1 Division of Endocrinology and
Metabolism, Melanin-concentrating hormone (MCH) and
obesity; eating
THE CONTROL OF BODY WEIGHT is a complex
process that involves integration of peripheral signals and central
neural mechanisms (18). Recently, much attention has focused on the
ob gene product leptin (44), levels of
which communicate the status of peripheral energy stores to the brain
via activation of hypothalamic leptin receptors, themselves a product
of the ob gene (9, 10). The neural
mechanisms through which leptin acts to influence energy balance are
the subject of intense study. Neuropeptide Y (NPY) is the best
characterized target of leptin action in the brain and is likely to
participate in mediating the neural consequences of leptin deficiency
(35, 38). However, the absence of a phenotype in NPY knockout mice (16)
suggests the existence of other critical appetite-regulating pathways.
Several lines of evidence support a role for the central melanocortin
system in the regulation of energy balance. First, targeted disruption
of the melanocortin-4 receptor (MC4R), a G protein-coupled receptor
expressed in the brain, results in obesity in mice (22). Second,
melanocortin analogs with agonist or antagonist properties on MC3R and
MC4R regulate feeding after intracerebroventricular (icv)
administration to mice (17). Finally, obesity due to the dominant
agouti alleles is the result of ectopic expression of the 131-amino
acid agouti protein (15), a secreted protein that acts as an antagonist
at MC1R and MC4R (8, 26).
The existence of a melanocortin system for the central regulation of
energy balance raises questions about the identity of the neuropeptides
involved in this system. Agonists for melanocortin receptors are
presumably one or more central products of the POMC gene, such as
MCH, first isolated from salmon in 1983, is a cyclic peptide present in
the brains of all vertebrate species examined (24). The name of this
compound derives from its ability to cause melanosome aggregation in
fish skin, an action that antagonizes the melanosome-dispersing effects
of Animals.
The feeding studies employed male Long-Evans rats weighing 300-400
g. Animals were obtained from Zivic-Miller Laboratories (Zeleinople,
PA) with 22-gauge cannulas placed in the lateral ventricle according to
the following coordinates: AP
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
-melanocyte-stimulating hormone (
-MSH) demonstrate opposite
actions on skin coloration in teleost fish. Both peptides are present
in the mammalian brain, although their specific physiological roles
remain largely unknown. In this study, we examined the interactions
between MCH and
-MSH after intracerebroventricular administration in
rats. MCH increased food intake in a dose-dependent manner and lowered
plasma glucocorticoid levels through a mechanism involving ACTH. In
contrast,
-MSH decreased food intake and increased glucocorticoid
levels. MCH, at a twofold molar excess, antagonized both actions of
-MSH.
-MSH, at a threefold molar excess, blocked the orexigenic
properties of MCH. MCH did not block
-MSH binding or the ability of
-MSH to induce cAMP in cells expressing either the MC3 or MC4
receptor, the principal brain
-MSH receptor subtypes. These data
suggest that MCH and
-MSH exert opposing and antagonistic influences on feeding behavior and the stress response and may function in a
coordinate manner to regulate metabolism through a novel mechanism mediated in part by an MCH receptor.
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
-melanocyte-stimulating hormone (
-MSH) (1). Although the agouti
protein may function as a direct antagonist at MC4R, agouti is not
normally expressed within the brain. Two observations suggest that
melanin-concentrating hormone (MCH) may act as an endogenous functional
antagonist of the central melanocortin system. MCH antagonizes the
-MSH- induced enhancement of the hippocampal response to auditory
stimuli (27). In female rats,
-MSH increases aggressive and
exploratory behaviors, and this effect is antagonized by MCH (19). In
addition, MCH blocks the
-MSH-induced grooming behavior (34).
