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The Journal of Neuroscience, March 15, 1999, 19(6):2362-2367
Role of the CNS Melanocortin System in the Response to
Overfeeding
Mary M.
Hagan1,
Paul A.
Rushing1,
Michael W.
Schwartz2,
Keith A.
Yagaloff3,
Paul
Burn3,
Stephen C.
Woods1, and
Randy J.
Seeley1
1 Department of Psychiatry, University of Cincinnati
Medical Center, Cincinnati, Ohio 45267-0559, 2 Department
of Medicine and Puget Sound Veterans Administration Health Care
System, Harborview Medical Center, University of Washington, Seattle,
Washington, 98195, and 3 Department of Metabolic Diseases,
Hoffman-La Roche, Inc., Nutley, New Jersey 07110
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ABSTRACT |
The voluntary suppression of food intake that accompanies
involuntary overfeeding is an effective regulatory response to positive energy balance. Because the pro-opiomelanocortin (POMC)-derived melanocortin system in the hypothalamus promotes anorexia and weight
loss and is an important mediator of energy regulation, we hypothesized
that it may contribute to the hypophagic response to overfeeding. Two
groups of rats were overfed to 105 and 116% of control body weight via
a gastric catheter. In the first group, in situ
hybridization was used to measure POMC gene expression in the rostral
arcuate (ARC). Overfeeding increased POMC mRNA in the ARC by 180%
relative to levels in control rats. For rats in the second group, the
overfeeding was stopped, and they were infused
intracerebroventricularly with SHU9119 (SHU), a melanocortin (MC)
antagonist at the MC3 and MC4 receptor, or vehicle. Although SHU (0.1 nmol) had no effect on food intake of control rats, intake of overfed
rats increased by 265% relative to CSF-treated controls. This complete
reversal of regulatory hypophagia not only maintained but actually
increased the already elevated weight of overfed rats, whereas
CSF-treated overfed rats lost weight. These results indicate that CNS
MCs mediate hypophagic signaling in response to involuntary overfeeding
and support the hypothesis that MCs are important in the central
control of energy homeostasis.
Key words:
POMC; leptin;  -melanocyte stimulating hormone; obesity; food intake; energy balance
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INTRODUCTION |
The matching of caloric intake to
caloric expenditure is a process required for the stability of body
adipose stores that is performed primarily by the CNS. Involuntary
overfeeding, where calories are provided in excess of caloric
expenditure by direct infusion into the stomach, produces a state of
positive energy marked by increased body weight and a >90% decrease
in voluntary food intake. Once the overfeeding regimen is terminated,
animals continue to suppress their intake until normal body weight is restored (Bernstein et al., 1975 ; Seeley et al., 1996a). This ability
of the body to suppress eating and lose weight after sustained periods
of positive energy balance represents a critical response for
successful regulation of body weight.
Considerable evidence implicates the hypothalamic melanocortin (MC)
system in the control of food intake and body weight. Melanocortins are
cleavage products of pro-opiomelanocortin (POMC). Neurons in the
arcuate nuclei of the hypothalamus (ARC) that synthesize POMC project
to areas such as the paraventricular nucleus of the hypothalamus (PVN),
where food intake is regulated. -Melanocyte stimulating hormone
(-MSH), an endogenous MC that binds with high affinity to MC3 and
MC4 receptors, is expressed in PVN neurons (Eskay et al., 1979;
Mountjoy et al., 1992). Central administration of -MSH and its
agonist MTII in rats reduces food intake (Fan et al., 1997; Ludwig et
al., 1998; Thiele et al., 1998). Conversely, central administration of
the MC receptor antagonists SHU9119 (SHU) (Fan et al., 1997; Seeley et
al., 1997b) and HSO14 (Kask et al., 1998) stimulate food intake. The
MC4 receptor appears critical to normal body weight homeostasis because
its targeted deletion results in obesity and hyperphagia (Huszar et
al., 1997).
