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Department of Metabolic Medicine, Imperial College School of Medicine, London, United Kingdom W12 0NN
Address all correspondence and requests for reprints to: Prof. S. R. Bloom, Department of Metabolic Medicine, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London, United Kingdom W12 0NN. E-mail: s.bloom{at}ic.ac.uk
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Abstract |
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Paraventricular nucleus injection of PRL-releasing peptide did not alter food intake. Dorsomedial hypothalamic nucleus injection of PRL-releasing peptide decreased 1 h food intake [PRL-releasing peptide (1 nmol) 83.4 ± 6.1% saline all; P < 0.05]; and continued until 8 h postinjection [PRL-releasing peptide (1 nmol) 89.2 ± 4.1% saline; P < 0.05].
To investigate the mechanism of this inhibition of food intake, we
examined PRL-releasing peptide’s effect on neuropeptide release from
hypothalamic explants. 
MSH release was increased [PRL-releasing
peptide (100 nmol), 5.4 ± 1.6 pmol/explant; change
vs. basal, P < 0.01], whereas
agouti-related protein release was unchanged. The release of
cocaine- and amphetamine-regulated transcript was inhibited
[PRL-releasing peptide (100 nmol), -33.5 ± 12.6 pmol/explant;
change vs. basal, P < 0.01].
PRL-releasing peptide dose-dependently increased neurotensin
release [PRL-releasing peptide (1 nmol), 3.7 ± 2.6 pmol/explant;
change vs. basal, P = NS;
PRL-releasing peptide (10 nmol), 7.2 ± 2.7 pmol/explant; change
vs. basal, P < 0.01; PRL-releasing
peptide (100 nmol), 36.8 ± 5.4 pmol/explant; change
vs. basal, P < 0.001].
Our data suggest that the dorsomedial hypothalamic nucleus is important in the inhibitory effect of PRL-releasing peptide on food intake and that PRL-releasing peptide alters the release of several hypothalamic neuropeptides important in the control of food intake.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The icv administration of PrRP decreases food intake (9). The objective of this study was 2-fold: to localize hypothalamic sites important in this effect and to investigate the hypothalamic neuropeptide circuits that could be involved in this action of PrRP.
The distribution of this peptide and its receptors provides anatomical clues about which hypothalamic circuits PrRP may control. Immunoreactive PrRP (PrRP-IR) is most abundant in the medulla oblongata, but there are significant amounts of peptide in the hypothalamus (10). PrRP mRNA expression is localized to the dorsomedial hypothalamic nucleus (DMN) of the hypothalamus, the commissural nucleus of the solitary tract, and the ventrolateral reticular nucleus in the brainstem (3, 11, 12). In the dorsocaudal hypothalamus PrRP-IR fibers from the DMN join fibers from the commissural nucleus of the solitary tract and reticular formation (12) and then project to the paraventricular nucleus (PVN) (3, 11), where PrRP has been shown to stimulate the expression of c-fos, indicating neuronal activation (12, 13). Within the hypothalamus PrRP receptor expression is highest in the DMN and PVN (12).
The PVN and DMN not only have high receptor expression, but are both known to be important in the control of feeding behavior (14, 15, 16). The control of feeding in the hypothalamus is functionally arranged into stimulatory and inhibitory systems that interact extensively (17). Anatomically the arcuate nucleus (Arc), PVN, DMH, ventromedial hypothalamic nucleus, and lateral hypothalamic area (LHA) are most important in the control of feeding (17).
Several neuropeptides important in the inhibition of food intake are active when injected into the DMN, where PrRP receptor expression is high, including the melanocortins, neurotensin, and CART. The alteration of hypothalamic release of these peptides by PrRP has been investigated in vitro.
