CONCLUSION
Methods of evaluating adiposity and adipose tissue
distribution have advanced substantially in the past
decade. Stimulated by the rising worldwide preva-
lence of obesity, new methods are under develop-
ment that promise to advance the field. The point
has now been reached, however, at which excellent
methods of quantifying fatness are available for
application in field, clinical, and research settings.
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97EVALUATION OF HUMAN ADIPOSITY
Part III
Appetite Regulation and Obesity
Prevention
MMMM
7
Role of Neuropeptides and Leptin
in Food Intake and Obesity
Bernard Jeanrenaud and Franc¸oise Rohner-Jeanrenaud
Lilly Corporate Center, Indianapolis, Indiana, USA and Geneva University School of Medicine,
Geneva, Switzerland
Interrelationships Between
Hypothalamic Neuropeptides and
Leptin in the Maintenance of Body
Weight Homeostasis, or Evolution to
Obesity
It is now accepted that body weight homeostasis is
maintained via a series of complex interactions that
occur between the brain, the hypothalamus in par-
ticular, and the periphery (1—3), notably via a hor-
mone, leptin, synthesized in and secreted from adi-
pose tissue (4). Secreted leptin, although it may have
direct peripheral effects, exerts its action principally
within the brain. Following its transport through
the blood—brain barrier, possibly via the short lep-
tin receptor isoform (ObRa), leptin reaches the hy-
pothalamic area where it binds to its long receptor
isoform (ObRb). Following a specific signaling cas-

cade, leptin inhibits many of the orexigenic neur-
opeptides, while favoring many of the anorexigenic
ones, as discussed below. By doing so, leptin exerts
its effects of decreasing food intake and body
weight, increasing fat oxidation and energy expen-
diture, thus favoring leanness (5—11).
In the present review, the characteristics of the
main orexigenic and anorexigenic neuropeptides
will be summarized (Figure 7.1) and putative effects
of leptin thereon described or, when such effects of
leptin are defective, the main reasons for the estab-
lishment of a state of obesity will be outlined (Fig-
ure 7.2).
OREXIGENIC NEUROPEPTIDES
Effects of Neuropeptide Y (NPY)
NPY is a 36 amino acid neuropeptide that is widely
distributed in the brain. In the hypothalamus, it is
synthesized in the arcuate nucleus and released in
the paraventricular nucleus. It stimulates food in-
take by binding to Y1 and /or Y5 receptor subtypes
(12—14). This increase in feeding can be observed
upon infusing the peptide intracerebroventricularly
(i.c.v.) in normal rats and is accompaniedby a rapid,
sustained and marked increase in body weight
(15,16). Central NPY infusion also stimulates insu-
lin secretion via an activation of the parasym-
pathetic nervous system reaching the endocrine
pancreas (17). Concomitantly, central NPY admin-
istration increases the activity of the hypothalamo-
pituitary-adrenal axis, with resulting hypercorticos-

teronemia and increased susceptibility to stressful
situations (15,17). Finally, central NPY reduces the
activity of the efferent sympathetic nerves reaching
brown adipose tissue, with resulting decrease in
energy dissipation as heat (18,19).
The metabolic consequences of the hormonal
International Textbook of Obesity. Edited by Per Bjo¨ rntorp.
© 2001 John Wiley & Sons, Ltd.
International Textbook of Obesity. Edited by Per Bjorntorp.
Copyright © 2001 John Wiley & Sons Ltd
Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic)
Figure 7.1 Diagram of food intake regulation by orexigenic and anorexigenic neuropeptides. Stimulators of food intake are depicted
as increasing the diameter of a tube by exerting a pressure (;) from inside, with agouti-related peptide (AGRP) mainly exerting its
action by inhibiting the melanocortin system (-MSH and MC4 receptor), the effect of which is to reduce this diameter. Inhibitors of
food intake are depicted as reducing (9) the diameter of the tube, with AGRP having little effect on the melanocortin system, allowing
the latter to largely contribute to reducing this diameter. NPY, neuropeptide Y; MCH, melanin concentrating hormone; ORE, orexins;
-MSH, -melanocyte-stimulating hormone and the melanocortin-4 (MC4-R) receptor; CRH, corticotropin-releasing hormone,
CART, cocaine- and amphetamine-regulated transcript; NT, neurotensin. Not all neuropeptides are represented. Solid lines indicate
marked effects, dotted ones weak effects
changes produced by central NPY infusion (in-
creased plasma insulin and corticosterone levels)
are increased adipose tissue and liver lipogenic ac-
tivity, changes mainly due to hyperinsulinemia
(15,16), together with decreased insulin-stimulated
glucose utilization by muscles (15,16). This muscle
insulin resistance is likely to be due to the combined
NPY-induced hyperinsulinemia/hypercorticostero-
nemia (1).
It should be noted that the NPY-elicited effects
are very marked when exogenous NPY is chroni-