Accordingly, we hypothesized that MC signaling may mediate the reduced
food intake that follows overfeeding. Overfeeding produces increased
adipose stores and raises plasma leptin levels (Frederich et al.,
1995a) and leptin mRNA (Frederich et al., 1995a; Harris et al., 1996;
Cha and Jones, 1998). Circulating leptin signals the CNS to decrease
intake to regulate body fat stores (Zhang et al., 1994; Frederich et
al., 1995b; Schwartz et al., 1996) and appears to be an important
determinant of hypothalamic MC activity. Leptin receptors are found on
ARC POMC neurons (Cheung et al., 1997), POMC expression in the ARC is
increased by leptin (Schwartz et al., 1997; Thornton et al., 1997;
Mizuno et al., 1998), and when CNS MC receptors are antagonized, the
ability of leptin to inhibit food intake is abolished (Seeley et al., 1997b).
We therefore proposed that the hypophagia and body weight loss observed
after involuntary overfeeding is caused by a cascade of events
beginning with elevated levels of negative feedback hormones such as
leptin that activate the hypothalamic MC system, which triggers an
anorexic response. To test this hypothesis, we assessed the effect of
involuntary overfeeding on hypothalamic POMC gene expression and
determined whether a centrally administered MC3/4 receptor antagonist,
SHU, is able to reverse the inhibited food intake and body weight loss
induced by involuntary overfeeding.
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MATERIALS AND METHODS |
Experiment 1: effect of involuntary overfeeding on arcuate nucleus
POMC mRNA levels
Male Long-Evans rats (n = 7) were overfed via
gastric catheter with a diet consisting of sweetened condensed milk
diluted with an equal volume of distilled water (2.1 kcal/ml) and
vitamins (Polyvisol with iron). Rats were overfed starting with two
meals of 8 ml each and increasing to five meals of 13 ml each on the final 3 d. The volume of diet was increased gradually in
increments to prevent unnecessary stress and adverse gastrointestinal
effects such as diarrhea. Chow was always available for voluntary
intake. Rats were kept on this regimen until they reached a mean body weight of 105% of the body weight of the control group
(n = 8), which was treated identically but infused with
equal volumes of physiological saline instead of the milk diet. This
weight that represented a significantly higher body weight than that of
the controls was achieved after 10 d of overfeeding. On day 11, the overfed rats were euthanized by CO2 inhalation and
decapitated for collection of brain tissue. Other parameters of these
rats (food intake, body weight change, plasma glucose, corticosterone, insulin, and hypothalamic corticotropin releasing hormone (CRH), arginine vasopressin, and NPY mRNA) were reported previously (Seeley et
al., 1996a). For the present experiment we assessed POMC mRNA in the ARC.
In situ hybridization. Brains were frozen and
sectioned at 14 µm with a cryostat. Slides for in situ
hybridization (ISH) to POMC mRNA were taken from the rostral ARC region
by an investigator blind to treatment conditions. A riboprobe
complementary to rat POMC mRNA (a generous gift of Dr. Robert Steiner,
University of Washington, Seattle, WA) was labeled with
33P as described previously (Schwartz et al., 1997).
Quantitation of POMC mRNA hybridization was performed by computer
densitometry of ISH autoradiograms. Values of POMC mRNA hybridization
for each animal were determined as the mean of six to eight sections.
The data are presented as the product of hybridization area × density as described (Schwartz et al., 1997). This method of
quantification does not distinguish change in mRNA per cell from number
of cells expressing message but rather provides an index of overall
mRNA levels.
Statistical analysis. Between-group mean values of POMC mRNA
were compared with an unpaired t test (for two-group
comparisons). Significance level was set at p < 0.05.