The melanocortin system is unusual, as it consists of both an
endogenous receptor agonist thought to be MSH and an endogenous
antagonist, agouti-related protein (AgRP) (18). These
peptides act via the melanocortin 3 receptor and the melanocortin 4
receptor (MC4R) present in the central nervous system. There is strong
evidence that the melanocortin system is important in the control of
energy homeostasis. Intracerebroventricular injection of MSH
inhibits feeding (19), as does intranuclear injection of
the long-acting MSH analog
[Nle4,D-Phe7]MSH
(NDP-MSH), whereas injection of AgRP-(83–132) increases feeding
(20). The DMN was shown to be one of the sites sensitive
to the action of MSH (20). The POMC gene knockout mouse
(21) and the MC4R knockout mouse are obese and hyperphagic
(22). In humans, abnormalities in both the MC4R gene and
the POMC gene are associated with severe obesity (23).
CART was originally described as a that increased 7-fold in response to amphetamine or cocaine administration (24). When the active fragment (55–102) is administered icv it decreases feeding (25, 26). Immunoneutralization with CART antiserum increases nocturnal feeding, supporting the argument that CART has a physiological role in the control of food intake (26). CART mRNA is found in the DMN (24), an area that shows c-fos activation after icv administration of the active fragment, CART-(55–102) (27).
Neurotensin is produced in the Arc, PVN, and DMN. When administered icv it inhibits feeding (28). This inhibition of feeding is mediated via the PVN and DMN (29, 30). Models of obesity such as the ob/ob mouse and the obese Zucker rat both display reduced neurotensin mRNA expression (31, 32). Recently, neurotensin has been demonstrated to be regulated by leptin and also to mediate part of the anorexic action of leptin in vivo (33).
We have employed direct intranuclear hypothalamic injection of neuropeptide to localize the hypothalamic site of PrRP’s anorectic action. To investigate the mechanism of this action we have used hypothalamic explant culture in vitro and measured PrRP-stimulated neuropeptide release from these cultures by RIA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH were
purchased from Peninsula Laboratories, Inc. (St. Helen’s,
UK). Human PrRP was synthesized using an automated peptide synthesizer
(model 396 MPS, Advanced Chemotech, Louisville, KY). HPLC using
C8 columns was used to purify peptides to
homogeneity, and the mol wt was verified by Maldi-Tof mass
spectrometry. Tissue culture materials were supplied by Life Sciences
Technology (Paisley, Scotland, UK), and all other reagents were
obtained from Merck & Co., Inc. (Rahway, NJ) or
Sigma (Poole, UK).
Animals
Male Wistar rats, weighing 250–300 g (specific pathogen free;
Imperial College School of Medicine, London, UK), were maintained under
a controlled environment (temperature, 21–23 C; 12-h light/dark
cycles; lights on at 0700 h) with ad libitum access to
food (RM1 diet, SDS Ltd., Witham, UK) and water. All animal
procedures were approved by the British Home Office Animals Scientific
Procedures Act 1986 (Project License 90/1077 and 70/3888).
Intracerebroventricular cannulation
Animals were anesthetized with a mixture of ketamine HCl (60
mg/kg; Ketalar, Parke-Davis, Pontypool, UK) and xylazine
(12 mg/kg; Rompun, Bayer Corp., Bury St. Edmunds, UK).
Prophylactic antibiotics, flucloxacillin (37.5 mg/kg) and amoxicillin
(37.5 mg/kg), were administered before surgery. Stainless steel
22-gauge cannulas (Plastics One, Inc., Roanoke, VA) were inserted
stereotactically into the third cerebral ventricle [0.8 mm caudal to
the bregma in the midline and 6.5 mm below the surface of the skull
using a Kopf stereotactic frame (Harvard Apparatus, Edensbridge,
UK); coordinates taken from the Paxinos and Watson atlas
(34)]. Three stainless steel screws were inserted into
the cranium, and the cannula was fixed to these with dental cement. The
animals were given 5 ml 0.9% saline for circulatory support and
buprenorphine (45 µg/kg; Schering-Plough Corp., Welwyn
Garden City, UK) for analgesia postoperatively. The animals were
allowed 1-wk recovery after surgery. They were then accustomed to
handling on a daily basis. Cannula placement was verified by observing
a sustained drinking response after icv injection of 150 ng
angiotensin II.
Hypothalamic intranuclear cannulation
The surgical procedure was performed as described above.