-MSH (4). In mammals, high concentrations of MCH are found in
neurons of the dorsolateral hypothalamus and the zona incerta, with
extensive projections throughout the brain (6, 36). Recently, a role
for MCH in feeding behavior was proposed based on several observations
(31): ob/ob mice
overexpress MCH mRNA compared with lean littermates, and fasting
increases hypothalamic MCH mRNA expression in both
ob/ob and wild-type mice. In addition, intracerebroventricular MCH administration stimulates food
intake in the rat (31, 33). Previous studies have suggested an
interaction between MCH and the hypothalamic-pituitary-adrenal (HPA)
axis (5, 7). Given the above observations, we have examined the ability
of MCH to function as a physiological antagonist of central
melanocortin action with respect to feeding and the HPA axis.
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
0.9 mm from bregma, DV
4.8
mm from dura, and ML +1.5 mm. Cannula placement was confirmed by
demonstration of increased thirst (water intake >5 ml in 1 h) after administration of ANG II (50 ng icv) and by histology. The
animals were housed singly, fed standard laboratory diet, and
maintained on 12:12-h reverse day-night cycles at 20°C. The dark
cycle began at 9:30 AM. Before the start of the studies, animals were
handled daily until tame to minimize the effects of stress on food
intake. Body weight was measured twice weekly. Any animal showing signs
of illness, such as weight loss, poor grooming, or decreased activity,
was removed from the study. Number of animals
(n) for these experiments ranged
from 8 to 18.
Feeding studies.
To reduce variation in feeding response to neuropeptide administration,
we employed a modification of the methods of Stanley and Leibowitz
(37). This approach uses a highly palatable food to induce a
reproducible hyperphagia, followed by a consistent period of sustained,
although slower, feeding. The animals were given the palatable food
(consisting of evaporated milk, dextrose, and powdered standard rodent
food in a ratio of 1.0:1.0:1.8) on the evening before each study. For
experiments depicted in Figs. 1 and 3, a fresh aliquot of palatable
food was provided 1 h before administration of the appetite-modulating
substance, and food intake was monitored at 2, 4, 6, and 24 h after
intracerebroventricular injection by weighing the remaining food. For
the experiment depicted in Fig. 2, animals were fasted overnight, and
the fresh aliquot of food was given at the time of
intracerebroventricular injection. This modification served to increase
baseline food intake during the initial few hours, thereby providing a
greater range in which the effects of the anorectic agent -MSH could
be demonstrated. Injections (icv) were conducted within 1 h of the
beginning of the dark period under calm conditions in a procedure
lasting ~1 min. Control animals, receiving 5 µl of artificial
cerebrospinal fluid (CSF) instead of neuropeptide, were handled in an
identical manner to experimental animals and were included in all
studies. After injection, the animal was returned to its cage and left undisturbed for the remainder of the study.
HPA axis studies. Handling stress was produced as previously described (13). The animal was gently removed from its cage, and baseline blood samples were obtained through the indwelling venous catheter. Subsequently, the animal was stroked for 30 s, given the intracerebroventricular injection, and returned to its cage. The total procedure lasted ~4 min. Control animals, receiving 5 µl of artificial CSF, were simultaneously studied in an identical manner. Additional blood samples were obtained at 45 and 90 min. For the experiments depicted in Fig. 5, the animals were treated similarly, except that blood samples were taken by tail bleed at 1 h after intracerebroventricular injection (no baseline obtained) in a procedure lasting <60 s.
Hormone assays.
Blood samples were immediately placed into heparinized tubes on ice,
plasma was obtained by centrifugation within 2 h, and specimens
were stored at 20°C until assayed. Corticosterone and ACTH
were determined by 125I
radioimmunoassays using kits from ICN Biomedicals (Costa Mesa, CA) and
Incstar (Stillwater, MN), respectively.
Receptor binding and activation studies.
To test the possibility that MCH acts by inhibition of -MSH binding
to melanocortin receptors, a variant of B16 melanoma cells,
B16-4GF, which do not express
-MSH receptors, was transfected with expression plasmids containing cDNA encoding either rat MC3R or
rat MC4R.
125I-[Nle4,D-Phe7]-
-MSH
(125I-NDP-MSH) was prepared, and binding assays were
performed using monolayers on 24-well plates as described (21).