Experiment 2: effect of intracerebroventricular
melanocortin-receptor antagonist on overfeeding-induced hypophagia
Subjects and surgery. Forty male Long-Evan rats
(260-280 gm) were individually housed in a temperature-controlled
environment (22°C) with a 12 hr light/dark cycle. Pelleted rat chow
and tap water were available at all times except where noted. Rats were anesthetized with sodium pentobarbital (60 mg/kg) and given a prophylactic injection of gentamicin (40 mg/kg, i.p.). A gastric catheter was surgically implanted as described previously (Seeley et
al., 1997a). In addition, a cannula was stereotaxically implanted into
the third cerebral ventricle (i3vt) as described previously (Seeley et
al., 1996b). After 1 week of recovery from surgery, placement of i3vt
cannulae was confirmed by the drinking response to infusion of 10 ng
angiotensin II in saline while the animals were water-repleted. The
criterion for inclusion in the study was drinking  5 ml of water in 1 hr.
Experimental protocol. Rats (now 340-380 gm) were assigned
to two weight-matched groups, one to receive gastric infusions of a
high-calorie (HC) diet and the other equal volumes of isotonic saline.
Unlimited chow was available at all times. To achieve a higher body
weight difference (110-116 vs 105% of control weight) in a reasonable
amount of time, a different HC diet was used. The diet was formulated
by Akiyama et al. (1996) and contained 50% fat (from corn oil), 25%
protein (from lactalbumin hydrosylate), and 25% carbohydrate (from
dextrose). Polyvisol with iron was included as a vitamin supplement.
Meals were delivered into the stomach via a multi-head peristaltic pump
and Tygon tubing.
Over days 1-16, gastric infusions were increased incrementally
from one meal of 10 ml on the first day to five meals of 15 ml each on
the last 2 d. Control rats were infused with equal volumes of
isotonic saline. Infusions were stopped after day 16, at which time the
overfed and control rats were weight-matched into two subgroups: one
overfed subgroup and one control subgroup to be infused with 0.5 nmol
SHU (Hoffman-La Roche, Nutley, NJ) and the other overfed and
control subgroups to be infused with vehicle (synthetic CSF) in
a 2 µl volume over 1 min. These SHU and CSF infusions were given
at the onset of dark on day 17, 24 hr after the last diet infusion.
Food containers were removed from the cages and weighed 2 hr before
drug infusions and replaced with premeasured amounts after drug
infusions. Food intake was measured after 1, 2, 3, 4, and 24 hr, and
body weight was recorded after 24 hr.
The results of Experiment 1 suggested that MCs may be biologically
important in responses to overfeeding because POMC mRNA was elevated in
overfed rats. Therefore, melanocortin agonist action might presumably
also be higher, rendering a lower dose of antagonist effective. To test
this possibility, on day 19 the overfeeding regimen was reinitiated on
the overfed animals for another 6 d, starting with three meals of
15 ml each and ending with five 15 ml meals on the final day. As
before, the control rats that received equal amounts of saline
intragastrically, continued to receive saline. At the end of 6 d
of gastric infusions, the overfed rats were again weight-matched into
two subgroups, one to receive a lower dose of SHU (0.1 nmol) and the
other to receive CSF. Likewise, the control rats were weight-matched
and subdivided into two groups, one to receive SHU (0.1 nmol) and the
other to receive CSF. In this way, previous experience with i3vt
infusion high-dose SHU or CSF was randomized across rats. Again,
gastric infusions were stopped, and 24 hr elapsed before SHU and CSF
infusions were administered at the onset of dark. Body weights and food intakes were measured as described above. This testing procedure was
repeated 24 hr after the first drug infusion. Furthermore, to explore
the degree to which SHU could reverse hypophagia and maintain obesity
in the overfed animal, infusions of 0.1 nmol SHU or CSF were repeated
again with 24 hr in between for a total of three infusions across 3 consecutive days.
Statistical analysis. One-way ANOVAs with four levels
(overfed/SHU vs overfed/CSF vs control/SHU vs control/CSF) were
conducted for each hour of intake. Significant group differences were
further analyzed using Tukey's highly significant test. Interactions, where noted, were derived from a two-way ANOVA (overfed or control vs
SHU or CSF), and paired-samples t tests were used to analyze differences within groups. ANOVAs and post hoc tests both
used significance levels set at p < 0.05.