Stainless steel 26-gauge cannulas (Plastics One, Inc.) were inserted in
the PVN (0.5 mm lateral, 1.8 mm caudal to the bregma in the midline,
and 8.0 mm below the surface of the skull) and DMN (0.5 mm lateral, 3.1
mm caudal to the bregma in the midline, 8.8 mm below the surface of the
skull). A Kopf stereotactic frame was used, and the coordinates were
taken from the Paxinos and Watson atlas (34). Three
stainless steel screws were inserted into the cranium, and the cannula
was fixed to these with dental cement. The animals were again allowed 1
wk recovery postsurgery.
Cannula placement was verified by histological examination of the
animal brains at the end of the study. In brief, the animals were
injected with India ink and immediately decapitated. The brains were
rapidly removed and snap-frozen in liquid nitrogen using isopentane as
a cryopreservative. A freezing cryostat (Bright, Huntington, UK) was
used to take 15-µm sections, and every fourth section was
counterstained with Cressyl violet to allow anatomical localization
(35). Cannula placement was assessed by an observer
blinded to the intended cannula placement and was considered acceptable
if the hypothalamic nucleus was identifiable and the cannula tract was
seen in the nucleus (Fig. 1
). The Paxinos
and Watson atlas (34) was used to identify the PVN and
DMN.
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All feeding studies were performed after a 24-h fast with the animals allowed ad libitum access to drinking water. All experiments were carried out during the early light phase (0900–1100 h).
Intracerebroventricular feeding study
Groups of rats (n = 10–12/group) were fasted for 24 h
before the study and allowed ad libitum access to water.
They were injected icv with saline or PrRP (1, 3, 5, 10, or 3 nmol)
or MSH (3 nmol) all dissolved in 0.9% saline and
administered in a total volume of 10 µl given over 1 min. MSH, is
a known anorexigenic peptide (35), was used as a positive
control. The animals were returned to their home cages with a
preweighed amount of rat chow. The food remaining in the cage food
dispenser was reweighed to the nearest 0.1 g at 1, 2, 4, 8, and
24 h postinjection using a GW 600 balance (ATP Instrumentation,
Ashby-de-la-Zouche, UK).
Intranuclear studies
Groups of rats (n = 8–10) were injected with 0.9% saline,
PrRP (0.1, 0.5, 1, 2, or 0.5 nmol) or NDP-MSH all dissolved in
0.9% saline (0.5 nmol) and administered in a total volume of 1
µl and given over 1 min. NDP-MSH is a longer acting analog of MSH
and was used as a positive control. The animals were again returned to
their home cages with a preweighed amount of rat chow. The food
remaining in the cage food dispenser was reweighed 1, 2, 4, 8, and
24 h later.
Behavioral observations
Animals (n = 4–5/group) were fasted for 24 h. They
were injected icv with saline, PrRP (1, 3, 5, 10, or 3 nmol), or
MSH (3 nmol) all dissolved in 0.9% saline, returned to their
home cages, and observed for 60 min. The observer was blinded to the
experimental procedure. Behavior was classified into eight categories:
feeding, grooming, drinking, sleeping, head down posture, locomotion,
rearing, and burrowing [adapted after Fray et al.
(37)] using standard descriptions of the behaviors (Table 1A). Each animal was observed for a
15-sec period every 6 min. Each 15-sec observation was further divided
into three periods, and the behavior for each 5-sec period scored.
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MSH-IR, AgRP-IR, and CART-IR, by
RIA. MSH and CART were measured on the same aCSF sample; the other
hormones were measured in other separate specimens.
RIA of neuropeptides
MSH-IR, neurotensin-IR, and CART-IR were measured using
established RIAs developed in this laboratory (39, 40).
The assays were performed in a total volume of 350 µl phosphate
buffer, pH 7.4, containing 0.3% BSA and incubated for 3 d. For
MSH, 200-µl samples were measured, and for neurotensin, 100-µl
samples were measured. The CART assay also had 0.1% Tween 20
(Sigma, Poole, UK) added to the assay buffer, and a
50-µl sample was used.
