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The Journal of Neuroscience, 1999, 19:RC26:1-7
RAPID COMMUNICATION
Anatomy of an Endogenous Antagonist: Relationship between
Agouti-Related Protein and Proopiomelanocortin in Brain
Didier
Bagnol1, 4,
Xin-Yun
Lu1,
Christopher B.
Kaelin3,
Heidi E. W.
Day1,
Michael
Ollmann3,
Ira
Gantz2,
Huda
Akil1,
Gregory S.
Barsh3, and
Stanley J.
Watson1
1 Mental Health Research Institute and
2 Department of Surgery, University of Michigan, Ann Arbor,
Michigan 48109-0720, 3 Departments of Pediatrics and
Genetics, Howard Hughes Medical Institute, Stanford, California 94305, and 4 Centre National de la Recherche Scientifique,
Neurobiologie des Fonctions Végétatives, Université
d'Aix-Marseille, Marseille 3, Cedex 20, France
 |
ABSTRACT |
Agouti-related protein (AGRP) is a recently discovered orexigenic
neuropeptide that inhibits the binding and action of
 -melanocyte-stimulating hormone derived from proopiomelanocortin
(POMC) at the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) and has been proposed to function primarily as an
endogenous melanocortin antagonist. To better understand the interplay
between the AGRP and melanocortin signaling systems, we compared their
nerve fiber distributions with each other by immunohistochemistry and
their perikarya distribution with MC3R and MC4R by double in
situ hybridization. Although deriving from distinct cell
groups, AGRP and melanocortin terminals project to identical brain
areas. Both AGRP and melanocortin neurons selectively express the MC3R,
which provides a neuroanatomical basis for a dual-input circuit with
biological amplification and feedback inhibition. These studies
highlight a broader complexity in POMC-mediated behavior in the brain.
Key words:
Agouti-related protein; proopiomelanocortin; ingestive
behavior; MC3R; MC4R; arcuate nucleus
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INTRODUCTION |
Naturally
occurring antagonists can act either by binding to and sequestering a
ligand or by binding to a receptor to prevent its response to another
molecule. Unique advantages for biological regulation are provided by
the latter mechanism, of which Agouti protein and Agouti-related
protein (AGRP) are prime examples (Ollmann et al., 1997 , 1998; Shutter
et al., 1997). These proteins inhibit the activity of melanocortins,
small peptides such as -melanocyte-stimulating hormone (-MSH) or
adrenocorticotrophic hormone derived from a large precursor,
proopiomelanocortin (POMC), that also gives rise to  -endorphin. AGRP
binds directly to melanocortin receptors but has little intrinsic
signaling activity, and instead functions primarily by inhibiting
-MSH binding (Ollmann et al., 1997; Shutter et al., 1997). Indeed,
the melanocortin receptors were originally identified by their ability
to activate adenylate cyclase in response to -MSH. However, recent
studies have suggested that physiological modulation of receptor
signaling may be accomplished mainly by alteration in the levels of
AGRP rather than -MSH. Starvation and leptin deficiency cause a
predominant rise in levels of AGRP mRNA rather than a decrease in POMC
mRNA levels in the hypothalamus (Thornton et al., 1997; Mizuno et al.,
1998; Mizuno Mobbs, 1999; Wilson et al., 1999). Artificial increases in
AGRP achieved pharmacologically or in transgenic animals cause elevated
food intake and obesity (Graham et al., 1997; Ollmann et al., 1997;
Grill et al., 1998; Rossi et al., 1998).
Because the action of AGRP has only been tested on melanocortin
receptors, the question remains, does AGRP work primarily as a
melanocortin antagonist, or might it have other functions? One approach
to this question is to examine its anatomy vis-a-vis the anatomy of the
melanocortins and to determine whether AGRP only exists where
melanocortins are found, or whether it is also expressed at other sites
independent of either the ligands or the receptor(s) that it is
purported to antagonize. To investigate the potential for presynaptic
and/or direct crosstalk between AGRP and POMC systems, we examined the
colocalization of AGRP or POMC with the MC3R and MC4R using double
in situ hybridization.
