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The Journal of Neuroscience, December 1, 1998, 18(23):10128-10135
Brainstem Application of Melanocortin Receptor Ligands Produces
Long-Lasting Effects on Feeding and Body Weight
Harvey J.
Grill1,
Abigail B.
Ginsberg1,
Randy
J.
Seeley2, and
Joel M.
Kaplan1
1 Department of Psychology and Institute of
Neurological Sciences, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, and 2 Department of Psychiatry,
University of Cincinnati, Cincinnati, Ohio 45267
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ABSTRACT |
Recent evidence suggests that the central melanocortin (MC) system
is a prominent contributor to food intake and body weight control. MC
receptor (MC-R) populations in the arcuate and paraventricular nuclei are considered probable sites of action mediating the orexigenic effects of systemically or intracerebroventricularly
administered ligands. Yet, the highest MC4-R density in the brain is
found in the dorsal motor nucleus of the vagus nerve, situated
subjacent to the commissural nucleus of the solitary tract, a
site of pro-opiomelanocortin mRNA expression. We evaluated the
contribution of the caudal brainstem MC system by (1) performing
respective dose-response analyses for an MC-R agonist (MTII) and
antagonist (SHU9119) delivered to the fourth ventricle,
(2) comparing, in the same rats, the fourth intracerebroventricular
dose-response profiles to those obtained with lateral
intracerebroventricular delivery, and (3) delivering an effective dose
of MTII or SHU9119 to rats before a 24 hr period of food deprivation.
Fourth intracerebroventricular agonist treatment yielded a
dose-dependent reduction of short-term (2 and 4 hr) and longer-term (24 hr) food intake and body weight. Fourth intracerebroventricular
antagonist treatment produced the opposite pattern of results:
dose-related increases in food intake and corresponding increases in
body weight change for the 24-96 hr observation period. Comparable
dose-response functions for food intake and body weight were observed
when these compounds were delivered to the lateral ventricle. Results
from deprived rats (no effect of MTII or SHU9119 on weight loss)
support the impression derived from the dose-response analyses that
the body weight change that follows MC treatments is secondary to their respective effects on food intake. Results support the relevance of the
brainstem MC-R complement to the control of feeding.
Key words:
fourth ventricle; lateral ventricle; food intake; water
intake; MTII; SHU9119; dorsal motor nucleus; caudal brainstem; POMC; arcuate nucleus; solitary nucleus
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INTRODUCTION |
The central melanocortin (MC) system
has rapidly become a focus of attention in the area of food intake and
body weight control. The MC 4 receptor (MC4-R) knock-out mouse
is obese, hyperinsulinemic, and hyperphagic (Huszar et al., 1997 ), as
is the agouti mouse, which chronically produces an ectopic protein that
acts as a competitive antagonist of the MC4-R (Lu et al., 1994).
Administration of the MC3/4-R agonist MTII into the forebrain
ventricles of rats and mice produces a dose-related suppression of food
intake (Fan et al., 1997; Thiele et al., 1998) and body weight (Thiele
et al., 1998). In mice, lateral intracerebroventricular delivery of the MC4/3-R antagonist SHU9119 (Hruby et al., 1995) stimulates feeding and
reverses the intake-suppressive effects of MTII (Fan et al., 1997).
Effects of intracerebroventricular leptin administration on food intake
and body weight in the rat (Campfield et al., 1996; Brunner et al.,
1997) are reversed by intracerebroventricular injection of SHU9119
(Seeley et al., 1997). Moreover, leptin treatment elevates hypothalamic
pro-opiomelanocortin (POMC) mRNA expression (Schwartz et al.,
1997; Mizuno et al., 1998). The latter results suggest that
melanocortin signaling plays an integral role in the action of
leptin on energy homeostasis.