AgRP-(83–132)-like immunoreactivity was measured using a method modified after Li et al. (41). In brief, the assay used 0.06 M phosphate buffer, pH 7.4, containing 1% BSA and 0.1% Tween 20. The sample volume was 100 µl. The rabbit AgRP antiserum was a gift from G. S. Barsh and was used at a final dilution of 1:200,000. Synthetic AgRP-(83–132) (Bachem, Merseyside UK) was used for the assay standard. AgRP-(83–132) was also radioiodinated with 125I by the Iodogen method. The iodinated peptide was separated by reverse phase HPLC (Waters C18 Novapak column, Millipore Corp., Milford, MA) over a 15–45% 90-min gradient of acetonitrile/water/0.1% trifluoroacetic acid. The [125I]AgRP-(83–132) was further purified using a Sep-Pak C18 cartridge (Millipore Corp.). The assay was incubated for 3 d at 4 C. Separation employed incubation with 100 µl goat antirabbit Ig antiserum (Pharmacia & Upjohn, Inc., Uppsala, Sweden) and 500 µl 0.01% Triton X-100 (Fisher Scientific Equipment, Loughborough, UK) at room temperature for 1–2 h. The sensitivity of the assay was 1 fmol/ml, and the minimal detectable amount was 2 fmol/explant. The intra- and interassay variabilities were established to be less than 10%.
Statistics
For the icv and PVN studies, data are presented as a percentage
of the saline control ± SEM, and groups were compared
by one-way ANOVA followed by a post-hoc Fisher’s least
significant difference test (Systat, Evanson, IL). For the DMN study, a
randomized cross-over design was employed, and each animal underwent
each experimental intervention with a 3-d recovery period between
experiments. Data for mean food intake are presented as a percentage of
the saline control value ± SEM, and groups
were compared by paired t test.
Behavioral data are presented as the percentage of time spent in a behavior in the first hour in the interquartile range. Comparisons are made by Kruskal-Wallis test (Systat).
Data from hypothalamic explant release experiments were compared by paired t test between the basal period and the test period and are presented as the change in peptide release (picomoles per explant) ± SEM. In all cases P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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]. This effect was no longer
evident by 8 h postinjection [PrRP (1 nmol), 67.2 ±
11.6% saline; PrRP (5 nmol), 89.5 ± 12.2% saline; PrRP (10
nmol), 67.0 ± 8.2% saline; all P = NS; Fig. 2B].
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MSH reduced 2-h food intake [MSH (3 nmol), 48.9 ± 13.7%
saline; P < 0.01] postinjection (Fig. 2A
). The effect
was not seen by 8 h [MSH (3 nmol), 61.3 ± 17.6% saline;
P = NS; Fig. 2B].
Effect of PVN injection of PrRP on food intake in 24-h fasted
rats
When injected into the PVN, PrRP over a dose range of 0.1–2 nmol
did not alter food intake at any time point (Fig. 3); for example, at 1 h
postinjection [PrRP (2 nmol), 90.0 ± 6.6% saline;
P = NS]. NDP-MSH significantly reduced food
intake at 1 h postinjection [NDP-MSH (0.5 nmol), 53.4 ±
7.4% saline; P < 0.001; Fig. 3A]. The anorectic
effect of NDP-MSH had worn off by 8 h (NDP-MSH, 81.4 ± 9.2%
saline; P = NS; Fig. 3B).
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]. Both 0.5 and 1 nmol PrRP continued
to decrease food intake at 8 h postinjection [PrRP (0.1 nmol),
94.2 ± 3.9% saline; PrRP (0.5 nmol), 86.8 ± 93.9% saline;
PrRP (1 nmol), 89.2 ± 4.1% saline; P < 0.05 for
0.5 and 1.0 nmol PrRP vs. saline; Fig. 4B]. At 24 h
postinjection, food intake had returned to control levels [PrRP (0.1
nmol), 96.1 ± 2.9% saline; PrRP (0.5 nmol), 87.2 ± 4.7%
saline; PrRP (1 nmol), 92.3 ± 4.4% saline; P =
NS; Fig. 4C].
