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Melanocortins and body weight: A tale of two receptors

Article in Nature Genetics · October 2000

DOI: 10.1038/79223 · Source: PubMed

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Melanocortins and body weight:

a tale of two receptors
David E. Cummings & Michael W. Schwartz
Department of Medicine, University of Washington, VA Puget Sound Health Care System and Harborview Medical Center, Seattle, Washington 09108, USA.
e-mail: davidec@u.washington.edu & mschwart@u.washington.edu

The phenotypes of mice lacking melanocortin-3 (Mcr3) and melanocortin-4 receptors (Mc4r) demonstrate that these isoforms
reduce body weight through distinct and complementary mechanisms. Mc4r regulates food intake and possibly energy expendi-
ture, whereas Mc3r influences feed efficiency and the partitioning of fuel stores into fat.

Few medical advances would have as
favourable an impact on public health as a
cure for obesity, arguably the most signifi-
cant contributor to illness worldwide1.
Prospects for significant advances in this
© 2000 Nature America Inc. • http://genetics.nature.com
Leptin regulation of energy homeostasis
is mediated through neuropeptides that
can be categorized as catabolic or anabolic.
Catabolic neuropeptides, which are stimu-
lated by leptin, decrease food intake and
Mc3r and body weight
These studies demonstrate an important
role for Mc4r in regulating food intake, but
do not exclude the possibility of additional
contributions from Mc3r. To address this

arena have accompanied rapid advances in
identifying the molecular determinants of
body weight. Among these, melanocortins
have a pivotal role, communicating weight-
loss signals that are essential for maintain-
ing normal body fat stores2. Until recently,
the receptors transmitting these signals
were unknown. Now, genetic studies in
mice have elucidated distinct and comple-
mentary roles for the leading candidates,
melanocortin-3 and melanocortin-4 recep-
tors (Mc3r and Mc4r). Analysis of Mc4r–/–
mice showed that this isoform is required
to limit food intake3 and possibly to acti-
vate energy expenditure4. On page 97 of
this issue, Chen et al.5 report that Mc3r–/–
mice have normal food intake, but store fat
more efficiently. These observations cor-
roborate those made by Butler and col-
leagues6 and published in this month’s
issue of Endocrinology.
An endocrine feedback loop
It has long been known that body fat con-
tent remains remarkably constant in nor-
mal individuals throughout the breadth of
adult life, despite enormous day-to-day
variation in energy intake and expenditure.
Adiposity is tightly regulated by a classical
endocrine feedback loop, some compo-
nents of which are illustrated (see figure).
The adipocyte hormone leptin circulates in
proportion to body adiposity and triggers
intricate neuropeptide responses in the
brain7 that modulate appetite and energy
expenditure, stabilizing body fat stores over
time. Most cases of obesity are characterized
by high leptin levels and leptin resistance.
Because leptin resistance is rarely due to a
mutant leptin receptor (only a handful of
OB-R mutations have been discovered in
humans), research efforts are now focused
on identifying the downstream targets of
leptin that mediate functional resistance.
increase energy expenditure. Anabolic neu-
ropeptides, which are suppressed by leptin,
do the opposite. Determining which of
these molecules are the critical players in
this redundant network is required before
suitable targets for anti-obesity drug devel-
opment can be identified.
Leptin and melanocortins
Among the catabolic mediators of leptin
action, melanocortins are particularly
indispensable2. In the hypothalamic arcu-
ate nucleus, leptin induces expression of
pro-opiomelanocortin (POMC), a ever, as the mice showed no perturbations
polypeptide precursor that is cleaved to
generate α-melanocyte stimulating hor-
mone (αMSH), the principle agonist of
the predominant neuronal melanocortin
receptor isoforms, Mc3r and Mc4r. A vital
role for melanocortin signalling in the reg-
ulation of body weight has been estab-
lished. POMC-deficient mice and humans
are hyperphagic, obese and leptin-resis-
tant8. Central melanocortin antagonism
produces a similar phenotype, whether
accomplished by overexpression of the
Mcr antagonist peptides, agouti or agouti-
related peptide (AgRP), or by infusion of a
synthetic antagonist. Conversely,
melanocortin agonism by αMSH or syn-
thetic analogues causes anorexia and
weight loss9. None of these experiments
distinguish the relative importance of
Mc3r versus Mc4r in mediating the cata-
bolic effects of melanocortins, as the lig-
ands used bind both receptors. Mc4r seems
critical for normal control of food intake,
as Mc4r-selective agonists cause dose-
dependent hypophagia and weight loss,
whereas Mc4r-selective antagonists yield
the opposite effects and attenuate the
anorectic response to leptin. A similar phe-
notype is seen in both mice3 and humans10
with inactivating Mc4r mutations.
question, Chen et al. generated Mc3r–/–
mice5. Mutants have increased body fat
with a reciprocal decrease in lean mass,
such that body weight remains normal.
This excessive adiposity is not caused by
increased food intake, which is actually
reduced. Instead, the phenotype arises
from increased feed efficiency—the
amount of weight gained and fat deposited
per calorie consumed. Indeed, mutants are
unusually susceptible to high-fat diet-
induced obesity. The mechanism of
increased feed efficiency is unclear, how-
in metabolic rate, thyroid hormone levels,
respiratory exchange ratio or body tem-
perature. However, Mc3r–/– mice are rela-
tively inactive5,6, which may at least partly
explain their obesity.
That Mc3r–/– mice store calories effi-
ciently is consistent with pharmacologic
studies showing that non-specific
melanocortin activation increases meta-
bolic rate4,11. Which Mcr mediates this
effect is unclear, however, as metabolic rate
in Mc4r–/– mice does not respond to
melanocortins, and yet is elevated at base-
line4. Therefore, whether Mc3r–/– mice
exhibit increased energy expenditure in
response to melanocortins is an important,
unanswered question.
Mice lacking both Mc3r and Mc4r reveal
that loss of Mc3r exacerbates the obesity
associated with Mc4r deficiency, consis-
tent with non-redundant functions for the
two receptors in regulating body weight.
One explanation for this finding is that
double mutants eat excessively, due to
absent Mc4r signalling, and store ingested
calories more efficiently, due to the
absence of both receptors.
Food intake can be reduced either by
activating physiological circuits involved
in normal feeding behaviour or by induc-