Of the central elements of the MC system that may contribute to intake
control, only those in the hypothalamus have been considered. Special
emphasis has been placed on the POMC neurons in the arcuate nucleus,
which produce melanocortins, the endogenous ligands for MC3/4-R (Adan
et al., 1994). MC3/4-R populations in the arcuate and paraventricular
nuclei are considered probable sites of action mediating the orexigenic
effects of systemically or intracerebroventricularly administered MC
ligands (Roselli-Rehfuss et al., 1993; Mountjoy et al., 1994; Fan et
al., 1997; Mizuno et al., 1998; Thiele et al., 1998). It would appear
premature, however, to rule out the potential contribution of the
caudal brainstem (CBS) portion of the melanocortin system. There are
only two central sites of recognized POMC mRNA expression: the arcuate
nucleus and the commissural nucleus of the solitary tract (cNST) in the
CBS (Palkovits et al., 1987; Bronstein et al., 1992). The dorsal motor
nucleus of the vagus nerve (DMX), immediately subjacent to the
cNST, contains the highest MC4-R density found in the brain
(Mountjoy et al., 1994). This receptor population has attracted the
attention of cardiovascular physiologists (Li et al., 1996) but has yet
to be explored for a role in energy homeostasis. This is surprising because of the clear feeding relevance of the DMX, NST, and
related CBS structures (Ritter et al., 1981; Hyde and Miselis, 1983;
Berthoud and Powley, 1985; Flynn and Grill, 1985; Grill and Kaplan,
1990; Calingasan and Ritter, 1993; Fraser et al., 1995; Grill et al., 1997; Kaplan et al., 1998).
The contribution of MC receptors in the caudal brainstem to intake and
body weight control is explored in the present study. First, we perform
dose-response analyses for MTII and SHU9119 delivered to the fourth
ventricle. Second, we compare, in the same rats, the fourth
intracerebroventricular dose-response profile for the two agents
to that obtained with lateral intracerebroventricular delivery.
Treatments are evaluated for their short-term (up to 4 hr) effects on
pelleted food and water intake and for their longer-lasting effects
(24-96 hr) on food intake and body weight. Third, to determine whether
body weight change is secondary to the effects of either agent on food
intake or whether, as is apparently with leptin (Hwa et al., 1996;
Levin et al., 1996), intake effects do not completely account for
changes in body weight, we deliver a suprathreshold dose of MTII or
SHU9119 to rats whose food is yoked to that of controls by withholding
food for 24 hr after treatment.
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MATERIALS AND METHODS |
Subjects
Male Sprague Dawley rats (Charles River Laboratories,
Wilmington, MA), weighing 350-375 gm at the time of surgery, were
housed and tested in hanging metal cages. Separate groups of rats,
naive unless otherwise noted, were run in each experiment. Rats were maintained on a 12 hr light/dark schedule, with lights off at 12:00
P.M. For experiments 1 and 2, pelleted food and water
were available ad libitum. For experiment 3, food, but not
water, was withheld for 24 hr after intracerebroventricular injection
and returned thereafter. The experimental protocols used conform to institutional standards for animal care.
Surgery
Rats were anesthetized with a mixture of ketamine (9 mg/kg) and xylazine (1.5 mg/kg, i.m.). A 22-ga
intracerebroventricular guide cannula (PlasticsOne) was positioned
stereotaxically above the fourth ventricle (on the midline, 2.5 mm
anterior to the occipital suture, 4.5 mm below dura, 2.0 mm above
injection site), and another cannula was positioned above the lateral
ventricle (0.9 mm posterior to bregma, 1.6 mm lateral to midline, 2.0 mm below the dura, 2 mm above the injection site). The two guide
cannulas were cemented to jewelers screws attached to the skull.
Obturators were inserted into the guide cannula. Rats recovered for a
minimum of 7 d, during which they were handled, and daily food,
water, and body weight measurements were taken.
Procedures
Injections. MTII and SHU9119 were gifts of Keith
Yagaloff and Paul Burn (Hoffmann-La Roche, Nutley, NJ). Doses
were prepared using sterile isotonic saline and kept frozen at  80°C
until use. The 28-ga injector, when inserted, extended 2 mm
beyond the tip of the guide cannula. A 3 µl volume was loaded into a
Hamilton microsyringe and was injected over a 4 min period. The
injector was withdrawn 1 min later. Average latency from injection to
lights out was 30 min. Rats received access to preweighed food and
water at the onset of lights out.
Verification of cannula placement. Placement of each
intracerebroventricular cannula was functionally evaluated before
testing by measurement of the rise in plasma glucose after injection of 210 µg of 5-thio-D-glucose in 3 µl of isotonic saline.
[This sympathoadrenal response triggered by intracerebroventricular
infusion has been described previously (Ritter et al., 1981; Flynn and
Grill, 1985).] Only rats that responded with at least a doubling of
plasma glucose after 5-thio-D-glucose injection were used
in experiments 1-3.
