Obesity as a Neuroendocrine Disease: Lessons to Be Learned from Proopiomelanocortin and Melanocortin Receptor Mutations in Mice and Men*
Sharon L. Wardlaw
Department of Medicine, Columbia University College of Physicians
and Surgeons, New York, New York 10032
Address correspondence and requests for reprints to: Dr. Sharon L. Wardlaw, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: sw22{at}columbia.edu * Supported by NIH Grants
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Introduction
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Proopiomelanocortin (POMC) is best known to the
clinical endocrinologist as the precursor for pituitary ACTH, which is
essential for maintaining adrenal cortical function. The most well
recognized POMC deficiency syndrome is seen in patients with pituitary
disease who fail to secrete ACTH normally and develop secondary adrenal
insufficiency. These patients typically complain of anorexia and weight
loss, which is corrected by glucocorticoid replacement. Recently,
several cases of genetic POMC deficiency have been described, and in
contrast to the usual hypopituitary patient with selective pituitary
POMC deficiency, these individuals have increased appetite and are
obese (1). A similar obesity syndrome has been described
in transgenic mice with targeted deletion of the coding region of the
Pomc gene (2). These POMC-deficient patients
and mice are obese despite having profound secondary adrenal
insufficiency. Thus, the effects on energy homeostasis are quite
different with generalized POMC deficiency as opposed to the typical
hypopituitary patient with POMC deficiency limited to the
pituitary. A number of recent studies have established that POMC
neurons in the hypothalamus are important regulators of energy
homeostasis and that the POMC-derived peptide
melanocyte-stimulating hormone (
-MSH) and brain melanocortin
receptors (MC-Rs) play a key role in this process. This short review
focuses on the regulation of feeding behavior and body weight by the
brain melanocortin neuropeptide system and the potential implications
for the treatment of human obesity.
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POMC
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Human POMC is a 267 amino acid precursor protein that is
synthesized in the pituitary, in the arcuate nucleus of the
hypothalamus, in the solitary tract of the medulla, and in several
peripheral tissues. The posttranslational processing of POMC is tissue
specific and results in the production of a number of peptides with
very different biological activities (Refs. 3, 4, 5 ; Fig. 1
). Functionally active peptides are
produced by endoproteolytic cleavage at adjacent pairs of basic amino
acids by the prohormone convertases PC1 and PC2 (6). In
the anterior pituitary, POMC is processed predominantly to ACTH, which
is critical for the maintenance of adrenocortical function, as well as
to ß-lipotropin (LPH) and a 16-kDa N-terminal fragment. In the
hypothalamus and in the intermediate lobe of the pituitary (which is
prominent in the rodent), POMC is more extensively processed: ACTH is
further processed to produce
-MSH and corticotropin-like
intermediate lobe peptide; ß-LPH is processed to ß-endorphin
and
-LPH; and N-terminal POMC is processed to
3-MSH. Within the brain, ß-endorphin
and the MSH peptides have wide-ranging effects on neuroendocrine
regulation, analgesia, behavior, and immune function. It is now clear
that
-MSH and brain MC-Rs also play an important role in regulating
feeding behavior and energy balance. The regulation of POMC gene
expression and peptide release is tissue specific. In the anterior
pituitary, POMC is stimulated by CRH and inhibited by glucocorticoids;
in the intermediate lobe, POMC is regulated by dopamine. In the
hypothalamus, a number of steroid hormones, neurotransmitters, and
neuropeptides have been reported to affect Pomc gene
expression or peptide release. These include sex steroids,
glucocorticoids, opioids, dopamine,
-aminobutyric acid, CRH,
and neuropeptide Y (NPY). It should be noted that the same treatment
may have quite different effects on Pomc expression in the
pituitary compared with the hypothalamus. For example, after
adrenalectomy, Pomc gene expression is markedly up-regulated
in the anterior pituitary but can be suppressed in the hypothalamus
(7, 8). It has recently been shown that POMC neurons in
the hypothalamus are important targets for leptin, a hormone secreted
by fat cells, which plays a key role in communicating the levels of
peripheral energy stores to the brain (Ref. 9 ; Fig. 2
). There is accumulating evidence that
-MSH is one of the downstream mediators of the effects of leptin on
energy homeostasis.