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RESULTS |
Experiment 1: in situ hybridization results of
POMC mRNA
As in previous experiments, hybridization of POMC mRNA was readily
detected in the ARC, but not in other brain areas, in film autoradiograms of coronal brain sections. Among overfed rats, POMC mRNA
hybridization was visibly increased, and as depicted in Figure
1, the level of mRNA for POMC in the ARC
was elevated by 180% in the overfed group relative to control levels
(p = 0.002).
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Figure 1.
Mean (+ SE) mRNA for POMC in the arcuate nucleus
of the hypothalamus for control rats and rats overfed to 105% of body
weight of controls. Values represent area × density measures
derived from computer densitometry. **p < 0.01.
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Experiment 2: changes in food intake and body weight during the
overfeeding regimen
After 16 d of overfeeding (and just before the first test of
0.5 nmol SHU), animals infused with the HC diet were receiving 146% of
control calorie intake, and as depicted in Figure
2A, daily voluntary
chow intake of overfed rats was reduced to 3% of that of the controls
(p < 0.001). At day 25 (data not shown), which
marked the end of the second episode of overfeeding, the overfed
animals were receiving 135% of control calories, and voluntary intake
of chow in the overfed rats was 4% of control intake
(p < 0.001). As depicted in Figure
2B, changes in food intake produced body weight in
overfed rats that was 10% higher than controls infused with equal
volumes of saline (p < 0.001). By the end of the second overfeeding episode, overfed rats attained a 16% higher body weight than that of the controls (p < 0.001).
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Figure 2.
A, Mean (± SE) daily spontaneous
kilocalories of intake for the overfed and control group during the
course of the first overfeeding episode. B, Mean (± SE)
body weight for the overfed and control group over the course of the
first and second overfeeding episodes. ***p < 0.001.
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Effect of 0.5 nmol SHU9119 on hypophagia and weight
Infusion of 0.5 nmol SHU increased 24 hr food intake in control
rats as depicted in Figure 3
(t test, p < 0.01). This dose of SHU also
blocked the potent hypophagia observed in the obese, CSF-treated
overfed rats (t test, p < 0.05), resulting
in an increase of food intake (t test, p < 0.001) that was greater than the increase produced by SHU in control
rats (t test, p < 0.01). This effect translated into an intake by overfed rats that matched the intake of lean animals treated with SHU (33.3 ± 2.4 vs 32.7 ± 2.0 gm, respectively). A significant interaction between overfeeding
conditions and drug (p < 0.05) indicated an
increased sensitivity of SHU in overfed animals. Because of this,
the same rats were again overfed.
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Figure 3.
Mean (+SE) 24 hr chow intake of rats treated with
0.5 nmol i3vt SHU or CSF vehicle. *p < 0.05;
**p < 0.01; ***p < 0.001.
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Effect of 0.1 nmol SHU9119 on hypophagia and body weight
Figure 4 depicts the third day of
drug infusions on which overfed rats given CSF had reduced food intake
relative to controls given CSF (10.2 ± 1 vs 26.5 ± 1 gm).
However, i3vt SHU (0.1 nmol) produced a nonsignificant increase in 24 hr food intake in control animals, and it caused a robust orexigenic
effect (137% of CSF-treated controls) in the overfed rats
(p < 0.001). As depicted in Figure 5, the increased sensitivity of SHU's
orexigenic effect in overfed animals persisted over the subsequent
2 d. By the third day, control animals receiving SHU had a
significant increase in 24 hr food intake compared with that of
CSF-treated controls. The data in Figure 5 are depicted as percentage
of food intakes relative to CSF-treated rats to better illustrate this
significant drug (SHU or CSF) by energy-state (overfed vs lean)
interaction. As depicted in Figure 6, SHU
increased body weight in control rats (from 403.3 ± 8 to
427.8 ± 10 gm; t test, p < 0.01) and
prevented the overfed group from losing weight (weight increased from
468 ± 12 to 481 ± 15), whereas CSF-treated rats lost weight
because of overfeeding-induced hypophagia (from 470 ± 8 to
448 ± 1 gm; t test, p < .001).