Measurement of food, water, and body weight. One hour before
lights out, the food hopper and water bottle were removed and weighed,
and daily food and water intake values were determined. At this time,
rats were removed from their cages, weighed, and returned to their
cages. A fresh supply of preweighed food and water was returned 1 hr
later, at the onset of lights out. Food intake was calculated by
subtracting the weight of the hopper from its initial weight and adding
the weight of crumbs collected from under each cage. Water intake was
determined by subtracting the volume of the bottle from its
initial volume. On injection days, food and water intake was also
determined at 2 and 4 hr after lights out.
Experimental Design
Experiment 1. A dose-response analysis for MTII
(vehicle, 0.01, 0.1, and 1.0 nmol) was composed for fourth and lateral
ventricle placements in the same rats (n = 10). All
rats were tested once under each of the eight injection conditions (2 cannulas × 4 doses), with testing order counterbalanced across
rats. Injection conditions were separated by 72 hr. Doses were taken
from the available literature (Fan et al., 1997; Thiele et al.,
1998).
Experiment 2. A dose-response analysis for SHU9119
(vehicle, 0.25, 0.50, and 1.0 nmol) was composed for fourth and
lateral intracerebroventricular placements (n = 8). The
same design described for experiment 1 was used, except that 96 hr
separated injection conditions.
Experiment 3. Rats (n = 9, run previously in
experiment 1) received suprathreshold doses of SHU9119 (0.5 nmol) and
MTII (1.0 nmol), and their respective vehicle controls were delivered
to the fourth ventricle. Food was withheld for 24 hr after
intracerebroventricular injection; water was available at all times.
The interinjection interval was the same as that used for experiments 1 and 2: 72 hr for MTII and its vehicle, and 96 hr for SHU9119 and its
vehicle. Condition testing order was counterbalanced across rats.
Statistical analyses
Results for experiments 1 and 2 were analyzed via a two-way
(cannula placement × dose) repeated-measures ANOVA. The four
conditions of experiment 3 were treated as levels of a one-way
repeated-measures ANOVA. Post hoc comparisons were performed
via an LSD test.
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RESULTS |
Experiment 1: MTII dose-response analysis
MTII yielded a dose-dependent inhibition of short- and longer-term
food intake. The response functions obtained from the two intracerebroventricular administration sites were indistinguishable, except for that seen for water intake over the short-term.
Figure 1 shows the 2 hr and cumulative 4 hr food intakes (mean + SEM), both of which varied as a function of
dose (F(3,27) = 8.23; p < 0.005; F(3,27) = 10.27; p < 0.001, respectively) but not of cannula placement (F < 1.00, NS). For both time points, significant food intake
suppression against vehicle baseline was obtained with the 0.1 and 1.0 nmol doses (p < 0.015). There were no
significant interactions between dose and cannula placement.
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Figure 1.
MTII dose-related food consumption (in
grams) for the 2 hr or cumulative 4 hr period beginning with
lights out. Lateral or fourth intracerebroventricular injections were
delivered 30 min before lights out.
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As shown in Figure 2, top row,
left, the food intake-suppressive effects of MTII dose were
strongly expressed in the 24 hr measure (F(3,27) = 27.10; p < 0.00001). Post hoc
analyses showed significant effects for the 0.1 and 1.0 nmol doses,
evaluated against vehicle baseline. For 24 hr intake, as for the
short-term measures, there was no main effect of cannula placement
(F(1,9) = 0.09, NS) and no significant
two-factor interaction. Daily (noncumulative) intake readings 48 and 72 hr after injection (Fig. 2, top row, middle and
right) did not vary with dose
(F(3,27) = 1.16, NS; F(3,27) = 1.51, NS, respectively) or with
cannula placement (F(1,9) = 1.51, NS;
F(1,9) = 0.22, NS, respectively); the
interaction terms also were not significant. Because of this lack of
drug effect on these latter daily intake measures, the effect obtained for the first 24 hr was carried forward into significantly suppressed cumulative intakes 48 and 72 hr after injection. This result is illustrated in Figure 3, top,
which shows cumulative food intakes for the 1 nmol dose against vehicle
delivered to the fourth ventricle.
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Figure 2.
Daily MTII dose-related food consumption (in
grams) for the 3 d after a single intracerebroventricular
injection (top). Daily change in body weight (in grams)
for the same period after MTII treatment (bottom).
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Figure 3.
Cumulative food intake (top) and
cumulative body weight change (bottom) after delivery of
1.0 nmol MTII or vehicle to the fourth ventricle.