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Figure 1. Schematic diagram of the POMC precursor
molecule and the major peptide products that are derived from this
precursor by endoproteolytic cleavage. JP, Joining peptide; CLIP,
corticotropin-like intermediate lobe peptide.
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Figure 2. Diagram depicting the effects of leptin on
hypothalamic POMC and AGRP neurons and their interaction with
hypothalamic MC-Rs. MC4-R signaling is stimulated by -MSH and
inhibited by AGRP. Leptin, which is secreted by fat cells, stimulates
POMC and inhibits AGRP, thus increasing MC4-R signaling and inhibiting
food intake. Leptin also inhibits NPY, which is synthesized in the same
neurons as AGRP. Stimulatory interactions are shown in solid
lines, and inhibitory interactions in dashed
lines.
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MC-Rs
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The biological effects of ACTH and the MSH peptides are mediated
by interactions with specific G protein-coupled, seven-transmembrane
receptors. Five MC-Rs have recently been cloned (Table 1
). The MC1-R is expressed almost
exclusively in melanocytes and mediates effects on skin pigmentation
and coat color (10). Mutations of the Mc1-r
gene are associated with alterations in coat color in animals. In the
human, MC1-R gene sequence variants have been reported in
over 80% of individuals with red hair and/or fair skin that tans
poorly (11). The MC2-R is expressed primarily in the
adrenal cortex and mediates the effects of ACTH on glucocorticoid
synthesis and release. A number of patients with familial
glucocorticoid deficiency have been shown to have mutations of the
MC2-R gene (12). The MC3-R and MC4-R are both
highly expressed in the brain and specifically in areas known to be
involved in regulating energy balance. The MC3-R is localized to the
hypothalamus and the limbic system and is highly expressed by arcuate
neurons, including POMC neurons (13, 14). The MC4-R is
more widely distributed throughout the brain, in the hypothalamus,
thalamus, cortex and brain stem (15). Within the
hypothalamus, the MC4-R is highly expressed in the paraventricular
nucleus and the lateral hypothalamic area, which are both important in
regulating energy balance. The MC5-R is expressed primarily in exocrine
glands and in skeletal muscle (16). Mc5-r
knockout mice have exocrine gland dysfunction and decreased production
of sebaceous lipids. The MC-Rs can be activated by both ACTH and
-MSH, except for the MC2-R, which is activated primarily by ACTH.
The MC3-R, unlike the other receptors, is also potently activated by
3-MSH. Disruption of the MC1-R, MC2-R, and
MC5-R results in abnormalities of pigmentation, adrenal function, and
exocrine gland function, respectively, but not in changes in energy
homeostasis. In contrast, there is considerable evidence that the MC4-R
plays an important role in energy homeostasis. As discussed below,
targeted disruption of this receptor produces hyperphagia and obesity
in transgenic mice (17), and MC4-R mutations
have been found in obese humans. A role for the MC3-R in energy
homeostasis is indicated by a recent study showing that disruption of
the MC3-R results in increased fat mass and decreased lean body mass
(18).
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Central melanocortin system and mouse models of obesity
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A number of studies have shown that intracerebroventricular
injection of
-MSH and other synthetic MSH agonists can suppress food
intake in the rodent and that this effect can be blocked by specific
-MSH antagonists (19, 20). Injection of SHU9119, a
synthetic
-MSH antagonist, increases food intake, indicating a role
for endogenous
-MSH in appetite control. Two naturally occurring MSH
antagonists, agouti protein and agouti-related protein, have been
identified that can stimulate food intake. Agouti is a 131-amino acid
protein that is normally expressed within hair follicles and regulates
the synthesis of pigments that produce coat color. Agouti antagonizes
the effects of
-MSH at the MC1-R, which results in a lighter coat
color. Naturally occurring mutations of the agouti locus
such as the lethal yellow (Ay) cause widespread
ectopic expression of agouti. These animals have a yellow coat color
and develop hyperphagia, hyperinsulinemia, obesity, and increased body
length. The obesity results from antagonism of the MC4-R due to ectopic
expression of agouti within the brain. A similar obesity syndrome is
produced by targeted disruption of the MC4-R (17).