8 nature genetics • volume 26 • september 2000

 © 2000 Nature America Inc. • http://genetics.nature.com
Putting the ‘feed’ in blood
feedback. Leptin signalling
through melanocortin neu-
rons to regulate food intake
and promote weight loss.
Hypothalamic neurons
expressing POMC also
express receptors for lep-
tin, which crosses the
leptin
blood–brain barrier. Acti-
vation of leptin receptors
stimulates nerve terminals
to release αMSH, a ligand
for Mc3r and Mc4r, which
are expressed on post-
synaptic neurons. Activa-
tion of Mc4r reduces food
intake and may also
increase energy expendi-
ture. Activation of Mc3r
may decrease the shunting adipose
of ingested calories into tissue
fat stores, but may also
induce illness.
© 2000 Nature America Inc. • http://genetics.nature.com
ing illness. Non-specific Mcr agonists
seem to do both, judging by the formation
of conditioned taste aversion. That selec-
tive Mc4r agonists reduce food intake
without aversive consequences12 suggests
that pharmacological activation of Mc3r
can cause illness. This hypothesis predicts
that Mc3r–/– mice will retain the
hypophagic, but not the aversive, response
to non-selective Mcr agonists, whereas the
reverse would be true for Mc4r–/– mice.
Moreover, Mc3r–/– mice should manifest
an intact anorectic response to leptin,
which causes anorexia without aversion,
whereas Mc4r–/– mice do not13.
Leptin regulates numerous neuroen-
docrine systems beyond those controlling
body weight, and a decline of leptin levels is
proposed to orchestrate adaptive responses
to starvation in these systems. The conse-
quences of reduced leptin levels during
food deprivation include suppression of
reproduction, lactation, linear growth, and
the thyroid axis, as well as stimulation of
nature genetics • volume 26 • september 2000
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brain
feed efficiency
adversive responses?
Mc3r
leptin
receptor α-MSH
melanocortin Mc4r
neuron
blood-brain
barrier
food intake
Bob Crimi
metabolic rate?
stress hormones14. These alterations help
animals survive starvation by suppressing
non-vital bodily functions and minimizing
calorigenesis, and some of these neuroen-
docrine responses may be mediated
through melanocortins. For example,
recent data indicate that melanocortins
have an important role in leptin regulation
of the thyroid axis15. The normal thyroid
hormone levels in Mc3r–/– mice5 indicate
that Mc4r might mediate melanocortin
effects on the thyroid axis. Studies of thy-
roid function in Mc4r–/– and Mc4r–/–
Mc3r–/– mice will help clarify this issue.
Clinical implications
How might MC3R contribute to human
obesity? The knockout phenotype raises
the possibility that mutations at this locus
might be part of a ‘thrifty genotype’, a
putative collection of alleles that was pos-
itively selected over evolution because
they promote fat storage in times of
plenty, thereby protecting against times of
news & views
famine16. Such genes would have been
advantageous throughout most of human
history, but deleterious in modern West-
ern societies, where calorie-dense food is
omnipresent. Leptin and its receptors are
poor candidates to be thrifty genes, as
their mutation causes not only weight
gain but also infertility, thus preventing
positive selection. By contrast,
melanocortin receptors are excellent can-
didates, as allelic variations associated
with haploinsufficiency should promote
fat storage without impairing fertility10.
This may explain the relatively high
prevalence of MC4R mutation (approxi-
mately 4%) in obese human popula-
tions17. Further investigation is required
to determine the extent to which poly-
morphisms in MC3R may also contribute
to human obesity, although initial studies
show no such linkage18.
Central melanocortin receptors are
promising targets for anti-obesity thera-
pies. MC4R agonists should decrease food
intake, whereas MC3R agonists should
decrease feed efficiency, and both com-
bined may promote weight loss more
effectively than either alone. Further
analysis of the behavioural and metabolic
responses mediated by these receptors will
help to guide the development of more
effective therapies for obesity. 
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