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MATERIALS AND METHODS |
Animals. Male Sprague Dawley rats (Charles River
Laboratories, Wilmington, MA) weighing 300-350 gm were used in this
study. Rats were housed in groups of two or three per cage with food and water available ad libitum in a 12 hr light/dark cycle
(lights on at 7 A.M.) under conditions of constant temperature and
humidity. Animals were allowed to habituate for 1 week before
experiments. Protocols for animal experimentation were approved by the
University of Michigan Institutional Animal Care and Use Committee.
Immunohistochemistry. For immunohistochemical studies male
unfasted Sprague Dawley rats were perfused via the ascending aorta with
a Zamboni's fixative solution, and brains were removed,
immersion-fixed, cryoprotected, frozen, and sectioned.
Thirty-micrometer-thick free-floating sections were incubated or
co-incubated with human AGRP affinity-purified antibody (1:30,000) or
 3-MSH
(Lys-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly-Pro-Arg-Asn-Ser-Ser-Ser-Ala-GlyGly-Ser-Ala-Gln, coupled to thyroglobulin with glutaraldehyde) antibody (1:20,000) following a procedure previously described (Wilson et al., 1999).
In situ hybridization histochemistry. For in situ
hybridization histochemistry male Sprague Dawley rats were killed by
rapid decapitation (2 hr after lights on), and brains were removed and frozen. A 345 bp fragment of the rat AGRP cDNA and a 936 bp fragment of
the rat POMC cDNA were used to synthesize antisense cRNA probes. The
rat MC3R (281-1270) probe was generated by PCR using Pfu polymerase (Statagene, La Jolla, CA) with genomic DNA as a substrate, and the rat
MC4R (141-1181) probe was generated by screening a rat EMBL3 genomic
library (Clontech, Palo Alto, CA) using the human MC4R as a probe.
Digoxigenin-11-UTP (Boehringer Mannheim, Mannheim, Germany)
antisense-labeled rat AGRP or POMC probes and
[-35S]UTP and
[-35S]CTP (Amersham, Arlington
Heights, IL) antisense-labeled MC3R or MC4R probes were simultaneously
hybridized on paraformaldehyde-fixed setions as previously described by
Curran and Watson (1995) and Wilson et al. (1999).
The specificity of hybridization was confirmed by control experiments
using sense probes or tissue that had been pretreated with ribonuclease
A (200 µg/ml) for 1 hr at 37°C before hybridization with antisense
probes. No specific hybridization signals were observed in these conditions.
Photomicrography and image analysis. The immunostained and
autoradiographic tissue sections were viewed using a Leica (Nussloch, Germany) DMR microscope, and images were captured with an MCID M5 image analysis system (Imaging Research, St. Catherine's Ontario, Canada). Images were prepared with Adobe (Mountain View, CA) Photoshop 4.0 software, and only the contrast or transparency was adjusted. For
double in situ hybridization, nonradioactive labeling was visualized under bright field as a blue precipitate, and radioactive labeling was identified under dark field by silver grain clusters. Digoxigenin-labeled neurons (AGRP or POMC mRNA-containing neurons) were
counted bilaterally and then examined for the presence of silver gains
(either MC3R or MC4R). A series of sections spaced 100 µm apart was
analyzed for each set of probes. No attempt was made to determine the
total number of cells in the arcuate nucleus; therefore, the cell
counting data represent a relative percentage of AGRP or POMC cells
expressing MC3R rather than an absolute number. The boundaries of
nuclei were determined according to the atlases of Kruger et al. (1995)
and Paxinos and Watson (1986).
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RESULTS |
Co-distribution of AGRP- and POMC-immunoreactive nerve fibers in
the brain
Previous studies by us and other groups have indicated that the
POMC and AGRP systems were derived from two distinct cell populations
in the arcuate nucleus (Shutter et al., 1997; Hahn et al., 1998;
Wilson et al., 1999). In the present study, we compared AGRP and POMC
projections in the brain, spinal cord, and pituitary with adjacent
sections. Immunoreactive POMC processes were widely distributed
throughout the brain (Table 1),
exhibiting a projection pattern identical to that previously described
for other POMC-derived peptides such as -endorphin and -MSH
(Watson et al., 1978a,b; Khachaturian et al., 1985). AGRP fibers
essentially overlapped with POMC projections. Three major projectional
systems of AGRP fibers could be delineated as has been described for
the POMC system (Khachaturian et al., 1985): rostral, lateral,
and caudal systems. The rostral and lateral projections of AGRP
in the forebrain were prominent and closely paralleled the rostral and
lateral POMC projections (Fig. 1). Within
the same fields, POMC projections were more broadly distributed.