These mice develop a maturity onset obesity syndrome characterized by
hyperphagia, hyperinsulinemia, hyperglycemia, and increased body
length. Mice heterozygous for the Mc4-r deletion exhibit a
phenotype intermediate between that of the wild-type and homozygous
littermates. Mc3-r knockout mice have increased fat mass and
reduced lean body mass but are not hyperphagic (18). When
exposed to a high-fat diet, these mice eat normal amounts of food but
gain more weight than wild-type mice, consistent with increased feed
efficiency. Mice lacking both the Mc3-r and the
Mc4-r weigh significantly more than mice lacking only the
Mc4-r. Thus, both receptors regulate energy balance in a
nonredundant manner.
An endogenous melanocortin antagonist, agouti-related protein (AGRP),
has now been identified in the hypothalamus (21, 22). AGRP
is a 132-amino acid peptide that is synthesized in the arcuate nucleus
and is structurally homologous to the agouti protein. Within the
arcuate nucleus, AGRP and POMC are expressed by separate neuronal
populations. AGRP is a potent MC3-R and MC4-R antagonist that, when
overexpressed in transgenic mice, causes hyperphagia and obesity. When
injected intracerebroventricularly, AGRP is a potent orexigenic agent
(23). There is almost complete coexpression of AGRP with
another orexigenic peptide, NPY, in arcuate neurons (24).
AGRP and NPY fiber tracts originate in the arcuate and project to other
hypothalamic and brain regions (24, 25). Fibers
immunoreactive for
-MSH form a population separate from AGRP fibers,
but their terminals are intermingled. It is believed that the
projections of these POMC and AGRP/NPY neurons to the paraventricular
nucleus and the lateral hypothalamic area are particularly
important in regulating feeding behavior (26, 27).
Interactions between AGRP and
-MSH at the MC4-R in these
hypothalamic regions seems to be critical in maintaining energy
homeostasis. Leptin receptor messenger RNA (mRNA) and protein is highly
expressed in both POMC and AGRP neurons, and leptin seems to regulate
Pomc and Agrp expression in a reciprocal manner
(9, 26, 28). POMC mRNA levels in the hypothalamus are low,
and AGRP levels are increased during fasting when leptin is suppressed
(29, 30, 31). Obese leptin-deficient mice (ob/ob)
and leptin receptor-deficient mice (db/db) have decreased
POMC and increased AGRP mRNA levels in the hypothalamus, which in the
ob/ob mice are restored to normal by leptin injection
(31, 32, 33, 34, 35). Intracerebroventricular injection of leptin has
also been shown to stimulate POMC mRNA levels and to suppress AGRP
levels in food-deprived rats (33, 36, 37, 38). Thus,
leptin can regulate MC4-R signaling by both increasing levels of the
agonist,
-MSH, and decreasing levels of the antagonist, AGRP (Fig. 2
).
Recently, a POMC-null mutant mouse strain was created (2).
The entire third exon of Pomc was deleted, thus removing the
coding region for all of the POMC-derived peptides. Homozygous
Pomc knockout mice have defective adrenal development,
altered pigmentation, and develop obesity. No macroscopically
discernible adrenal glands were found in these animals, but on
microscopic examination some evidence of rudimentary adrenal cortex or
medulla was reported. Serum levels of corticosterone and aldosterone
were undetectable in the mutant mice, and plasma epinephrine levels
were also markedly reduced compared with the wild-type mice. Thus,
POMC-derived peptides seem to be critical not only for steroidogenesis
but also for normal adrenal development. Although glucocorticoids are
known to be necessary for normal lung development and for production of
surfactant proteins, no lung abnormalities were noted in the initial
description of the Pomc knockout mice. Glucocorticoid
receptor-deficient mice die shortly after birth with lung atelectasis
(39). In contrast, homozygous CRH knockout mice, which are
also glucocorticoid deficient, survive unless the mother is also CRH
and glucocorticoid deficient (40), indicating that
placental transfer of maternal glucocorticoids can compensate for the
fetal glucocorticoid deficiency. It is likely that the Pomc
knockout mice will have similar pulmonary abnormalities if deprived of
maternal glucocorticoids.