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Figure 2, bottom row, shows the changes in daily
(noncumulative) body weight after MTII treatment. Body weight 24 hr
after injection was significantly reduced as a function of MTII dose (F(3,24) = 38.6; p < 0.00001),
with no significant cannula placement effect (F < 1, NS) and no two-factor interaction. Despite no effect of the drug on
intake between 24 and 48 hr after injection, body weight for the same
period significantly increased as a function of MTII dose
(F(3,24) = 11.3; p < 0.00008).
There was a trend toward a further dose-related increase in body weight
between 48 and 72 hr (Fig. 2, bottom row, right)
that was not, however, statistically reliable. (There were no
significant cannula placement effects or two-factor interactions for
these periods.) The body weight increases between 24 and 72 hr after
injection ameliorated the acute weight loss observed over the first 24 hr after injection. For the lowest effective dose (0.1 nmol), the
recovery of weight initially lost was such that 48 and 72 hr after
injection, there was no significant net body weight change relative to
vehicle conditions. The body weight recovery was not complete for the 1.0 nmol dose (Fig. 3, bottom), however, because cumulative
body weight loss, relative to vehicle, remained significant 48 and 72 hr after treatment (p < 0.0001) (Fig. 3,
bottom).
As can be seen in Figure 4, top
row, the effects of MTII on short-term water intake were
dramatically different for the two intracerebroventricular placements.
For both the 2 and 4 hr readings, MTII tended to decrease cumulative
water intake when delivered to the fourth ventricle, but when delivered
to the lateral ventricle, MTII increased water intake. This impression
is underscored by significant dose × ventricle interactions
(F(3,24) = 4.17; p < 0.02;
F(3,24) = 3.24; p < 0.04, respectively, for the 2 and 4 hr ANOVAs). The dose-related stimulation
of drinking that followed lateral intracerebroventricular injection of
MTII does not appear to derive from the osmotic properties of the MTII
injection but may relate to the stimulation of MC3-Rs and MC4-Rs on the
neurons of several forebrain periventricular nuclei known to
participate in the neural control of drinking (Ramsey and Thrasher,
1990; Roselli-Rehfuss et al., 1993). The stimulatory effect of MC
agonist on drinking is a novel result; in the mouse, lateral
intracerebroventricular MTII (3 nmol) reduced short-term water intake
(Fan et al., 1997). The injection site disparity in MTII response had
disappeared by the 24 hr cumulative water intake reading (Fig. 3,
bottom) in which there was an overall suppressive effect of
MTII dose (F(3,24) = 6.27; p < 0.003) but no ventricle effect (F(1,8) = 2.42, NS) or two-factor interaction (F(3,24) = 1.36, NS). The MTII effect was expressed in significant reductions in water
intake for the 0.1 (p < 0.04) and 1.0 (p < 0.002) nmol doses evaluated against
vehicle baseline values. For the 48 and 72 hr readings, there were no
significant main effects or interactions.
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Figure 4.
Cumulative water intake for the 2-72 hr period
after intracerebroventricular delivery of MTII.
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Experiment 2: SHU9119 dose-response analysis
SHU9119 produced a marginally significant elevation of cumulative
food intake for the 2 and 4 hr postinjection readings
(F(3,21) = 2.75; p = 0.068;
F(3,21) = 2.69; p = 0.072, respectively) (Fig. 5, left)
and a significant dose-related elevation of cumulative water intake
over the same period (F(3,15) = 3.16;
p = 0.055; F(3,15) = 3.50;
p < 0.05, respectively) (Fig. 5, right).
For these short-term measures, there was no significant effect of
cannula placement on food or water intake, nor was there any
significant two-factor interaction.
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Figure 5.
SHU9119 dose-related food (in grams) and water (in
milliliters) consumption for the 2 hr or cumulative 4 hr period
beginning with lights out. Lateral or fourth intracerebroventricular
injections were delivered 30 min before lights out.
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Figure 6, top row,
left, shows the substantial dose-related increase in food
intake during the 24 hr after SHU9119 injection (F(3,21) = 39.0; p < 0.00001).
The elevation in 24 hr intake was significant (against vehicle
baseline) for all doses delivered to either ventricle
(p < 0.0005). Daily (noncumulative) intake readings taken 48, 72, and 96 hr after injection were each
significantly elevated by SHU9119 in a dose-related manner
(F(3,21) = 17.70, 10.07, and 8.49, respectively;
p < 0.0007). Post hoc tests showed that the intake value of each dose exceeded that for the vehicle from
24-96 hr, except for the weakest dose at the 96 hr measurement point.