AGRP-immunoreactive fibers appeared to be thinner and to have more
varicosities than POMC fibers. AGRP terminals were densely packed to
form compact immunoreactive patches in some forebrain regions, such as
the bed nucleus of the stria terminalis, ventral division, the organum
vasculosum of the lamina terminalis, the paraventricular nucleus of the
hypothalamus, the arcuate nucleus, the dorsomedial nucleus of the
hypothalamus, and the perifornical nucleus and lateral hypothalamus
(Figs. 1, 2, 3E-H).
These findings of the distribution of AGRP immunoreactivity were
consistent with the recent reports as described in the mouse, diestrous
rat, and fasted monkey (Broberger et al., 1998; Haskell-Luevano et al.,
1999). In the caudal projections to the brainstem and spinal cord, POMC
innervation was much heavier and broader than that of AGRP, as shown in
Table 1. AGRP was greatly reduced or absent from many POMC-innervated
areas in the brainstem and cervical spinal cord (Table 1), suggesting
that a substantial portion of the caudal POMC system originates from
cells in the nucleus of the solitary tract Bronstein et al., 1992,
whereas the rostral and lateral projections of POMC and AGRP probably
originate in parallel from the arcuate nucleus of the hypothalamus.
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Table 1.
Distribution and relative abundance of AGRP- and
POMC-immunoreactive fibers and terminals in the rat CNS
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Figure 1.
Color scale illustration of AGRP
(A-D) and POMC (E-H)
immunoreactivity in the rat brain. Images of coronal brain sections
were acquired with NIH Image software. The intensity of the labeling
ranges from blue (low, L) to
red (high, H), which is a
summation of density of fibers and intensity of immunostaining per
fiber. The distribution patterns of AGRP and POMC are very similar.
Note the high intensity of AGRP-immunoreactive fibers in bed nucleus of
the stria terminalis, ventral division (BSTV;
A), organum vasculosum lamina terminalis
(OVLT; A), medial preoptic nucleus
(MPO; B), paraventricular hypothalmic
nucleus (PVN; C), retrochiasmatic area
(Rch; C) lateral hypothalamus
(LH; C), and arcuate nucleus
(Arc; D). ac, Anterior
commissure; DMD, dorsomedial hypothalamic nucleus,
diffuse; DMC, dorsomedial hypothalamic nucleus, compact;
ME, median eminence; VMH, ventromedial
hypothalamic nucleus.
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Figure 2.
Photomicrographs illustrating AGRP
(A-H) and POMC (I-P)
immunohistochemistry in the hypothalamic nuclei. Areas include Rch
(A, I), Arc (B,
J), MPO (C,
K), PVN (D, L),
OVLT (E, M), BSTV
(F, N), paraventricular nucleus of
the thalamus (G, O), and ME (H,
P). Note the small size of AGRP immunoreactive perikarya versus large
POMC immunoreactive perikarya in the Rch and Arc (A,
B, I, J). The
density of AGRP immunoreactive fibers is more prominent than for POMC
fibers in the Arc (B, J), PVN
(D, L), and BSTV (F,
N). Note the presence of moderate to dense
innervation of AGRP and POMC in the internal part of the median
eminence. 3V, Third ventricle; other abbreviations as in
Figure 1. Scale bars, 100 µm.
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Using double-labeling immunohistochemistry, we found that AGRP fiber
boutons were closely apposed to POMC neurons in the arcuate nucleus
(Fig. 3E). These findings
suggest that AGRP and POMC neurons interact locally in their cell body
regions and are consistent with the observation that NPY neurons (which
always contain AGRP in the arcuate nucleus) make synaptic contact with
POMC neurons (Csiffary et al., 1990).
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Figure 3.
A-D, Representative
photomicrographs of double in situ hybridization
histochemistry indicating that AGRP or POMC mRNA colocalize with MC3
receptor mRNA (A, B), but not with MC4
receptor mRNA (C, D). The
white silver grain clusters represent MC3 or MC4
receptor mRNAs, which were detected by 35S-labeled
riboprobes. AGRP (A, C) and POMC
(B, D) mRNAs were visualized by
digoxigenin-labeled riboprobes (in blue). Thirty-one to
44% of AGRP (A) and POMC
(B) cells expressed MC3R (red
arrows), whereas none of them displayed MC4R (in
C, D, respectively AGRP and POMC cells).