Despite the lack of corticosteroids, the homozygous Pomc
mutant mice develop hyperphagia and obesity. Increased weight gain was
noted in the second postnatal month, and by the third postnatal month
weights were about twice those of the wild-type mice. There was also a
significant increase in body length, as was reported for
Mc4-r knockout mice. Serum leptin levels were markedly
increased in homozygous Pomc mutant mice. Interestingly,
leptin levels were also increased in heterozygous mutant mice although
body weight was normal. When homozygous Pomc mutant mice
were treated with daily ip injections of a synthetic
-MSH agonist,
there was a significant decrease in food intake and substantial weight
loss. After 2 weeks of treatment, the mutant mice had lost 46% of
their excess body weight; there was no weight loss in the similarly
treated wild-type littermates. When the
-MSH agonist injections were
stopped, the mutant mice returned to their pretreatment weight. The
effectiveness of
-MSH injection in this model makes the development
of
-MSH agonists an attractive therapeutic target, especially
because, as described below, genetic defects in both POMC and the MC4-R
have now been described in human obesity.
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POMC and MC-R mutations and human obesity
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Recently, Krude et al. (1) reported two
patients from Germany with genetic POMC deficiency
characterized by adrenal insufficiency, red hair pigmentation, and
early-onset obesity. The first patient was found to be a compound
heterozygote for two mutations in exon 3 that resulted in ACTH and
-MSH deficiency. She had a normal birth weight and was diagnosed
with adrenal insufficiency when she developed cholestasis at 3 weeks of
age and was treated with hydrocortisone replacement. Increased appetite
and obesity was first noted at 4 months of age. The second patient was
homozygous for a mutation in exon 2, which abolishes POMC
translation. His birth weight was normal, and obesity was first noted
at 5 months of age. Adrenal insufficiency was diagnosed at 12 months of
age when he developed hypoglycemia and hyponatremia and was treated
with hydrocortisone replacement. Subsequent development in both
children was normal, except for the abnormal eating behavior and
obesity. Both children had pale skin and red to red-orange hair color.
The heterozygous parents in both families had normal adrenal function
and did not have obesity or red hair. More recently, two other
pediatric patients were described with a similar POMC deficiency
syndrome (41). A 4-yr-old boy from Slovenia was found to
be a compound heterozygote for two new POMC mutations, and a
boy from The Netherlands was found to have the same previously
described POMC exon 2 mutation. Impaired processing of POMC
has also been associated with human obesity in two instances. In one
patient the processing abnormality was due to mutations in the
prohormone convertase 1 gene (42); in the second patient
the cause remains obscure (43). Further evidence that POMC
may modulate weight level in humans is provided by a study in a
population of Mexican Americans showing a linkage of serum leptin
levels and fat mass to an interval on chromosome 2, which includes the
POMC locus (44). Subsequent studies in a French and in an
African-American population have reported similar associations
(45, 46).
In contrast to POMC mutations, which are a relatively rare
cause of human obesity, MC4-R mutations are more commonly
associated with morbid obesity. A number of studies have now reported
heterozygous mutations in the human MC4-R gene that are
associated with obesity in a dominant fashion. Vaisse et al.
(47) screened 209 morbidly obese patients and found that
4% had heterozygous MC4-R mutations; no such mutations were
found in controls. Farooqi et al. (48) screened
243 subjects with severe, early-onset obesity and found that 3.3% had
potentially pathogenic MC4-R mutations. The majority of
subjects reported, to date, with null alleles of the MC4-R
or missense mutations that alter MC4-R function have been obese.
