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Endocrine Unit, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom W12 ONN
Address all correspondence and requests for reprints to: Prof. S. R. Bloom, Imperial College School of Medicine Endocrine Unit, Hammersmith Hospital, London, United Kingdom W12 0NN.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CART has been implicated in the control of feeding behavior. CART mRNA
and peptide are colocalized with the anorectic peptide 
MSH in the
ARC and with the orexigenic peptide melanin-concentrating hormone in
the lateral hypothalamic area (LHA) (7, 8, 9). Nerve
terminals immunoreactive for the orexigenic peptide NPY are
closely apposed with CART peptide-containing cell bodies in the PVN,
ARC, LHA, and DMN (8, 10). Intracerebroventricular (icv)
injection of the active fragment of CART, CART(55–102), has been shown
to activate the immediate early gene c-fos in the PVN, DMN,
ARC, and supraoptic nucleus (SON) of the hypothalamus
(11).
Additional data suggested a role for CART as an endogenous inhibitor of food intake. Hypothalamic CART peptide and mRNA levels are decreased in fasted Wistar rats, obese leptin-deficient ob/ob mice, and obese leptin receptor-defective Zucker rats (12). Intracerebroventricular administration of a polyclonal CART antiserum significantly increased nocturnal feeding in satiated rats (12, 13). Several groups, including our own, reported inhibition of food intake after icv injection of CART(55–102) (11, 12, 13, 14). Kristensen et al. noted that icv administration of CART(55–102) caused movement-associated tremor, but reported no changes in spontaneous locomotor activity levels when monitored in isolated activity test chambers for 1 h postinjection (12).
To further characterize the areas of the hypothalamus in which CART influences feeding, CART(55–102) was injected into discrete hypothalamic nuclei. The nuclei into which CART(55–102) was injected in this study contain both CART mRNA and peptide and have been implicated in the regulation of food intake and energy expenditure. Food intake and behavioral effects were monitored after the injection of peptide. As these studies elicited unexpected results, feeding and behavioral effects of icv CART(55–102) were reexamined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Intranuclear and icv cannulation
Animal surgical procedures and handling were carried out as
previously described (15). Animals were anesthetized by ip
injection of a mixture of Ketalar (ketamine HCl, 60 mg/kg;
Parke-Davis, Pontypool, UK) and Rompun (xylazine, 12
mg/kg; Bayer Corp. UK Ltd., Bury St. Edmunds, UK) and
placed in a Kopf stereotaxic frame. For intranuclear cannulation,
animals were implanted with permanent 26-gauge stainless steel guide
cannulae (Plastics One, Inc., Roanoke, VA) projecting into the medial
preoptic area (MPO), SON, anterior hypothalamic area (AHA), PVN, VMN,
DMN, ARC, and LHA of the hypothalamus, according to coordinates of
Paxinos and Watson (16) (Table 1
). For icv cannulation, permanent
22-gauge stainless steel guide cannulae were stereotactically placed
0.8 mm posterior to the bregma on the midsagittal line and implanted
6.5 mm below the outer surface of the skull, into the third cerebral
ventricle [coordinates calculated using atlas of Paxinos and Watson
(16)]. All compounds were dissolved in 0.9% saline, and
each study involved an injection of peptide or saline in a volume of 1
µl (for intranuclear studies) or 5 µl (for icv studies) over 1 min.
Substances were administered by a 31-gauge (for intranuclear studies)
or a 27-gauge (for icv studies) stainless steel injector placed in and
projecting 1 mm below the tip of the cannulas. All substances were
administered in the early light phase (0900–1000 h). Correct
intranuclear cannula placement was confirmed histologically at the end
of the study period. After injection of 1 µl black ink, animals were
decapitated, and brains were removed, immediately frozen in liquid
nitrogen, and stored at -70 C. Brains were sliced on a cryostat
(Bright, Huntingdon, UK) into 15 µm coronal sections and stained with
cresyl violet. Correct icv cannula placement was confirmed by a
positive dipsogenic response to angiotensin II (150 ng/rat). Only those
animals with correct placement of cannulas were included in the data
analysis.