Some MC3R and MC4R cells contained other neurotransmitters than AGRP
and POMC (A-D, white arrows). Some AGRP
and POMC cells do not display MC3R and MC4R (B-D,
blue arrows). E-H, Double-labeling
immunohistochemistry on coronal brain sections showing both AGRP- and
POMC-immunoreactive fibers in the arcuate nucleus
(E), lateral hypothalamus
(F), central amygdala (G),
and dorsomedial hypothalamus (H). 3-MSH
immunoreactivity was detected by DAB (in brown), whereas
AGRP immunoreactivity was detected by NiCl amplification (in
black). Note in E POMC-immunoreactive
cells being surrounded by AGRP-immunoreactive fibers
(arrows), suggesting synaptic contact between AGRP
fibers and POMC neurons. Scale bars: A,
B, 50 µm; C, D,
F-H, 25 µm; E, 15 µm.
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Expression of melanocortin receptors by AGRP or POMC cells
Colocalization of MC3R/MC4R with AGRP and POMC cells was first
investigated in the present study. We found that MC3R mRNA was
contained in both AGRP and POMC neurons with a rostrocaudal gradient in
the arcuate nucleus (Arc). MC3R mRNA was identified in 55% of AGRP
neurons in rostral Arc and in 28% for the most caudal Arc sections
(Fig. 3A) with an average of 44% (all of the Arc sections
counted). Similarly, we found that MC3R mRNA was expressed in
43% of POMC neurons in rostral Arc and 13% for the most caudal
sections (Fig. 3B) with an average of 31% (all Arc sections
counted). In contrast, neither AGRP nor POMC cells displayed MC4R mRNA
(Fig. 3C,D).
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DISCUSSION |
In the present study we extended the recent reports about AGRP
projections in the CNS and compared the distribution of AGRP and POMC
systems with each other with double immunohistochemistry methods as
well as with melanocortin receptor subtypes using double in
situ hybridization techniques.
Anatomical coregistration of AGRP with POMC peptides demonstrated by
our study implies that AGRP might be completely dependent on the
melanocortin receptors for its actions. This is supported by in
vitro data indicating that AGRP suppresses MSH-induced cAMP accumulation via either MC3R or MC4R (Ollmann et al., 1997). Comparing MCR mRNA distribution and AGRP terminal projections reveals a strong
overlap in most areas rich in MC3R mRNA and a subset of areas
expressing MC4R mRNA (Roselli-Rehfuss et al., 1993; Mountjoy et al.,
1994). In addition, we found a good correlation between AGRP projection
fields and the reported MCR binding sites (Tatro, 1990). These
observations strongly support the hypothesis that MCRs are the putative
receptors for AGRP, although we cannot rule out the possibility of the
existence of distinct AGRP receptors that might be distributed
identically to MCRs.
The wide distribution of AGRP terminals suggest that AGRP participates
in the regulation of food consumption through several hypothalamic
structures, including the paraventricular, arcuate, dorsomedial, and
lateral hypothalamic nuclei, as well as the amygdala, an area
implicated in emotional aspects of feeding behavior. Interestingly, AGRP and POMC-immunoreactive fibers are not found in the ventromedial hypothalamic nucleus, even though this region contains abundant MC3R
mRNA and -MSH binding sites and has been referred to historically as
a "satiety center" (Brobeck, 1946). These discrepancies could reflect functional receptor trafficking to the axon terminals. Besides
feeding behavior likely mediated by hypothalamic regions, the
widespread co-distribution of AGRP and POMC projections in the
forebrain and brainstem implicates AGRP in the control of other
behaviors or functions attributed to POMC, including stress, thermoregulation, pain, and reproduction (Khachaturian et al., 1985).
We also observed AGRP and POMC fibers in the internal layer of the
median eminence. These fibers extend into the posterior lobe of the
pituitary and suggest that AGRP could be released into the systemic
circulation and function as an endocrine hormone.