cally infused i.c.v., resulting in high central concen-
trations of the neuropeptide. Physiologically, how-
ever, it is thought that these changes are modest,
occurring via the spontaneous fluctuations of hy-
pothalamic NPY levels, which transiently change
nutrient partitioning toward fat accretion and de-
creased oxidation processes. This situation persists
until leptin is secreted into the blood as a result of
hormonal changes such as transient hyperin-
sulinemia in response to meal taking. Secreted lep-
tin reaches the brain and decreases hypothalamic
NPY levels by exerting its negative feedback inhibi-
tion on the expression and amount of this neur-
opeptide (20—22). Experiments have shown, how-
ever, that in addition to NPY, other brain
neuropeptidic systems play a role in the regulation
of food intake. Thus, in transgenic mice made defi-
cient in NPY, the expected decrease in both food
intake and body weight fails to occur (23,24). Trans-
genic mice lacking the NPY-Y1 or Y5 receptor
actually gain more weight, not less, than the con-
trols. (25,26). This indicates that the regulation of
food intake and body weight is redundant, i.e. that
several pathways are implicated and that when one
of them is knocked out, others take over to main-
tain a normal body weight homeostasis.
102 INTERNATIONAL TEXTBOOK OF OBESITY
Figure 7.2 Diagram of the central effects of leptin on food intake. Leptin is depicted as decreasing the diameter of a tube relative to a
normal one (dotted lines), due to its dual effect of reducing ( ) the expression or amount of neuropeptides that stimulate food intake
(neuropeptide Y, NPY; melanin concentrating hormone, MCH; orexin, ORE; agouti-related protein, AGRP) and of increasing (!) the

expression or amount of neuropeptides that inhibit food intake (cocaine- and amphetamine-regulatedtranscript, CART; corticotropin-
releasing hormone, CRH; the melanocortin system with proopiomelanocortin, POMC, -MSH and the melanocortin-4 receptor,
MC4-R). The effect of leptin on food intake (FI) is accompanied by increased fat oxidation and energy (E) expendidure, the three
parameters together producing leanness
NPY and Obesity
When considering the hormono-metabolic changes
produced by central NPY, one realizes that experi-
mentally produced increases in central levels of this
neuropeptide reproduce most of the abnormalities
observed in experimental or genetic obesity syn-
dromes (15,16), as well as in human obesity. The
pathological relevance of increased hypothalamic
NPY levels in mimicking obesity syndromes is sup-
ported by the observation that NPY expression and
levels are indeed increased in the ob/ob, db/db obese
mice and in the fa/fa obese rat (1,20—22). Increased
NPY levels in ob/ob mice are due to the lack of
synthesis and secretion of leptin in adipose tissue,
the ob (leptin) gene being mutated. As a result of this
mutation, plasma leptin levels are nil, leptin fails to
exert its negative feedback on hypothalamic NPY
levels which remain continually elevated maintain-
ing, probably with other neuropeptides that are
influenced by leptin, the obesity syndrome (1,27). In
the db/db and the fa/fa obese rodents, the ob gene of
adipose tissue is normal, but the long form leptin
receptor is mutated in its intracellular (db/db) (5) or
extracellular (fa/fa) (28) domain. Even though leptin
is overproduced by adipose tissue, bringing about a
state of hyperleptinemia, it cannot act centrally and

hypothalamic NPY levels remain high. The latter,
probably in concert with other neuropeptides,
maintain the obesity syndrome (29).
Effects of Melanin Concentrating
Hormone (MCH)
MCH is a cyclic neuropeptide comprising 19 amino
acids which is present in many areas of the brain,
notably in the lateral hypothalamus (30). Its name
derives from its ability to cause melanosome aggre-
gation in fish skin, an action which is antagonized
by -MSH, the melanosome-dispersing factor. Re-
cently, a role for MCH in the central regulation
of food intake has been discovered, i.c.v. MCH
103ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY
administration increasing food intake in normal
rats (31,32). As for the melanosome aggregation/
dispersion system, the action of -MSH is the oppo-
site of that of MCH, resulting in decreased food
intake (33). The antagonistic action of MCH and
-MSH extends to the regulation of the hy-
pothalamo-pituitary-adrenal (HPA) axis, MCH de-
creasing plasma corticosterone and ACTH levels
relative to controls, while -MSH does the contrary,
increasing plasma corticosterone and ACTH levels.
(33).
I.c.v. administration of a single dose of MCH
results in stimulation of food intake that is dose-
dependent, lasts for about 6 hours (32,33), but is
moderate in amplitude when compared to the effect
of NPY (34). The feeding effect of central MCH

