The new england journal of medicine
To Eat or Not to Eat —
How the Gut Talks to the Brain
Judith Korner, M.D., Ph.D., and Rudolph L. Leibel, M.D.
New insights into the complex metabolic circuitry
of energy homeostasis have refined our understand-
ing of the pathophysiology of obesity. Some of these
insights regarding energy homeostasis are based on
the identification of new functions for peptides that
were discovered decades ago (see Figure). It is now
known that a-melanocyte–stimulating hormone,
a peptide derived from proopiomelanocortin and
long recognized for its role in skin pigmentation
through activity at the melanocortin 1 receptor
(MC1R), decreases food intake and increases energy
expenditure through interaction in the hypothala-
mus with another melanocortin receptor, MC4R. In
mice, targeted deletion of the Mc4r gene results in
obesity, hyperphagia, and hyperinsulinemia and re-
duces energy expenditure. Deletion of Mc3r, the gene
encoding a melanocortin receptor that is highly ex-
pressed in the hypothalamus and limbic system,
also results in increased adiposity due to decreased
energy expenditure but does not cause hyperphagia.
Although susceptibility to common obesity is ap-
parently polygenic, mutations in MC4R are found
in approximately 1 to 7 percent of humans whose
body-mass index (the weight in kilograms divided
by the square of the height in meters) is more than
40 and who become severely obese before the age
of 10 years. Antagonism of anorexigenic (appetite-
suppressing) melanocortin signals is caused by
orexigenic (appetite-stimulating) peptides such as
agouti-related protein and neuropeptide Y, which
are coexpressed in a different subgroup of neurons
within the hypothalamus. Agouti-related protein an-
tagonizes the interaction between a-melanocyte–
stimulating hormone and MC4R, and neuropeptide
Y decreases the expression of the gene encoding
proopiomelanocortin (POMC). Various polymor-
phisms in the gene encoding agouti-related protein
(AGRP) have been associated either with protection
against obesity or with anorexia nervosa. Neuropep-
tide Y also decreases the synthesis of thyrotropin-
releasing hormone and increases the synthesis of
melanin-concentrating hormone, another orexigen-
ic peptide.
Circulating concentrations of leptin and insulin
influence these central mechanisms that control
food intake and energy expenditure. The concentra-
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tion of leptin in the blood is highly correlated with
total fat mass; obese persons have high concen-
trations of leptin. Excess body fat that results in
increased leptin production may actually be a cor-
rection for primary or secondary impairment of
leptin-induced signal transduction in the hypothal-
amus. The decrease in body fat that occurs with diet-
induced weight loss causes leptin concentrations to
decrease and triggers responses that aim to con-
serve body fat. Ultimately, body-fat mass reflects the
long-term balance between energy expenditure and
energy intake. The latter appears to have the pre-
dominant role in maintaining this balance.
How, then, do we decide when and how much
to eat? Long-term signals associated with body-fat
stores are provided by leptin and insulin. These cir-
culating molecules also modulate short-term sig-
nals that determine meal initiation and termination.
Signals that provide short-term information about
hunger and satiety include gut hormones, such as
cholecystokinin, ghrelin, and peptide YY3–36 (PYY),
and signals from vagal afferent neurons within the
gastrointestinal tract that respond to mechanical de-
formation, macronutrients, pH, tonicity, and hor-
mones. Neural and humoral signals are then inte-
grated in specific regions of the hypothalamus and
brain stem.
In this issue of the Journal (pages 941–948), Bat-
terham et al. report a study of PYY, a peptide that is
secreted postprandially, in proportion to the calo-
ries ingested, by endocrine L cells lining the distal
small bowel and colon. The investigators found
that a single infusion of PYY, as compared with an
infusion of saline, reduced appetite and food con-
sumption by approximately 30 percent at an all-
you-want-to-eat buffet lunch provided two hours
after the infusion. In the obese subjects, the endog-
enous postprandial PYY response was diminished
as compared with that in the lean subjects, even
though the obese subjects consumed a greater num-
ber of calories. The PYY infusion reduced hunger in
both the obese and lean groups and had no effect on
subjects’ reports of the palatability of the meals or
their feelings of nausea.
The initial release of PYY occurs shortly after food
intake, presumably through neural mechanisms,
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 perspective

To forebrain and pituitary and

Thyrotropin-releasing, adrenal glands
Paraventricular
nucleus corticotropin-releasing, and Ingestive and autonomic responses
melanin-concentrating
hormones produced in
Y1R different neurons of the
paraventricular nucleus and
lateral hypothalamic area
MC4R

+
Lateral
–
Y2R hypothalamic
area
PYY
– Y1R
NPY
GHsR AgRP
Nucleus of the
POMC
(a-MSH) Arcuate solitary tract
nucleus
LEPR

INSR Insulin
Ghrelin Leptin

Pancreas

Large intestine Stomach Adipose tissue Small intestine

PYY

Interactions among Hormonal and Neural Pathways That Regulate Food Intake and Body-Fat Mass.
In this schematic diagram of the brain, the dashed lines indicate hormonal inhibitory effects, and the solid lines stimulatory effects. The para-
ventricular and arcuate nuclei each contain neurons that are capable of stimulating or inhibiting food intake. Y1R and Y2R denote the Y1 and
Y2 subtypes of the neuropeptide Y (NPY) receptor, MC4R melanocortin 4 receptor, PYY peptide YY 3–36, GHsR growth hormone secretagogue
receptor, AgRP agouti-related protein, POMC proopiomelanocortin, a-MSH a-melanocyte–stimulating protein, LEPR leptin receptor, and
INSR insulin receptor.