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Study 2: effect of intranuclear injection of CART(55–102) on food
intake in the satiated rat
After the observed increase in food intake in 24-h fasted rats
following injection of CART(55–102) into selective hypothalamic
nuclei, satiated rats cannulated into the DMN were injected with either
saline or 0.2 nmol CART(55–102) (n = 10–12/group), and their
food intake monitored. After injection, animals were returned to their
home cages containing a preweighed amount of chow, and their food
intake was measured at 1, 2, 4, 8, and 24 h post injection as
described above.
Study 3: effect of icv injection of CART(55–102) on food intake
and behavior in the 24-h fasted and satiated rats
Intracerebroventricularly cannulated, satiated and 24-h fasted
rats (n = 9–10/group) were injected in the early light phase with
saline or 0.2 nmol (1 µg) or 0.4 nmol (2 µg) CART(55–102). Animals
were then immediately returned to their home cages, which contained a
preweighed amount of chow. Food intake of the satiated animals was
determined at 1, 2, 4, 8, and 24 h postinjection as detailed
above. Twenty-four-hour fasted rats were observed for behavioral
analysis. The rats were observed continuously for 4 h
postinjection by observers blinded to the experimental treatment.
Behavior was classified into nine different categories: feeding,
drinking, grooming, burrowing, rearing, locomotion, sleeping, head
down, and flattened body posture/movement- associated tremor (Table 2), adapted from Fray et al.
(17). Each rat was observed for 10 sec every 6 min during
the test session. This 10-sec period was further divided into three
parts, and the behavior of the rat in each section of the time period
was scored. So as not to disturb the behavioral analysis, food intake
was only measured at 4, 8, and 24 h postinjection.
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Statistical analysis
Intranuclear food intake data for 24 h fasted rats are
expressed as the mean ± SEM percentage of the control
value. Statistical analysis for both doses of peptide at each nucleus
and time point was carried out by paired t test. DMN food
intake data for satiated rats and icv food intake data are expressed as
the mean ± SEM. Data at each time point
were compared by ANOVA, followed by a post-hoc least
significant difference analysis (Systat, Evanston, IL). Behavioral data
are expressed as the median number of occurrences of behavior
(interquartile ranges are expressed in square brackets).
Comparisons between groups were made by Mann-Whitney U test. f
P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MPO. There was no significant alteration in feeding after the
administration of 0.04 nmol CART(55–102) at any time point measured
(Fig. 1A). After the injection of
0.2 nmol CART(55–102) a decrease in food intake was seen only at
1 h after injection (56 ± 15% of control; P
< 0.05).
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). After the injection of 0.2 nmol CART(55–102), an increase
in feeding was observed at 2–4 h postinjection (212 ± 34%;
P < 0.05).
AHA. There was no significant alteration in feeding after the
administration of 0.04 nmol CART(55–102) at any time point measured
(Fig. 1C). Administration of 0.2 nmol CART(55–102) increased feeding
at 2–4 h postinjection (252 ± 42%; P <
0.01).
PVN. Similar to injection into the SON and AHA, there was no
significant alteration in feeding after the administration of 0.04 nmol
CART(55–102) at any time point measured (Fig. 1D). Again,
administration of 0.2 nmol CART(55–102) increased feeding at 2–4 h
postinjection (186 ± 29%; P < 0.05). Food
intake at all other time points was not significantly different from
control levels.
VMN. Both 0.04 and 0.2 nmol CART(55–102) caused a dramatic
increase in feeding at 1–2 h postinjection when administered into the
VMN [0.04 nmol, 261 ± 60% (P < 0.05); 0.2
nmol, 1253 ± 179% (P < 0.001); Fig. 1E]. This
increase in feeding was no longer apparent 4 h postinjection.
DMN. Rats cannulated into the DMN showed no significant
alteration in feeding after the administration of 0.04 nmol
CART(55–102) (Fig. 1F). Administration of 0.2 nmol CART(55–102)
significantly increased feeding in both the 1–2 and 2–4 h
postinjection periods (1–2 h, 240 ± 35%; 2–4 h, 368 ±
29%; both P < 0.001). A slight reduction in feeding
was seen at 8–24 h postinjection (79 ± 6%; P <
0.05).