administration is counteracted not only by -MSH
as just mentioned, but also by glucagon-like peptide
(GLP-1) and neurotensin (34).
As is the case for NPY, central leptin administra-
tion decreases hypothalamic MCH expression and
prevents MCH-induced increase in food intake
(35,36). However, contrary to what is observed with
NPY, long-term central MCH administration fails
to produce sustained increases in food intake or in
body weight gain, thus obesity (32). This is in con-
trast with the observation that, in the obese ob/ob
mouse, hypothalamic MCH expression is increased
and may participate in the final development of the
obese phenotype (31).
To strengthen the physiological role of MCH in
food intake regulation, mice carrying a targeted
deletion of the MCH gene have been produced.
When compared to controls, these mice are hy-
pophagic, leaner, have decreased carcass lipids, and
increased metabolic rate (37). Thus, MCH does rep-
resent an important hypothalamic pathway in the
regulation of body weight homeostasis, a pathway
further completed recently by the discovery of a 353
amino acid G-protein-coupled receptor, to which
MCH specifically binds (38,39). Such a receptor is
present in the hypothalamus and many other brain
regions, in keeping with the several functions, be-
yond the feeding behavior, that are under the influ-
ence of MCH (38,39).
Effects of Orexins

Orexin A and B (from the Greek word for appetite)
have been discovered recently and are also referred
to as ‘hypocretins’ (due to their hypothalamic loca-
tion and sequence analogy to secretin) (40,41).
Orexin A (33 amino acids) and orexin B (28 amino
acids) neurons are restricted to the lateral and pos-
terior hypothalamus, whereas both orexin A and
orexin B fibers project widely into different areas of
the brain (42—45). The corresponding cloned recep-
tors, OX1 and OX2, are found in the hypothalamus
(ventromedial hypothalamic nucleus, paraventricu-
lar nucleus) a distribution that is receptor-specific
(41,46).
The stimulatory effect of central administration
of orexin on food intake is much weaker than that
of NPY, and is smaller than that elicited by MCH.
Orexin A is more potent than orexin B in eliciting
feeding, and its effect is consistent, whereas that of
orexin B is not (47, 48). When given peripherally,
orexin A rapidly enters the brain by simple diffusion
as it is highly lipophilic, while orexin B with its low
lipophilicity is degraded, thus failing to reach the
brain adequately (49). The fact that orexin B is
easily inactivated by endopeptidases could be one
of the reasons for its relative inefficiency in regula-
ting food intake. In a way similar to what has been
observed with NPY, some of the centrally elicited
effects of orexin A, e.g. the stimulation of gastric
acid secretion, are mediated by an activation of the
parasympathetic nervous system, favoring anabolic

processes (50).
Leptin administration produces a diminution of
orexin A levels in the lateral hypothalamus (51), a
finding that is in keeping with the observation of the
presence of numerous leptin receptors on orexin-
immunoreactive neurons in the lateral hy-
pothalamus (52). Additional data must be gathered
for the physiological role of the orexin system in
food intake regulation to be better understood.
Effects of Opioids
The endogenous opioid system has long been
known to play a role in the regulation of ingestive
behavior. The opioid peptides exert their action via
a complex receptor subtype system implicating ka-
ppa, mu and delta receptors for, respectively, dynor-
phin, -endorphin and the enkephalins (53). The
specific modulation of taste and food intake can be
partly understood by the use of selective receptor
subtype agonists and antagonists (54,55). Typically,
104 INTERNATIONAL TEXTBOOK OF OBESITY
the central administration of opioid agonists stimu-
lates food intake, decreases the latency to feed, in-
creases the number of interactions with the food,
favors fat as well as sucrose ingestion, and increases
body weight gain (54,56—60). In contrast, the central
administration of opioid antagonists does the re-
verse, decreasing food intake and body weight
(55,60—62).
The three major types of opioid receptors, mu,
kappa, delta, have been cloned and belong to the