Specific binding was >95% of total binding as determined
by its inhibition in the presence of 1 µM
-MSH. Effects of
hormones on melanogenesis in B16-F1C29 mouse melanoma cells were
assayed as described (39).
Peptides.
MCH and -MSH were obtained from Bachem Biosciences (King of Prussia,
PA). The agents were dissolved in artificial CSF (in mM: 147 NaCl, 1.3 CaCl2, 0.9 MgCl2, and 4.0 KCl) and injected in a total volume of 5 µl over 1 min. Artificial CSF was sterilized by autoclave, and neuropeptide solutions were kept frozen until use.
Recombinant mouse agouti protein, prepared as described (28), was
obtained from Dr. Greg Barsh (Stanford, CA).
Statistics. Data were analyzed by ANOVA, using Statview 4.0 software from Abacus Concepts (Berkeley, CA). Error bars in figures represent SE.
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RESULTS |
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Effects of MCH and -MSH on food intake.
To quantitate changes in appetite after central neuropeptide treatment,
we used a modification of the methods of Stanley and Leibowitz (37).
This approach employs a highly palatable food to elicit a reproducible,
transient hyperphagia, followed by a sustained period of feeding at a
slower rate (see METHODS). Injection (icv) of MCH, in the range of 0.1-25 µg, stimulated feeding
behavior in a dose-dependent manner (Fig.
1).
-MSH, as previously reported (40),
reduced food intake by about half over a 4- to 6-h period (Fig.
2). The anorectic action of
intracerebroventricular
-MSH was significantly attenuated by
coadministration of MCH at a twofold molar excess (Fig. 2). Conversely,
the appetite-stimulating effect of 5 µg of intracerebroventricular
MCH was completely blocked by
-MSH (Fig.
3A). However, when
MCH was administered at a three molar excess (25 µg),
-MSH had no
effect on stimulation of feeding (Fig.
3B). Thus, in parallel with their
behavior in the skin of teleost fish, MCH and
-MSH behave as
functional antagonists in the regulation of food intake in the
mammalian central nervous system.
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Effects of MCH and -MSH on HPA axis.
To further assess this functional antagonism, we determined the effects
of these two peptides on the activation of the HPA axis. HPA axis
activity was assessed by determination of plasma corticosterone, the
predominant circulating glucocorticoid in rodents, after a mild
handling stress, as described in
METHODS. Consistent with prior reports
(13), handling produced a moderate rise in corticosterone, from 3.1 ± 0.1 to 10.2 ± 2.8 µg/dl at 45 min (Fig.
4A). Central
administration of MCH not only blocked this stress-induced rise but
also reduced 45-min corticosterone levels 60% below baseline values,
from 5.8 ± 1.1 to 2.4 ± 0.5 µg/dl (Fig.
4A). The change in corticosterone
level was associated with decreased ACTH levels (Fig.
4B). In contrast,
-MSH increased both corticosterone and ACTH levels (Fig. 4,
A and
B). Furthermore, MCH at a twofold
molar excess prevented the
-MSH-induced rise in corticosterone
(Fig. 5) and ACTH (data not shown).
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MCH does not antagonize -MSH via known melanocortin
receptors.
Five subtypes of the melanocortin receptor have been identified (12).
Among these, the brain and especially the hypothalamus contain mRNA
encoding only two principal subtypes, MC3R and MC4R (29, 32), whereas
mRNA coding for other known melanocortin receptors is either absent or
present in exceedingly low amounts (3, 20). To determine whether MCH
may antagonize
-MSH action by inhibiting
-MSH activation of the
MC3R or MC4R, we tested the ability of MCH to inhibit agonist binding
to, and activation of, these receptors in vitro. At concentrations of
0.1 nM-1 µM, MCH had no effect on the binding of the superpotent
-MSH agonist, 125I-NDP-MSH, to
heterologous cells stably expressing the rat MC3R (B16-G4F-rMC3) or the
rat MC4R (B16-G4F-rMC4). In contrast,
-MSH and the MCH receptor
antagonist, mouse agouti protein, produced the expected dose-dependent
inhibition of tracer binding (Fig. 6,
A and
B). Similarly, concentrations of MCH
from 4 to 400 nM did not affect the ability of
-MSH,
1-MSH,
2-MSH, or ACTH to activate
adenylate cyclase in cell lines bearing MC3R or MC4R (neither
EC50 nor
Rmax was altered). For example,
the EC50 for activation of MC3R
with ACTH is 3.85 × 10
9 M in the absence of MCH
and 2.99 × 10
9 M in
the presence of 400 µM of MCH.