However, some patients with these mutations are not obese. It, thus,
seems that haploinsufficiency mutations in the MC4-R gene
cause obesity with variable expressivity. Farooqi et al.
(48) report that affected children were hyperphagic and
had increased growth velocity. A marked increase in bone mineral
density was also seen in all affected subjects in that study. The
thyroid, adrenal, and reproductive axes were reported to be normal in
these patients. Thus, the human phenotype caused by impaired MC4-R
function seems to resemble that reported previously in the
Mc4-r knockout mouse.
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The melanocortin system as a potential target for the treatment of
obesity
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The studies described above clearly indicate an important role for
the central melanocortin system in maintaining energy balance and have
potential therapeutic implications for human obesity. An important
consideration in developing effective
-MSH agonists is that the
potential compounds cross the blood-brain barrier and gain access to
the appropriate hypothalamic MC-Rs. A number of animal studies have
demonstrated inhibitory effects of either native
-MSH or of
-MSH
analogs on feeding behavior (20, 49). In most of these
studies, however, peptides were administered directly into the brain by
the intracerebroventricular route. Peripheral administration of an
-MSH analog was effective, however, in the Pomc knockout
mouse (2). MSH analogs have been administered to a small
number of human subjects to evaluate effects on skin tanning and on
erectile function. Both [Nle4,
DPhe7]
-MSH, referred to as melanotan (MT)-I,
and Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2,
referred to as MT-II, have been shown to be effective in promoting
tanning when given sc for several weeks (50, 51). MT-II
was also noted to produce penile erections in normal men and in men
with psychogenic erectile dysfunction (52). Side effects
noted in these studies included flushing, nausea, anorexia,
gastrointestinal discomfort, and fatigue. Although these analogs are
likely acting on the MC1-R in the skin to produce tanning, the exact
locus of action of the other reported effects is still unknown. The
challenge will be to develop stable, well-tolerated
-MSH analogs
that gain access to central MC-Rs. Other approaches might include
compounds that stimulate hypothalamic POMC synthesis and increase
-MSH release or inhibit AGRP synthesis and release. There is still
much to be learned about the downstream effects of MC-R activation and
how the melanocortin pathway interacts with other central and
peripheral regulators of energy homeostasis (53).
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Conclusions
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The central melanocortin system, which consists of POMC, AGRP, and
the brain MC-Rs, plays a key role in regulating feeding behavior and
energy homeostasis. A growing number of studies in both the mouse and
the human with genetic defects in the synthesis or processing of POMC,
or with defects in MC-R signaling, clearly indicate the importance of
this system. A genetic POMC deficiency syndrome characterized by
adrenal insufficiency, red hair pigmentation, and early-onset obesity
has recently been described in the human. It is particularly striking
that obesity occurs in patients with generalized POMC deficiency and in
Pomc knockout mice despite the presence of adrenal
insufficiency. The contrast between these patients with generalized
POMC deficiency and with the more typical patients who have POMC
deficiency limited to the pituitary underscores the critical role that
hypothalamic POMC plays in regulating energy balance. The importance of
the MC4-R in this process is demonstrated by the Mc4-r
knockout mouse and by the growing number of obese patients reported
with MC4-R mutations, making this the most common known
monogenic cause of human obesity. The melanocortin regulatory system
seems to be sensitive to variations in MC4-R expression, as
indicated by the fact that heterozygous mutations produce obesity in
both mice and in humans. Thus, there is considerable evidence that the
hypothalamic melanocortin pathway regulates human feeding behavior and
energy homeostasis and that abnormalities in this pathway can lead to
obesity. A more detailed understanding of the control of this pathway
and its integration with a growing number of other hypothalamic
signaling pathways involved in maintaining energy balance will
hopefully lead to effective new therapies for human obesity.
Received September 7, 2000.
Revised November 3, 2000.
Accepted November 10, 2000.
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