ARC. Both 0.04 and 0.2 nmol CART(55–102) caused a significant
increase in feeding at 1–2 h postinjection when administered into the
ARC (0.04 nmol, 225 ± 38%; 0.2 nmol, 265 ± 43%; both
P < 0.05; Fig. 1G). This increase was maintained
throughout the 2- to 4-h postinjection period following 0.2 nmol
CART(55–102), but returned to control levels after 0.04 nmol
CART(55–102) (0.2 nmol, 209 ± 18%; P < 0.01).
A subsequent decrease in feeding with respect to control levels was
observed after the injection of 0.2 nmol CART(55–102) during the 4- to
8-h postinjection period (61 ± 11%; P <
0.05).
LHA. Administration of 0.04 nmol CART(55–102) into the LHA
caused a decrease in feeding only at 4–8 h postinjection (68 ±
10%; P < 0.05; Fig. 1H). In contrast, injection of
0.2 nmol CART(55–102) elicited a significant increase in feeding at
2–4 h postinjection (280 ± 34%; P < 0.001),
whereas a reduction in feeding was measured at 8–24 h postinjection
(83 ± 5%; P < 0.001).
Study 2: effect of intranuclear injection of CART(55–102) on food
intake in the satiated rat
The data below are expressed as the mean ± SEM
percentage of the saline control value. Mean saline values for each
time point are: 0–1 h, 2.3 ± 0.2 g; 1–2 h, 1.3 ±
0.3 g; 2–4 h, 1.5 ± 0.3 g; 4–8 h, 5.8 ±
0.5 g; and 8–24 h, 18.2 ± 0.7 g. CART(55–102)
significantly increased feeding after injection into the DMN of
satiated rats (Fig. 2). Administration of
0.2 nmol CART(55–102) increased feeding by approximately 200% of the
saline control value (191 ± 21% of saline control;
P < 0.001) at 1–2 h postinjection. Food intake during
the 2–4 h postinjection period was still significantly elevated above
the control level (160 ± 24% of control; P <
0.05). A subsequent decrease in feeding with respect to control levels
was observed during the 4- to 8-h postinjection period (64 ± 11%
of control; P < 0.05). Food intake at 8–24 h
postinjection was not significantly different from control levels (Fig. 2).
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).
CART(55–102) (0.2 nmol) decreased feeding to 50 ± 15% of the
control value (P < 0.01), and 0.4 nmol CART(55–102)
reduced feeding to 33 ± 13% of the control value
(P < 0.001) in the 4 h after injection (Fig. 3A).
In the higher dose group food intake was still inhibited during the 4-
to 8-h period (66 ± 13% control; P < 0.001),
but returned to control levels at the later time point (Fig. 3A).
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). CART(55–102) (0.2 nmol) decreased feeding to 41
± 18% of the control value (P < 0.05), and 0.4 nmol
CART(55–102) markedly reduced feeding to 9 ± 7% of the control
value (P < 0.01) in the 4-h postinjection period (Fig. 3B). Food intake was still significantly inhibited in the higher dose
group during the 4- to 8-h (14 ± 9% of control;
P < 0.001) and 8- to 24-h (52 ± 10% of control;
P < 0.01) postinjection periods (Fig. 3B).
Twenty-four-hour fasted, saline-treated rats exhibited a common
behavioral satiety sequence of grooming and sleeping after an initial
period of feeding, whereas 24-h fasted CART(55–102)-treated rats
displayed an abnormal behavioral pattern (Table 3, A–C) (18). Rats treated
with CART(55–102) exhibited a significant reduction in feeding
episodes, with no increase in grooming or sleeping during the first
hour postinjection compared with saline-treated animals (Table 3A).
Fifty and 78% of rats injected with 0.2 and 0.4 nmol CART(55–102),
respectively, adopted a flattened body posture and exhibited a
movement-associated tremor throughout the 4-h observational period
compared with saline-injected controls (Table 3, A–C). No
saline-treated animals demonstrated this behavior. Rats treated with
CART(55–102) (0.2 or 0.4 nmol) that did not exhibit this abnormal body
posture and associated tremor showed a significant increase in head
down and burrowing behavior compared with saline controls (Table 3,
A–C).