Thus, the magnitude of the treatment effect on cumulative intake
progressively increased over the 4 postinjection days (Fig. 7, top). There were relatively
small but significant main effects of cannula placement for the 24, 48, and 72 hr daily intakes (F(1,7) = 8.87, 11.29, and 7.95, respectively; p < 0.026), but there
were no significant interactions between placement and SHU9119
dose.
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Figure 6.
Daily SHU9119 dose-related food consumption (in
grams) for the 4 d after a single intracerebroventricular
injection (top). Daily change in body weight (in grams)
for the same period after SHU9119 treatment
(bottom).
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Figure 7.
Cumulative food intake (top) and
cumulative body weight change (bottom) after delivery of
0.5 nmol of SHU9119 or vehicle to the fourth ventricle.
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Figure 6, bottom row, shows the noncumulative daily
body weight changes for the 4 d after SHU9119 treatment. The 24 hr
weights were significantly elevated as a function of dose
(F(3,21) = 7.33; p < 0.0015).
The trend toward a greater effect with lateral versus fourth
intracerebroventricular administration was marginally significant (F(1,7) = 5.28; p = 0.055); the
two-factor interaction term was not significant. Despite the successive
daily increases in food intake, there were no further increments in
body weight beyond the first postinjection day. The weight gain over
the first 24 hr did carry forward to yield a significant increase in
net weight gain 96 hr after injection for each dose relative to vehicle
baseline (Fig. 7, bottom, 0.5 nmol result).
Water intake for the 24 hr postinjection period was increased as a
function of SHU9119 dose (F(3,15) = 17.48;
p < 0.00004). As was the case for 24 hr pellet intake,
the main effect of cannula placement on water intake was significant
but small (F(1,5) = 23.29; p < 0.005); there was no significant two-factor interaction. Daily water
intakes between 24 and 96 hr after injection did not vary with either
drug dose or cannula placement.
Experiment 3: effects of fourth MTII (1 nmol) and SHU9119 (0.5 nmol) intracerebroventricular injections at the onset of a 24 hr period
of food deprivation
Weight loss by the end of the 24 hr deprivation period was not
reliably accentuated by MTII or attenuated by SHU9119 (Fig. 8, bottom). The overall
one-way ANOVA, with all four injection conditions (SHU9119, MTII, and
respective vehicles) as levels, did yield a significant result
(F(3,24) = 3.09; p < 0.05).
Post hoc tests, however, showed that 24 hr weight loss
for the SHU9119 condition was not significantly different from that of
its vehicle control (p = 0.22) and that weight
loss under MTII did not differ from its control values
(p = 0.18). Values for the two vehicle conditions also did not differ (p = 0.11). Rats
lost somewhat more weight under MTII (40.1 gm) than under SHU9119 (36.3 gm), but the difference was not statistically reliable
(p = 0.09).
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Figure 8.
Daily food intake (top) and body
weight change (bottom) up to 96 hr after fourth
intracerebroventricular injection [MTII (1.0 nmol), SHU9119 (0.5 nmol), or vehicle] in rats (n = 9) that were
food-deprived for 24 hr after treatment. There were no significant
differences between values obtained for the two vehicle conditions run;
values for the vehicle conditions were combined for clarity of
presentation.
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There was an overall effect of injection condition on the amount of
food ingested during the first 2 hr of refeeding after food deprivation
(F(3,24) = 4.75; p < 0.01).
Post hoc tests showed that the effect was carried
primarily by significant differences in intake between the MTII
condition (mean, 5.34 gm) and the other three conditions
(p < 0.015), which did not differ from each
other (means: SHU9119, 12.72 gm; vehicle for SHU9119, 12.09 gm; and vehicle for MTII, 11.29 gm). A comparable pattern of significant results was obtained for cumulative intake over the first 4 hr of
refeeding (F(3,24) = 9.88; p < 0.0002) (means: SHU9119, 17.88 gm; vehicle for SHU9119, 18.21 gm; MTII,
9.90 gm; and vehicle for MTII, 16.14 gm).