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Figure 4.
Mean (+ SE) grams of 24 hr chow intake of control
and overfed rats on the third day of i3vt lower dose (0.1 nmol)
SHU or CSF vehicle. ***p < 0.001.
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Figure 5.
Mean (+ SE) 24 hr chow intake in animals treated
i3vt with 0.1 nmol SHU9119 or CSF vehicle on 3 consecutive days.
Error bars represent the percentage of each group's mean control
intake. **p < 0.01; ***p < 0.001.
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Figure 6.
Mean (+ SE) of the percentage body weight gained
or lost after 3 d of 0.1 nmol i3vt SHU infusions relative to the
weight of each group's CSF-treated animals before the infusion.
Percentages were derived from the formula {[% body weight gain or
loss per animal]  (mean % body weight gain for CSF-treated
groups)} × 100. ***p < 0.001.
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DISCUSSION |
The purpose of these experiments was to test the hypothesis that
MC activity is increased in involuntarily overfed rats and that this
response contributes to the ensuing hypophagia. In the first
experiment, the level of mRNA for the MC precursor protein POMC was
assessed in the hypothalamus of overfed and control rats. POMC mRNA in
the ARC was significantly elevated (an increase of 180%) in overfed
compared with control animals. Body weight was only elevated by 5% in
these rats. The increased levels of ARC POMC mRNA in response to
overfeeding paralleled the increased levels of CRH mRNA in the PVN in
the same animals, as reported previously (Seeley et al., 1996a).
Because CRH (Krahn and Gosnell, 1988) and POMC post-translational
products (ACTH, -MSH) are potent inhibitors of food intake (Poggioli
et al., 1986; Schioth et al., 1996), these results suggest that
hypothalamic overexpression of CRH and POMC may mediate the effect of
overfeeding to reduce food intake.
In the second experiment, the effect of i3vt administration of a
selective MC receptor antagonist was assessed on the hypophagia and
body weight loss that occurs after overfeeding. Intragastric overfeeding produced a 97% suppression of voluntary food intake and
increased body weight by 16%. Central infusion of the higher dose of
SHU9119 (0.5 nmol) elicited a 47% increase in 24 hr food intake in
control rats relative to CSF-treated control rats and a 143% increase
of 24 hr intake in overfed animals compared with their hypophagic,
overfed controls.
To elucidate what appeared to be a more sensitive response of the
overfed animals to MC antagonism, the rats were again overfed, and a
lower dose of SHU9119 (0.1 nmol) was given. Overfed animals responded
to SHU with a 137% increase of food intake, representing a complete
reversal of the hypophagia induced by overfeeding. In contrast, this
low dose of SHU had no significant effect on food intake in control
(nonoverfed) rats. In the overfed group, 3 d of SHU-induced
feeding resulted in the maintenance and even slight increase of these
animals' already obese weight. In contrast, overfed animals not
treated with SHU lost weight precipitously because of voluntary low
food intake.
Taken together, these findings suggest that increased signaling at MC
receptors is an important component of the hypothalamic response to
restore energy balance. The long-term feeding manipulations that were
used in these experiments and the robust effects of SHU in the overfed
animals support increased body weight as a stimulus of MC effects in
the hypothalamus. However, there was also evidence that excess food
intake and not just excess body weight provides this stimulus.
Specifically, in Experiment 1, a significant elevation in POMC mRNA was
observed in rats that were only 5% heavier than lean rats, suggesting
that food intake and not body weight changes promotes MC effects. Also,
SHU increased food intake in lean rats but not nearly to the extent
that it did in the overfed rats. Therefore, it appears that MC-mediated effects are promoted by food intake, but their biological role in
promoting energy balance may be more salient in conditions that
threaten energy balance, such as obesity.
