in our rats placed in a situation of a light fast (12 h), we
showed that this basal liberation is augmented by >40% in the
food-deprived animals. This high release is associated with an
increased activity of the animals. As latency to eat in satiated
animals is decreased after artificial augmentation of hypothalamic NPY
by exogenous injection (12, 21, 29), it might induce the search for
food and motivation to eat (15). This result is in good agreement with
those obtained after a much longer fast of 3 days (19). We noted that
when food was available, the secretion returned to ad libitum levels
within 90 min. This return was delayed to 3 h after a 20-h fast in rats
on scheduled feeding regimen and to 24 h in 3-day-fasted rats (19). It
therefore appears that the level of secretion is proportional to the
duration of fast and can adapt itself to the energy need. In the case
of the 12-h fast, all reserves of NPY were not mobilized, since it was
still possible to stimulate the release through hyperosmotic potassium.
This might confirm this adaptive mechanism to the importance of food
deprivation, but the effects of KCl are not specific. The
KCl-stimulated NPY release might also derive from a pool not related to
food intake, having its origin in the brain stem, and the associated
feeding behavior may be related to the release of other neuromediators.
Further experiments are needed to clarify this point.
In Zucker rats, we used another strategy that is even more relevant to
the normal behavior of the rats. We measured the NPY release during the
light-dark transition. This period is well known for its activation of
feeding behavior in the rat. It is characterized by a peak of NPY
concentration in the ARC as well as the PVN (17). The basal NPY release
in Zucker rats was lower than that of the Long-Evans rats. This was
probably related to the animals themselves by combining a strain effect
with an age effect, since our Zucker rats were older than the
Long-Evans rats.
In the lean Zucker rat, we showed a progressive increase in the
liberation of NPY, which reached its maximum 20 min after the lights
were off. This increase was associated in time with the first meal that
occurred very rapidly after lights off. NPY release declined slowly
after this first period of food ingestion and increased slightly when
the second meal was consumed. These results agree with those obtained
in the fasting experiment. They mimic the situation observed with
punctual measurements of the tissue concentration and argue for a role
of NPY in triggering feeding behavior in early dark. In the obese
Zucker rats, the release of NPY was completely different. It did not
vary significantly during the whole experimental period even if it
presented a jagged profile. However, the mean level of secretion
corresponded to the peak measured in lean animals and was significantly
higher than the basal state in the lean animals. Food ingestion did not affect the release in the obese rats. The feeding behavior profile looked like that observed in the lean rats, but due to the very large
variability between obese animals, it was impossible to have clear-cut
meals at the same time. These data reinforce several ideas on the role
of NPY in obesity established from variations of concentration and
expression. First, the exacerbated release, which is also observed
during the light period (13), could continuously stimulate feeding
behavior and explain the disappearance of the classical light-dark
rhythm of food intake in the obese rat (1, 10). This high release could
also participate in the decreased sensitivity to exogenous NPY (32). It
corresponds to a maximal synthesis of the peptide in the ARC that
cannot be further enhanced by fast (5). Its insensitivity to food
ingestion agrees with the absence of effect of refeeding after fasting
(5).
In conclusion, this study of the dynamic release of NPY in the PVN
sheds light on the physiology of this peptide in unrestrained lean and
obese animals. This release is particularly sensitive to the repletion
of the energy stores in the lean animals. The sustained anarchic NPY
release in the Zucker fa/fa rat is a
feature of obesity in this animal model. This type of study, which is much more complicated to perform in animals with spontaneous nocturnal activity, was necessary to understand its regulation well and to
identify elements for developing new processes and/or
strategies for treating obesity.
Perspectives
This study emphasized the role of both an enhanced and dysregulated
release of NPY in obese rats. These changes could participate in the
modified feeding behavior of these rats and therefore contribute to the
development of their overweight. Future strategies for limiting these
disorders include the development of drugs that could control the
synthesis of this peptide. Research is also necessary to better
understand the mechanisms controlling the secretion of this peptide. A
well-controlled release would also help in normalizing intake and
weight gain. It must also be kept in mind that each behavior is the
result of a balance between neuropeptides or more generally
neuromediators. For now, a multitargeted drug strategy, such as that
currently used with AIDS, appears essential to fight these disorders.
In the future, the best option would be to prevent the development of
these disorders rather to treat them when they are established. This
will need additional research as well as a change in the general
approach to these problems at both research and political levels.
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ACKNOWLEDGEMENTS |
The authors thank F. Giannangeli for excellent technical assistance
in animal cannulation and C. Habert for preparation of the manuscript.
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FOOTNOTES |
This study was supported by a grant of Ministère de la Recherche
et de la Technologie "Aliment 2002" (MRT 92.G.0341). The results
were presented in abstract form at the Benjamin Franklin-Lafayette Symphagium (La Napoule, France).
Address for reprint requests: B. Beck, INSERM U308, 38 rue Lionnois,
54000 Nancy, France.
Received 13 November 1996; accepted in final form 25 August 1997.
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Abstract
Introduction