A significant effect of injection condition was obtained for the amount
consumed during the first 24 hr of refeeding (i.e., 48 hr after
treatment) (F(3,24) = 14.56; p < 0.00002) (Fig. 8, top). Food intake for the MTII
condition was significantly lower than that for either vehicle
condition (p < 0.002) and that for the SHU9119
condition (p < 0.00001). Values for the SHU9119
condition were significantly higher than those for both vehicle
conditions (p < 0.04). There were no
significant effects (overall ANOVA or paired comparisons) on the daily
intake readings taken 72 or 96 hr after injection (Fig. 8).
For all four injection conditions, a substantial portion of the weight
loss during the deprivation period was recovered during the first day
of refeeding (i.e., 24-48 hr after injection). The degree of body
weight recovery did vary with injection condition (F(3,24 = 8.58; p < 0.0005).
Underlying the effect was a significantly greater rebound for the
SHU9119 condition than for the other three conditions
(p < 0.03) and significantly less recovery for
the MTII condition compared with its vehicle control
(p < 0.03). Figure 8, compare top,
bottom, shows that the difference in weight recovery between
the MTII and SHU9119 conditions was commensurate with the
between-condition difference in amount consumed for the first refeeding
day. The differences across conditions in weight recovery over the
first refeeding day were made up for during the second (i.e., 48-72 hr
after treatment). Thus, there was significantly greater weight gain for
the MTII condition and each control condition, relative to that under
the SHU9119 condition (p < 0.05). By the following day (i.e., 72-96 hr after treatment), there were no significant between-condition differences in body weight change (F(3,24) = 0.16, NS) and no differences in net
weight change to this point from the time of treatment.
There was an overall effect of injection condition on the amount of
water consumed during the first 24 hr after injection (F(3,24) = 3.56; p < 0.03) when
food was unavailable. Post hoc tests, however, showed
that the effect was carried primarily by a significant difference in
intake between the MTII (mean, 12.1 gm) and SHU9119 (mean, 27.5 gm)
conditions (p < 0.005). Water intake under MTII
or SHU9119 did not differ from their respective control injection
values (p > 0.21) for the 24 hr period of food deprivation. Water intake was affected by injection condition during
the first refeeding day (F(3,24) = 37.49;
p < 0.0006). During this period, water intake was
reduced by MTII and augmented by SHU9119 (p < 0.05). Thereafter, there were no effects of treatment on daily water
intake (F < 2.21).
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DISCUSSION |
The effects on food intake and body weight that we report for
fourth (brainstem) ventricular injection of MC-R ligands are qualitatively similar to what has been observed for lateral or 3rd
(forebrain) ventricular application (Fan et al., 1997; Thiele et al.,
1998). Here, we directly compared fourth and lateral
intracerebroventricular placements with an integrated design using the
same animals and found that the overall sensitivities of the two
placements to MTII and SHU9119 were comparable in terms of threshold
dose, degree of effect across doses, and duration of effect. For MTII,
the dose-response curves for short-term and longer-term effects on food intake, body weight, and water consumption did not significantly differ for the two ventricular placements. For SHU9119, there were no
effects of cannula placement on shorter-term treatment outcomes.
Although significant placement effects on longer-term response to
SHU9119 were noted, the magnitude of the between-ventricle effects on
food intake and body weight change were relatively small. There were,
moreover, no significant interactions between injection site and
SHU9119 dose. The comparable dose-response functions (Figs. 2, 6) for
the two ventricles in response to the MC agonist and antagonist argue
strongly that the anatomical perspective on the MC contribution to
intake and body weight control should be revised and expanded to
include the CBS receptor complement.
Opposite effects on food intake and body weight were obtained with the
MC agonist and antagonist for the 24 hr after injection. MTII treatment
lowered intake and body weight over this period, whereas SHU9119
yielded increased intake and body weight. For MTII, no effect on intake
and body weight was seen beyond this time (experiment 1). For SHU9119,
however, a single injection continued to augment daily food intake for
the 3 subsequent days examined. The 96 hr duration of the intake
facilitatory effect of SHU9119 is the longest yet reported (Fan et al.,
1997; Thiele et al., 1998). The opposing effects of MTII and SHU9119
suggest that a broad range of dynamic action on feeding can be mediated by the same or primarily overlapping populations of MC receptors.
The dose-related intake stimulatory effect of the MC4/3 antagonist
SHU9119 seen here and elsewhere (Fan et al., 1997) appears to indicate
a contribution of endogenous melanocortin activity to feeding control.