G-protein-coupled family. Recently, another recep-
tor highly homologous to the opioid receptors, but
one that does not bind any opioid peptide with high
affinity, has been cloned (63). This opioid receptor-
like (ORL-1) is widely distributed within the central
nervous system (CNS), the hypothalamus, hip-
pocampus, and the amygdala, in particular (64).
The endogenous ligand for this opioid-like orphan
receptor has now been isolated (63). It is called
nociceptin (as it increases pain responsiveness), or
orphanin FQ. It is an 18 amino acid peptide which
resembles dynorphin A and has a marked affinity
for ORL-1 (63—65). Nociceptin and ORL-1 thus
constitute a new peptidergic system within the
CNS, a system of potential interest as it is present
not only in rodents, but also in humans (64,65).
When given centrally, nociceptin stimulates food
intake in satiated rats, an effect that is blocked by an
opioid antagonist, naloxone. As naloxone does not
act at the level of ORL-1, this indicates that stimula-
tion of food intake by nociceptin involves, at some
ill-defined steps, the function of the ‘classical’ opioid
system (65). Microinjection of nociceptin into two
brain areas implicated in food intake (the ven-
tromedial hypothalamic nucleus and the nucleus
accumbens) also results in increased in food intake
(64). The physiopathological implications of these
findings will soon be unraveled.
Opioids and Obesity
The susceptibility to diet-induced obesity in the rat

is strain dependent. For example, some strains of
rats (e.g. Osborne-Mendel) overeat and become
obese when fed a diet rich in fat. Other strains (e.g.
S5B/P1) are resistant to high fat diet-induced obes-
ity (66). In this context, it is interesting that central
administration of a kappa opioid receptor antagon-
ist decreases the intake of a high fat diet in the
obesity-prone rats, while it does not do so in the
obesity-resistant ones. In contrast, the central ad-
ministration of a kappa opioid receptor agonist
increases the intake of a high fat diet in obesity-
prone rats, while it increases the intake of any type
of diet in obesity-resistant animals (66). It is thus
conceivable that the sensitivity to opioids differs
from strain to strain, possibly from species to spe-
cies. It is also possible that, within the brain areas
constituting the opioid system, the distribution of
the opioids, that of their receptors, may vary from
strain to strain. This may lead to a strain-specific
opioid dependency of the food intake process and
evolution to obesity (66).
The likely importance of the opioid system in
obesity is illustrated by the observation that the
peripheral administration of compounds with po-
tent opioid antagonistic activity to obese rats re-
sults in rapid, marked and sustained decreases in
food intake and body weight gain (67,68).
ANOREXIGENIC PEPTIDES
Effects of Cocaine- and
Amphetamine-Regulated Transcript

(CART)
Cocaine- and amphetamine-regulated transcript
(CART) is a recently discovered hypothalamic pept-
ide which is regulated by leptin and is endowed with
appetite-suppressing activity (69,70). In the rat, the
CART gene encodes a peptide of either 129 or 116
amino acid residues (70). In contrast, only the short
form of CART exists in humans (70). The mature
peptide contains several potential cleavage sites and
CART may be post-transcriptionally processed
into several biologically active fragments. Thus, in
most tissues studied, CART peptides are short,
CART (42—89) being found in the rat hypothalamus
(71). This tissue processing of CART resulting in
neuropeptides of different lengths may indicate that
different CART peptides have different biological
functions (71).
Acute i.c.v. CART administration to normal rats
produces a dose-dependent decrease in food intake
(69,72). CART also transiently decreases the NPY-
elicited feeding response in normal rats (69). Finally,
CART appears to have a tonic inhibitory influence
on food intake, as treatment of rats with anti-CART
antiserum results in increased food intake (69).
CART is regulated, in part, by leptin as chronic
105ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY
peripheral leptin administration to the leptin-defi-
cient ob/ob mice results in a definite augmentation
of the low expression of CART measured in the
hypothalamic arcuate nucleus of these animals, an