Rmax is 0.95 without MCH and 0.93 in the presence of 400 µM
MCH.
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DISCUSSION |
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This study demonstrates that MCH and -MSH produce functionally
opposing actions within the mammalian central nervous system with
regard to feeding and HPA axis. Interestingly, this mutual antagonism
extends from effects on fish melanophores to complex behavior in the
mammalian central nervous system. These antagonistic actions involve
several pathways, two of which are described in this paper, regulation
of food intake and the HPA axis, as well as actions on complex
behaviors related to grooming, auditory gating, and aggression, which
have previously been described (19, 27, 34). These actions are mediated
by at least two receptors, MC4R (responding to
-MSH) and an as yet
unidentified receptor for MCH. MCH is well placed both anatomically
(lateral hypothalamus) and functionally to be a key participant
alongside products of the POMC gene in the melanocortin system for
regulation of energy balance.
Central MCH administration stimulates food consumption through a dose range of 0.1-25 µg in accordance with, and extending, a recent observation by us (31). This result is at variance with that of Presse et al. (30), who described decreased food intake after administration of MCH into the lateral ventricle at extremely low doses (1 ng-0.1 mg). An orexigenic effect of MCH was recently reported by Rossi et al. (33) using a dose similar to ours. This group examined doses as low as 10 ng in an attempt to duplicate the data of Presse et al., which demonstrated inhibition in low doses. Like us, Rossi et al. failed to see inhibition of eating at any dose. We believe that these data clearly demonstrate an orexigenic effect of MCH. At present, both the precise anatomic targets of MCH and the physiological concentrations of MCH at these targets are unknown. Hence, it is difficult to distinguish between a physiological and a pharmacological effect. This is a problem in assessing action of many centrally administered compounds, such as NPY (11). Further studies involving direct injection of MCH into potential target areas as well as measurement of ambient MCH levels will be required to address this question.
We have also confirmed that -MSH can inhibit food intake after
intracerebroventricular injection in rats. The fact that higher doses
of one neuropeptide (MCH) can antagonize the actions of the other
(
-MSH), and vice versa, is of interest and can be viewed as a
mutually functional antagonism. The simplest hypothesis to explain the
observed functional antagonism of
-MSH by MCH is a model in which
MCH binds competitively to central MCH receptors and prevents their
activation by
-MSH (26). However, the fact that MCH does
not affect
-MSH binding or
-MSH action on cells expressing
either cloned MC3R or MC4R excludes this possibility, at least
with regard to these previously identified receptors.
The receptor through which MCH exerts its actions, whether in teleost fish or mammalian brain, has yet to be identified, although specific MCH binding sites have been demonstrated in B16F10 melanoma cells (14). It remains to be determined whether this receptor or some other species mediates the central actions of MCH. It should be noted that the physiological antagonism of two molecules is most often exerted through binding to unique receptors (i.e., insulin vs. glucagon, parathyroid hormone vs. calcitonin) that converge on downstream signaling pathways, rather than through competitive interactions at a common receptor. Thus identification of the central MCH receptor is an important goal.