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]. This was still evident at 8 h postinjection
[NDP-MSH (0.5 nmol), 73.3 ± 4.4% saline; P <
0.001; Fig. 4B]. The inhibition of food intake was returning to
control values at 24 h postinjection [NDP-MSH (0.5 nmol),
89.7 ± 3.4% saline; P < 0.05; Fig. 4C].
Effect of icv injection of PrRP on behavioral responses in fasted
male rats
PrRP at the highest dose of 10 nmol significantly increased
grooming in the first hour, as did MSH used as a positive control
[PrRP (10 nmol), 24% (range, 14–25%) of time spent in the behavior;
MSH, 50% (range, 33–58%) of time spent in the behavior; saline,
1% (range, 0–10%) of time spent in the behavior; P
< 0.05]. There was a trend for a decrease in feeding, but this failed
to reach significance [PrRP (10 nmol), 19% (range, 11–33%) of time
spent in the behavior; saline, 43% (range, 33–63%) of time spent in
the behavior; P = 0.08; Table 1]. MSH, a known
anorectic peptide, also decreased feeding, but this did not reach
statistical significance [MSH (3 nmol), 33% (range, 17–39%) of
time spent in the behavior; saline, 43% (range, 33–63%) of time
spent in the behavior; P = 0.08]. PrRP did not affect
any other behavior significantly (Table 1).
Effect of PrRP on neuropeptide release in vitro from static
hypothalamic explant culture
MSH. We found that PrRP stimulated the release of MSH
from hypothalamic explant in vitro [PrRP (0.01 nmol),
2.3 ± 2.0 pmol/explant; change vs. basal,
P = NS; PrRP (1 nmol), 2.9 ± 2.0 pmol/explant;
change vs. basal, P = NS; PrRP (100
nmol), 5.4 ± 1.6 pmol/explant; change vs. basal,
P < 0.01; Fig. 5A].
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]. CART. PrRP inhibited the release of CART from hypothalamic explants [PrRP (0.01 nmol), -23.8 ± 17.0 pmol/explant; change vs. basal, P = NS; PrRP (1 nmol), -14.0 ± 20.0 pmol/explant; change vs. basal, P = NS; PrRP (100 nmol), -33.5 ± 12.6 pmol/explant; change vs. basal, P < 0.01; Fig. 5C].
Neurotensin. PrRP dose-dependently stimulated the release of
neurotensin from hypothalamic explants [PrRP (1.0 nmol), 3.7 ±
2.6 pmol/explant; change vs. basal, P = NS;
PrRP (10 nmol), 7.2 ± 2.7 pmol/explant; change vs.
basal, P < 0.01; PrRP (100 nmol), 36.8 ± 5.4
pmol/explant; change vs. basal, P < 0.001;
Fig. 5D].
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PrRP has been reported to activate c-fos expression in the PVN after icv administration (7). There are immunoreactive PrRP fibers present in the PVN, seen mainly around the parvocellular neurons (42), but there is only a low level of PrRP receptor expression at this site (12). The PVN is thought to be important in the signaling of satiety and thus is a putative site of action for PrRP in the inhibition of food intake. PrRP in our studies had no effect on feeding when injected into the PVN in fasted rats. This may suggest that the PVN is not a major site of action for PrRP in the control of food intake.
Our studies show that DMN injection of PrRP produces a moderate, but significant, decrease in food intake. PrRP mRNA, PrRP-IR peptide, and PrRP receptor mRNA are found at high levels in the DMN (12). In the hypothalamus the DMN is the only site of pro-PrRP mRNA expression, and PrRP receptor expression is also highest here (12). Studies using animals with lesions of the DMN have shown that this nucleus plays a role in the signaling of satiety (43, 44). The anorexia following DMN injection of PrRP occurs within the first hour and is more rapid in onset than the effect seen after icv administration. The inhibition of feeding after DMN injection of PrRP is also of longer duration than when PrRP is administered icv. These results could suggest that the DMN is an important site in PrRP’s inhibitory effect on food intake.