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, A–C). A dose-dependent
increase in feeding episodes was observed after CART(55–102)
administration, although it was not significant from control levels
until 1–2 h postinjection (Table 4B). This increase in feeding
episodes was associated with increasing burrowing and a subsequent
decrease in sleeping episodes, both of which were significantly altered
from saline-injected control animals (Table 4, A–C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It could be argued that the effects reported here lack anatomical specificity due to diffusion. Although very small doses of peptide were administered in the intranuclear studies, the possibility of diffusion beyond the area of injection must be considered. An increase in food intake was seen after injection of CART(55–102) into the SON, an area that has not previously been implicated in the control of feeding. It could be hypothesized that this increase was due to diffusion to the DMN, VMN, or ARC, nuclei that have been shown in this study to elicit a significant increase in feeding after CART(55–102) administration. If this were the case, however, then an increase in feeding would have been expected after injection into the MPO, which is anatomically nearer to the highly responsive nuclei than the SON. We have shown that injection of CART(55–102) into the MPO does not increase feeding. This suggests that the response after injection into the SON is specific and is unlikely to be due to diffusion. Our data therefore suggest that for the doses chosen in this study the diffusion effect from one nucleus to another is small.
Intracerebroventricular injection of CART(55–102) into both 24-h fasted and satiated rats resulted in a significant and sustained reduction in feeding, comparable to previous findings (12). We also noted that icv administration of CART(55–102) was associated with marked abnormalities in behavior. After icv injection of 0.4 nmol CART(55–102), nearly 80% of animals adopted a flattened body posture and exhibited movement-associated tremor, both of which were evident as early as 10 min postinjection. None of the animals treated with CART(55–102) showed an increase in grooming or sleeping episodes, behaviors that would be expected after the administration of an anorectic peptide (18). After an initial period of feeding, the saline-treated rats exhibited the expected behavioral satiety sequence of grooming and sleeping (18). Movement-associated tremors have been documented in previous studies after icv administration of CART(55–102), although in the studies performed it was not thought to alter the ability to feed (11, 12). The presence of motor abnormalities and tremor in CART(55–102)-treated animals could suggest that the inhibition in feeding seen after icv administration is an adverse, rather than a true anorectic, effect. Injection of equivalent doses of CART(55–102) into the ARC increased feeding episodes, but was not associated with any of these behavioral abnormalities.
CART(55–102) has previously been proposed as an anorectic
neuropeptide. Kristensen et al. (12) have shown
a significant reduction in ARC and DMN CART mRNA expression after a
48-h fast. However, studies within our laboratory have shown an
increase in CART immunoreactivity in discrete regions of the
hypothalamus under similar conditions (20). Interestingly,
it has recently been reported that CART knockout mice show a slight,
but consistent, reduction in body weight and fat mass, although these
trends did not reach significance (21). It is possible,
therefore, that CART is differentially regulated within the
hypothalamus. Recent studies have shown both amplificatory and
inhibitory effects after application of CART peptide to
-aminobutyric acidergic populations in the PVN (22).
These different responses could represent two types of CART appetite
circuits within the hypothalamus, one orexigenic and the other
anorectic. This theory may help to explain why a delayed increase
in feeding after intranuclear CART(55–102) injection is seen in both
the fasted and satiated states. Alternatively, the injected
CART(55–102) might activate an inhibitory autoreceptor. Such a
mechanism has been recently postulated for the melanocortin-3 receptor
effect on the melanocortin feeding system (23).
Our data indicate that the effects of CART on feeding regulation are complex, but suggest a novel role for CART peptide as an orexigenic neuropeptide.
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Footnotes |
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Received January 24, 2001.
Accepted for publication April 4, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) or 0.2 nmol (
) of CART(55–102) given into MPO (A), SON (B),
AHA (C), PVN (D), VMN (E), DMN (F), ARC (G), and LHA (H) over a 24-h
period in 24 h fasted rats. Data are expressed as a percentage of the
saline control value. *, P < 0.05; **,
P < 0.01; ***, P < 0.001
(vs. saline).