The presence of MC3R in both AGRP and POMC neurons demonstrated by the
present study suggests that MC3R may mediate the potential interaction
between AGRP and POMC systems. Moreover, the colocalization of Mc3R
with AGRP and POMC neurons suggest that MC3R may act at the upstream of
MC4R in the control of food intake. Because activation of MC3R by
melanocortins is stimulatory (i.e., it increases levels of cAMP), and
its blockade by AGRP is inhibitory, we would propose two possible roles
for MC3R in the POMC and AGRP neuronal circuit. Expression of the MC3R
by POMC neurons provides a potential circuit for amplification of
AGRP-mediated signals, because AGRP-induced inhibition of POMC neurons
via the MC3R would reinforce the postsynaptic effects of AGRP.
Furthermore, the expression of the MC3R by AGRP neurons provides a
potential circuit for negative autoregulation of POMC-mediated signals,
because POMC-induced activation of AGRP neurons via the MC3R would
terminate the postsynaptic effects of POMC. Both of these types of
actions would tend to reinforce orexigenic behavior but limit signals
for satiety and may explain why AGRP or other melanocortin antagonists
exert a prolonged effect after intracerebroventrical administration
(Grill et al., 1998; Rossi et al., 1998). From an evolutionary
perspective, biological amplification of food-seeking behavior and/or
feedback inhibition of satiety behavior may offer a selective advantage
in situations in which reproductive success is limited by nutrient
availability. Given the colocalization of AGRP with NPY (Broberger
et al., 1998; Hahn et al., 1998) (D. Bagnol, X.-Y. Lu, and S. J. Watson, unpublished observations) and of POMC and CART
(cocaine- and amphetamine-regulated transcript; Elias et al., 1999), it
is further suggested that regulation of AGRP and POMC neurons could be
accomplished not only via MC3R but also by NPY and CART receptors to
coordinate their neurotransmission.
These studies also highlight a broader complexity in POMC-mediated
behavior in the brain. POMC mediated behaviors can be elicited through
the release of several peptides acting on several classes of receptors,
including the activation of µ and  opioid receptors by
-endorphin. AGRP might allow partial suppression of melanocortin peptide activity although leaving POMC-mediated opioid actions intact.
Given that opioid and melanocortin actions can be either synergistic or
antagonistic depending on the behavior under study (Khachaturian et
al., 1985; Adan and Gispen, 1997), the presence or absence of AGRP
activity may serve to alter the balance between these two components of
POMC neurotransmission. Thus, POMC-mediated behavior would be under the
control of the amount of AGRP as well as the amount and mix of
POMC-derived peptides released at the terminals and the presence of
melanocortin receptors or opioid receptors in their vicinity. This
represents a novel mechanism whereby a multitransmitter neuron may have
its impact selectively altered by local antagonism of one of its
potentially active products. The full complexity of this type of
neuronal regulation has yet to be appreciated. Still, the essential
elements of this system include natural agonist-antagonist pairs,
parallel neuronal fiber pathways, possible coordination of
cross-regulation via shared receptors, and the actions of other
co-transmitters. This level of regulation suggests several new
principles of neurotransmitter signaling and may apply to other newly
discovered endogenous antagonists, such as the recently reported
5-HT-moduline, a naturally occurring peptide antagonist that blocks the
action of 5-HT at the 5-HT1B receptor (Massot et al., 1996).
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FOOTNOTES |
Received May 21, 1999; revised July 15, 1999; accepted July 21, 1999.
This work was supported by National Institutes of Health Grants P01
MH-42251 (from National Institute of Mental Health; to S.J.W.), DK28506
(to G.S.B.), and R01 DK-54032-01 (to I.G.). We thank Sharon Burke and
Robert Pavlic for technical assistance and Drs. Serge Campeau and
Manuel Lopez-Figueroa for advice and comments.
D.B. and X.-Y.L. contributed equally to this work.
Correspondence should be addressed to Stanley J. Watson, Mental Health
Research Institute, The University of Michigan, 205 Zina Pitcher Place,
Ann Arbor, MI 48109-0720.
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 1999, 19:RC26 (1-7). The
publication date is the date of posting online at
www.jneurosci.org.
| |
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Copyright © 0000 Society for Neuroscience 0270-6474/0/$05.00/0
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ABSTRACT
INTRODUCTION