A major peripheral signal of positive energy and one that may be
communicating with a central MC system to regulate food intake and body
weight in response to overfeeding is leptin (Zhang et al., 1994;
Schwartz et al., 1996). Considerable evidence suggests that MC receptor
signaling may be mediating leptin's anorectic effects. The leptin
receptor is expressed in ARC POMC neurons (Cheung et al., 1997), and
expression of POMC mRNA in the ARC is increased by i3vt administration
of leptin (Schwartz et al., 1997). Mice deficient in or resistant to
leptin (ob/ob and db/db mice) have a major
reduction of ARC POMC mRNA (Schwartz et al., 1997). In addition, the
anorectic effects of leptin, and leptin-induced c-fos expression in the
PVN, are both blocked in rats pretreated with 0.5 nmol SHU9119 (Seeley
et al., 1997b), the same dose found here to block overfeeding-induced hypophagia.
These data are consistent with the hypothesis that leptin activation of
MC receptor reduces food intake when animals have been rendered obese
involuntarily. The pathway would be (1) activation of leptin receptors
on POMC neurons in the ARC by increased circulating leptin caused by
overfeeding, and (2) activation of these neurons to release
POMC-derived -MSH (or some other endogenous MC) that binds and
activates MC3/4-R (Adan et al., 1994) in the PVN, ventromedial, dorsomedial, or lateral hypothalamic nuclei (Mountjoy et al., 1994) to
(3) initiate a cascade of events that decreases food intake (Seeley et
al., 1997b; Mizuno et al., 1998; Woods et al., 1998).
MC regulation of energy balance may also include extra-hypothalamic
sites and negative-energy feedback signals other than leptin. For
example, POMC and -MSH are expressed in the commissural nucleus of
the solitary tract (Palkovits et al., 1987; Bronstein et al., 1992).
Recently, Grill et al. (1999) observed increased 24 hr intake and body
weight in rats injected in the lateral or fourth ventricle with SHU9119
(0.25-1.0 nmol), doses that were comparable to those used in the
present experiment. Because the response to SHU administration in the
fourth ventricle was equipotent with the response to i3vt injection, it
appears that blockade of MC receptors in either the brainstem or the
forebrain can elicit feeding. The role of the brainstem MC system in
the response to overfeeding warrants additional study.
Another negative feedback signal that might cause MC receptor
activation is insulin, which is increased 25% in overfed animals compared with controls (Seeley et al., 1996a). ARC POMC mRNA has recently been found to be decreased in insulin-deficient rats and to
normalize with insulin administration, and POMC mRNA is also increased
in normal rats treated systemically with insulin (Kim et al., 1999).
Finally, there is evidence to suggest that leptin and insulin may not
work independently but rather in an interactive capacity to regulate
the effects of positive energy (Malmstrom et al., 1996; Wabitsch et
al., 1996).
In summary, the present results indicate that involuntary overfeeding
is associated with increased POMC mRNA expression in the ARC and that
the overfeeding-induced hypophagia is disrupted by MC3/4 blockade.
These findings, therefore, extend the working model of MCs to include
involuntary, induced obesity. In obesity, the negative feedback system
to limit food intake and body weight that involves CNS MC may be
compromised. Further understanding of the peripheral and central
mechanisms that are responsive to positive energy balance hold
important implications for human obesity. In particular, therapeutics
targeted at MC functioning may be especially promising.
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FOOTNOTES |
Received Oct. 26, 1998; revised Dec. 21, 1998; accepted Jan. 7, 1999.
This work was supported by grants from National Institutes of Health
(DK54080, DK54890, DK17844, NS32273). We also thank Brian Seeley and
Kathi Blake for their assistance in the data collection.
Correspondence should be addressed to Dr. Mary M. Hagan, College of
Medicine, Department of Psychiatry, University of Cincinnati Medical
Center, P.O. Box 670559, Cincinnati, OH
45267-0559.
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Top
Abstract
Introduction