The functional antagonism of MCH and -MSH also extends to regulation
of the HPA axis. A strong relationship between the regulation of
feeding and the HPA axis has previously been noted. Actions of
peripheral signals, such as leptin (2), and central neuropeptides, such
as NPY and corticotropin-releasing hormone, on both of these axes have
been amply documented. Here we show that MCH inhibits glucocorticoid
secretion by an ACTH-dependent mechanism. This finding builds on
previous reports that salmon MCH (bearing a 70% homology in amino acid
sequence to mammalian peptide) inhibited ACTH release from isolated rat
pituitary in vitro (5) and that central MCH injection in rats reduced
peak circadian ACTH levels and inhibited stress-induced ACTH secretion
(7). Another study, however, found increased ACTH levels after
intracerebroventricular injection (23). Although the reason for this
discrepancy remains unexplained, our data support the role of MCH as an
inhibitor of ACTH secretion. In contrast,
-MSH was shown in the
present study to increase glucocorticoid levels by stimulating ACTH
secretion. This in vivo demonstration of
-MSH stimulation of ACTH
release is consistent with previous studies showing that
-MSH stimulates release of ACTH from primary cultures of
rat anterior pituitary cells (25). Finally, we show that MCH can fully
attenuate the effects of
-MSH on corticosterone levels. Future
studies will address the possibility that this antagonism is involved
in the integration of feeding and the HPA axis under one or more
physiological conditions.
An interesting parallel can be drawn to mice with mutations at the
agouti locus (28). The agouti gene product, normally expressed in the
skin of various mammals, competitively inhibits the binding of -MSH
to the MC1R (26). As a result of this antagonism, the black hair
produced under the influence of
-MSH develops a band of yellow,
providing a dusky appearance (called agouti) to the coat. The viable
yellow and lethal yellow mouse mutations cause ubiquitous
overexpression of agouti protein and result, as expected, in a
completely yellow coat color (26). In addition to pigmentary changes,
however, the agouti mutants manifest hyperphagia and obesity (43).
Moreover, they also have lower corticosterone levels than other obese
mouse strains (41). These phenotypic changes, analogous to the acute
effects of MCH described here, may demonstrate the consequences of
chronic melanocortin antagonism by ectopically expressed agouti in the
hypothalamus.
The mechanisms underlying the pleiotropic metabolic effects of agouti
overexpression are not known; the most likely candidates for central
molecular targets mediating agouti action are MC4R, for which agouti is
a potent and specific antagonist (26), and perhaps MC3R. Despite the
qualitatively similar effects of agouti overexpression and acute MCH
administration on feeding behavior and the HPA axis, the present
results indicate that MCH does not antagonize these central
melanocortin receptors. Thus MCH may comprise a functional hypothalamic
analog of agouti protein, operating through a unique, as yet
unidentified receptor. It is also possible that MCH antagonizes other
appetite suppressing peptides (GLP-1 and urocortin) and that -MSH
can antagonize orexigenic peptides, such as NPY. Further studies are
required to address this issue.
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ACKNOWLEDGEMENTS |
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We thank Drs. Joe Majzoub and Lou Muglia for thoughtful suggestions, Jean Flanagan and Margaret Entwistle for expert technical assistance, and Drs. Greg Barsh and Mike Ollman for kindly providing the mouse agouti protein to the laboratory of J. B. Tatro. We also thank Jennifer Marron for assistance in preparing the manuscript.
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FOOTNOTES |
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The animals used were housed at the Diabetes and Endocrinology Research Center Animal Core Facility at the Joslin Diabetes Center or the Beth Israel Deaconess Hospital.
D. S. Ludwig was supported by grants from the Charles H. Hood Foundation and the Lawson Wilkins Pediatric Endocrine Society. J. S. Flier was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R08-DK-02440, and J. B. Tatro was supported by National Institute of Mental Health Grant MH-44694. This work was supported by grants from the American Diabetes Association, DERC Pilot and Feasibility Study (to E. Maratos-Flier), the Health Research Council of New Zealand, and a Wellcome Trust Senior Research Fellowship (to K. G. Mountjoy).
Present address of R. C. Frederich: Div. of Endocrinology, Department of Medicine, Chandler Medical Center, University of Kentucky, Lexington, KY 40536.
Address for reprint requests: E. Maratos-Flier, Joslin Diabetes Center, One Joslin Place, Rm. 620, Boston, MA 02215.
Received 20 June 1997; accepted in final form 16 December 1997.
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