POMC peptides ( -MSH, ACTH-4-9-NH2, and  -MSH) are the
endogenous ligands for the MC3-R and/or MC4-R (Adan et al., 1994). Food
intake is suppressed when exogenous ACTH or -MSH is delivered to the
forebrain ventricles (Tsujii and Bray, 1989; Ferrari et al., 1992).
Additional support for the hypothesis that endogenous MC activity
contributes to intake control comes from recent demonstrations that
arcuate nucleus POMC mRNA expression (and presumably levels of
intake-inhibitory melanocortins) are reduced by food restriction or
deprivation (Brady et al., 1990; Kim et al., 1996; Schwartz et al.,
1997; Mizuno et al., 1998). Further, Mizuno et al. (1998) noted that
decreases in POMC mRNA are common to a variety of obesity models.
Previous discussion of the relevance of endogenous MC contributions to
intake control have been limited in focus to the forebrain. The
elevation of intake and body weight after fourth
intracerebroventricular injection of SHU9119 reported here recommends
expanding this discussion to include endogenous MC activity in the CBS.
Inspection of the dose-response data from experiments 1 and 2 provides
the impression that the observed changes in body weight were secondary
to the respective actions of MTII and SHU9119 on food intake. This
impression was reinforced by the results of experiment 3 in which
deprivation was used as a yoking strategy, i.e., to equate the intake
(at zero) after delivery of the two drugs with otherwise opposite
ingestive effects. Any effect on body weight change during the
deprivation period could then be ascribed to a primary metabolic action
of the MC-R ligand(s). We found, however, that weight loss was not
reliably accentuated by MTII or SHU9119 (Fig. 8). During the first
refeeding day (24-48 hr after injection), somewhat less weight was
recovered after MTII than after SHU9119 treatment. It would appear
unlikely that this contrast reflects a delayed metabolic effect(s) of
the treatments, because the difference in body weight recovery was
commensurate with the between-condition differences in amount ingested
during that first refeeding day (Fig. 8). Thus, no evidence of a
primary metabolic action of these MC-R ligands was obtained under the present testing paradigm.
The pattern of body weight recovery seen in response to the 24 hr
intake-suppressive effect of MTII is consistent with the pattern of
body weight recovery observed after 24 hr food deprivation in
vehicle-treated rats. In both contexts, body weight recovery proceeded
over the ensuing days in the absence of appreciable compensatory
feeding. The body weight recovery seen after deprivation is driven by
coordinated reductions of energy expenditure (metabolic rate,
thermogenesis, and activity) (Rashotte et al., 1995). Similar mechanisms may underlie the recovery of body weight seen after MTII
treatment. The pattern of body weight gain and recovery that follows
SHU9119 treatment is reminiscent of that seen with the cafeteria
feeding model of reversible obesity (Rothwell and Stock, 1979, 1981).
In both situations, weight gain was limited despite a persistent
hyperphagia. Increases in energy expenditure have been hypothesized to
limit weight gain during hyperphagia and the recovery of body weight
once cafeteria feeding was discontinued (Rothwell and Stock, 1979). The
hyperphagia stimulated by SHU9119 treatment may engage similar
compensatory increases in energy expenditure.
Our suggestion that the effects of MC injection on body weight in rats
appear secondary to treatment effects on feeding contrasts with
judgments about leptin action in the mouse. The indication that the
body weight effects of leptin exceed expectations based on intake
suppression is derived from work on the ob/ob mouse (Levin et
al., 1996). If a similar feeding-independent action of leptin on body
weight can be established in the rat, then an interesting tension would
arise given current views about the MC mediation of leptin effects
(e.g., Mizuno et al., 1998). It is possible that MC may in part mediate
leptin effects on intake but that a separate mechanism mediates the
potential influence of leptin on metabolic rate.
Single injections of the MC-R ligands in ad libitum fed rats
had long-term intake effects that were altered by food deprivation. In
the dose-response studies (experiments 1 and 2), intake effects of
SHU9119 persisted for 96 hr, whereas the effects of MTII lasted 24 hr.
Deprivation prolonged the effect of MTII effect but shortened that of
SHU9119. When food was withheld for 24 hr after injection, the
intake-suppressive effect of MTII extended to 48 hr after injection,
the period of the first refeeding day (24-48 hr). The facilitatory
effect of SHU9119 was evident on the first refeeding day (24-48 hr)
but not thereafter. The basis for the interaction between physiological
state and the longevity of MC ligand action is a matter of speculation.