before ingested nutrients arrive in the distal portion
of the small intestine and the colon. The subsequent
release of PYY is stimulated by nutrients, particular-
ly carbohydrates and lipids, within the lumen of the
distal portion of the small intestine and the colon.
PYY decreases food intake through inhibition of gut
motility (acting as an “ileal brake” to cause a sense
of satiety) and by way of vagal afferent neurons that
ascend from the gastrointestinal tract to the hind-
brain and interactions with humoral receptors in the
hypothalamus. In studies in animals, PYY inhibited
the hypothalamic neuropeptide Y–expressing neu-
rons and agouti-related protein–expressing neurons
through inhibitory neuropeptide Y2 receptors,
thereby disinhibiting adjacent proopiomelanocor-
tin–expressing neurons and decreasing food intake.

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 The new england journal
The study by Batterham et al. also shows that in-
fusion of PYY decreases fasting concentrations of
the orexigenic peptide ghrelin. Ghrelin is a 28-ami-
no-acid, acylated peptide secreted by oxyntic cells in
the stomach fundus. Ghrelin acts on growth hor-
mone secretagogue receptors to increase the release
of growth hormone from the pituitary. Recently, the
putative roles of ghrelin in energy homeostasis and,
in particular, premeal hunger and meal initiation
have been identified. Circulating ghrelin concentra-
tions increase preprandially and decrease postpran-
dially. Ghrelin increases food intake through the
stimulation of ghrelin receptors on hypothalamic
neuropeptide Y–expressing neurons and agouti-
related protein–expressing neurons. Although PYY
infusion reduces the concentrations of ghrelin in
lean and obese subjects who are fasting and dimin-
ishes the preprandial rise in ghrelin in lean subjects,
the extent to which suppression of ghrelin secretion
contributes to a PYY-mediated reduction in food in-
take is unclear.
If ghrelin signals hunger and PYY signals satiety,
can these hormones be manipulated therapeutical-
ly? Gene-knockout studies in mice reveal that one
cannot easily fool the homeostatic mechanisms
that maintain body fat: experimental knockouts of
the ghrelin gene, AgRP, and the neuropeptide Y gene
(Npy) and a double knockout of AgRP and Npy are
not associated with any obvious effects on energy
metabolism or food intake. In contrast, inactivating
mutations of POMC, the genes that encode leptin
and the leptin receptor, and MC4R produce pro-
foundly obese phenotypes in mice as well as in hu-
Office-Based Practice
and Opioid-Use Disorders
H. Westley Clark, M.D., J.D., M.P.H.
In the case of Webb v. United States, the U.S. Supreme
Court ruled that the 1914 Harrison Narcotic Drug
Act made it illegal for physicians to prescribe nar-
cotics for the purpose of keeping a patient “com-
fortable by maintaining his customary use.” For
more than 80 years, it remained illegal in the United
States for physicians to prescribe opioid medica-
tions for the treatment of opioid dependence. The
exception was the dispensing of methadone or
levomethadyl acetate through regulated programs.
Physicians prescribing opioids such as morphine,
fentanyl, codeine, hydrocodone, and oxycodone on
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of medicine
mans. It appears that orexigenic pathways are so
critical to survival that the absence of one peptide is
compensated for by the actions of others. Studies
of gut hormones after weight loss induced by diet-
ing or surgery have provided some clues to potential
pharmacologic therapies. Weight loss by caloric re-
striction is associated with an increase in hunger and
circulating concentrations of ghrelin. After gastric
bypass surgery, hunger diminishes, circulating con-
centrations of ghrelin decrease, and circulating con-
centrations of PYY increase. Hormonal changes af-
ter bypass surgery may therefore play a part in the
suppression of hunger and the long-term mainte-
nance of reduced body weight.
Although single intraperitoneal injections of PYY
decrease food intake for up to seven days in rats,
the results of a single infusion in humans cannot be
extrapolated to predict long-term outcomes. The use
of PYY may prevent counterregulatory mechanisms
from overriding the stimulation of anorexigenic
pathways. However, the development of antibodies
or tachyphylaxis through receptor down-regulation
may limit the efficacy of prolonged PYY adminis-
tration. It is unlikely that any one molecule or de-
rivative will provide a magic bullet to induce and
maintain weight loss. Successful pharmacologic
treatment for obesity may be possible only by si-
multaneously targeting the interlocking, redundant
systems that drive food intake and act to resist the
loss of body fat.
From the College of Physicians and Surgeons, Columbia Univer-
sity, New York.
a long-term basis needed to worry about whether
their patients were truly in pain or whether they
had become dependent on these pain medications.
For patients found to be dependent on an illicit opi-
oid, such as heroin, physicians were forced to treat
withdrawal symptoms with nonnarcotic agents,
which provided only symptomatic relief, or to refer
patients to a regulated program.
The Harrison Narcotic Drug Act and decisions
such as Webb v. United States essentially gave the fol-
lowing message to physicians: “Treat an addict; go
to jail.” Physicians consequently were reluctant to
september 4, 2003