We have examined the effects of icv injection of PrRP on behavioral
responses and found that PrRP (10 nmol) increases grooming and also
tended to decrease feeding, although this failed to reach statistical
significance. Increased grooming is associated with stress responses,
which would be expected to decrease feeding behavior (45).
However, the physiological significance of excess grooming is not
clear, as, for example, icv administration of orexin A increases both
grooming and feeding episodes (46). It is interesting that
MSH, a specific inhibitor of feeding, showed an almost identical
pattern of behavioral changes as 10 nmol PrRP. The animals displayed no
other behavioral responses to PrRP administration.
To investigate the possible mechanisms of action by which PrRP reduces
food intake, we studied the ability of PrRP to alter the production of
hypothalamic peptides known to be involved in appetite control. We
demonstrated that PrRP can alter the hypothalamic release of several
neuropeptides important in the control of food intake in
vitro. MSH is an important inhibitor of food intake.
Intracerebroventricular injection of MSH decreases feeding
(19), and chronic administration of HS104, a selective
MC4R antagonist, increases food intake, leading to obesity, suggesting
that there is a hypothalamic inhibitory MSH tone that reduces food
intake (47). Previous work from this laboratory has shown
that direct injection of MSH into the DMN reduces food intake
(35). Our present studies have shown that PrRP increased
MSH secretion without altering the release of AgRP from the
hypothalamus in vitro. This release of MSH, in the
absence of increased AgRP could be one of the hypothalamic mechanisms
by which PrRP reduces food intake.
Intracerebroventricular injection of CART-(55–102) inhibits food intake (25), and our investigations show that PrRP inhibited the secretion of CART in vitro from hypothalamic explants. This inhibition of hypothalamic release of an anorectic peptide by PrRP appears contradictory; however, recent studies in our laboratory have demonstrated that CART increases food intake in rats when administered via direct intranuclear injection (48). This effect is most pronounced in the Arc, DMN, VMN, and LHA. Further studies have suggested that the anorectic properties of icv administered CART are due to a nonspecific behavioral effect that is observed after direct intranuclear injection of the peptide. Therefore, the reduction of hypothalamic CART release may be a second mechanism by which PrRP can reduce food intake.
Our studies demonstrate that PrRP can dose-dependently stimulate the release of neurotensin from hypothalamic explants. Neurotensin is known to inhibit food intake (28) and has recently been implicated as a mediator of the central anorexic effect of leptin (33). The DMN contains high levels of neurotensin (29, 49), and it has been shown that neurotensin-IR neurons project from the DMN to the PVN (50), where injection of neurotensin has been shown to inhibit food intake (50). The increase in neurotensin by PrRP could be an important mediator of the anorectic effect of PrRP.
Our studies suggest that PrRP alters the release of several neuropeptides involved in the control of food intake. All of these peptides have an action involving the DMN, where we have shown that injection of PrRP decreases feeding. These in vitro findings suggest a possible mechanism of action by which PrRP decreases food intake.
In conclusion, our data support the hypothesis that the DMN an important PrRP site of action in the inhibition of food intake in the rat. Our data also suggest that PrRP alters the secretion of several hypothalamic peptides important in the control of food intake.
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Acknowledgments |
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Footnotes |
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Abbreviations: aCSF, Artificial cerebrospinal fluid; AgRP, agouti-related protein; Arc, arcuate nucleus; CART, cocaine- and amphetamine-regulated transcript; DMN, dorsomedial hypothalamic nucleus; icv, intracerebroventricular; -IR, immunoreactive; LHA, lateral hypothalamic area; MC4R, melanocortin 4 receptor; NDP-MSH, [Nle4,D-Phe7]MSH; PrRP, PRL-releasing peptide; PVN, paraventricular nucleus.
Received February 27, 2001.
Accepted for publication June 7, 2001.
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References |
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-melanocyte stimulating hormone in
vivo. Endocrinology 139:4428–4431-melanocyte-stimulating hormone. Diabetes 49:177–182[Abstract]
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neuropeptide) ±
SEM. A,