We lack information about when the interaction takes place over a 24 hr
deprivation period. We expect that it is unlikely that these ligands
continue to act at a given location for a substantial length of time.
Therefore, we must also acknowledge a lack of information about other
neurochemical systems and perhaps peripheral control systems that
support the longer-term effects of these agents. The latter issue, of
course, represents a gap in our understanding about how, in nondeprived rats, MTII effects 24 hr intake and particularly how intake is affected
up to 96 hr after a single injection of SHU9119.
The evidence presented suggests that there are at least two MC-R
populations that can mediate food intake effects of MC ligand treatments. We think it unlikely, despite the caudal flow of CSF, that
lateral intracerebroventricular effects are mediated exclusively by CBS
MC-Rs. If this were the case, we would expect the dose-effect curve
for lateral intracerebroventricular injection to be shifted to the
right of that obtained with fourth intracerebroventricular application
(Ladenheim and Ritter, 1988). Conversely, it would appear unlikely that
the response to fourth intracerebroventricular injection is mediated
exclusively by forebrain MC-Rs. First, india ink injected through the
fourth intracerebroventricular cannula is not seen rostral to the CBS
after death (Flynn and Grill, 1985; Grill et al., 1997). We can
also note the example of angiotensin II, with a forebrain receptor
substrate for the drinking response, which even at high doses is
ineffective when delivered to the fourth ventricle (Fitzsimons and
Kucharczyk, 1978). We cannot rule out the possibility that the response
to fourth intracerebroventricular injection of these particular MC-R
ligands results, in part, from a portion of the infusate reaching
forebrain receptors. The argument that forebrain substrates exclusively
mediate the intake response to brainstem delivery would appear
untenable, however, given that the fourth intracerebroventricular
dose-response curves are not shifted to the right of the respective
lateral intracerebroventricular functions. A very compelling indication
that fourth and lateral intracerebroventricular injection of MTII
stimulates different receptor subpopulations is found in the short-term
(2-4 hr) water intake responses described here in which brainstem
injection yielded a reduction commensurate with the food intake
response, but forebrain injection resulted in a dose-related increase
in drinking. Further support for the relevance of brainstem MC-Rs to
feeding control could be provided by intraparenchymal injection
studies. The intake effect seen with fourth intracerebroventricular
application may result from stimulation of the prominent group of
MC4-Rs in DMX but could also reflect the contribution of MC4-Rs in
other CBS structures, such as NST, parabrachial nucleus, and
various nuclei of the reticular formation (Mountjoy et al., 1994) and
perhaps MC3-Rs in the raphe and periaqueductal gray (Roselli-Rehfuss et al., 1993).
Further experiments are required to determine whether the disparate
populations of MC-Rs are concurrently stimulated under physiological
conditions. Anatomical evidence indicates that -MSH produced by
POMC-containing neurons in the arcuate nucleus is found in brainstem,
as well as in hypothalamic structures (Palkovits et al., 1987). Changes
in peptide release from arcuate POMC neurons (e.g., by deprivation or
changes in leptin levels) (Schwartz et al., 1997; Mizuno et al., 1998),
then, is one mechanism by which activity at forebrain and brainstem
MC-Rs may be coordinated. POMC-containing cells in NST project
to the same or overlapping set of brainstem targets but do not appear
to give rise to ascending projections to hypothalamic structures
(Pilcher and Joseph, 1986; Palkovits et al., 1987). The possibility
remains, however, that cNST POMC activation indirectly affects
arcuate POMC neurons, which in turn stimulates hypothalamic MC-Rs. In
the present study, we explored the consequences of exogenous ligands
that targeted sets of receptors that were different or at least
partially nonoverlapping. Additional work will be required to explore
the implications of a coordinated activation of CBS and hypothalamic
MC-Rs, if established as a general rule, for feeding control in the
short and longer term. Potentially informative studies may entail
application of an MC-R agonist to one (ventricular or parenchymal)
location and an antagonist delivered to a different site.
| |
FOOTNOTES |
Received July 6, 1998; revised Sept. 11, 1998; accepted Sept. 15, 1998.
This study was supported by National Institutes of Health Grants
DK-21397 and DK-54080. We thank Keith Yagaloff and Paul Burn (Hoffmann-La Roche, Nutley, NJ) for their generous gift of MTII and SHU9119.
Correspondence should be addressed to H. Grill, University of
Pennsylvania, 3815 Walnut Street, Philadelphia, PA 19104.
| |
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Top
Abstract
Introduction