increase that is paralleled by the observed decrease
in body weight. CART expression is also markedly
reduced in the genetically obese leptin-resistant fa/
fa rat, thus possibly playing a role in the hyper-
phagia of this animal (69). The physiological and
pathological importance of CART has yet to be
substantiated, although preliminary results with
chronic infusion of the neuropeptide appear to indi-
cate that it markedly reduces food intake and body
weight of both normal and obese rats.
Effects of Corticotropin-releasing
Hormone (CRH)
Apart from its role as controller of the hy-
pothalamo-pituitary-adrenal (HPA) axis, CRH, a
41 amino acid neuropeptide, also functions as a
central effector molecule that brings about a state of
negative energy balance and weight loss. This is due
to the ability of central CRH to decrease food in-
take (73), to increase the activity of the sympathetic
nervous system and to stimulate thermogenesis
(73—75). CRH also influences gastrointestinal func-
tions, inhibiting gastric acid secretion and gastric
emptying, processes that are controlled by the para-
sympathetic nervous system (76—79). Chronic i.c.v.
CRH administration in normal (73), genetically
obese fa/fa rats (80), as well as in monkeys (81),
decreases food intake and body weight, partly by
acting on energy dissipating mechanisms. Central
microinjections of CRH were shown to inhibit
NPY-induced feeding (82), in keeping with the no-

tion that the locally released CRH could restrain
the effect of NPY and/or of other orexigenic signals.
Leptin administration results in transient increases
in hypothalamic CRH levels, thus potentially favor-
ing the CRH effects just mentioned (22). The leptin
effect on CRH could occur via its increasing CRH
type 2 receptor (CRHR-2) expression in the ven-
tromedial hypothalamus, as these receptors are po-
tentially responsible for the CRH-mediated de-
crease in food intake and sympathetic nervous
system activation (83,84).
The Melanocortin System and Effects of
-Melanocyte-stimulating hormone
(-MSH)
Pro-opiomelanocortin (POMC) is the precursor of
many different molecules, the melanocortins,
among which are ACTH, -endorphin, the
melanocyte-stimulating hormones (-,-,-MSH).
The -melanocyte-stimulating hormone -MSH is
a 13 amino acid peptide which binds with different
affinities to five different subtypes of G-protein-
coupled receptors. An involvement of -MSH in
body weight homeostasis via an interaction with
the melanocortin-4 (MC4), possibly the MC3 recep-
tors, has been recently described. MC3 receptors
are present mainly in the hypothalamus, MC4 re-
ceptors throughout the brain and in the sympath-
etic nervous system (85,86). When administered
i.c.v. to normal rats, -MSH decreases food intake
(34), as does the central administration of a stable

linear analog of -MSH, NDP-MSH (87). The rela-
tionships existing between the melanocortins, their
receptor subtypes and feeding have been illustrated
by studying synthetic melanocortin receptor agon-
ists and antagonists, amongst which are the com-
pounds called MTII and SHU9119 (85,88). The
i.c.v. administration of the agonist MTII markedly
and dose-dependently inhibits food intake, while
that of the antagonist SHU9119 markedly and
dose-dependently stimulates food intake process
(85,89). The co-injection of equal concentrations of
the agonist and of the antagonist results in a food
intake that is identical to that of control rats (85). In
addition, MTII inhibits or suppresses, depending
on the dose, the feeding response elicited by neur-
opeptide Y (85), in keeping with the observation
that both MC3 and MC4 receptors are found in
CNS sites in which NPY neurons are also present
(90).
The effect of -MSH in decreasing food intake is
under the ‘tonic’ inhibitory influence from a
melanocortin-receptor antagonist called ‘agouti-re-
lated protein’ (AGRP). When an active fragment of
AGRP is administered i.c.v. to rats, an increased
food intake is observed. Moreover, when -MSH is
similarly administered, the observed decrease in
food intake is blocked by the further addition of
AGRP (91).
The fundamental importance of the MC4 recep-
tors has been highlighted by obtaining transgenic

106 INTERNATIONAL TEXTBOOK OF OBESITY
mice lacking the MC4 receptors (MC4-R-deficient
mice). These mice (female and male) exhibit in-
creased food intake and become obese. Both sexes
have marked hyperinsulinemia, hyperleptinemia,
with either normoglycemia (females) or hyper-
glycemia (males), plasma corticosterone levels being
normal. These data support the view that MC4
receptors are essential in the cascade of events nor-
mally leading to decreased food intake and leanness
(92). The decreased food intake produced by -
MSH and the subsequent cascade of events sum-
marized above is accompanied by a change in the
activity of the sympathetic nervous system. Thus,
activation of the MC3/MC4-receptor system by the
agonist MTII administered centrally results in a
marked, specific, dose-dependent activation of the
sympathetic nerves innervating the brown adipose
tissue, as well as the renal and lumbar beds, while no
change in blood pressure or heart rate is observed
(93). The combination of decreased food intake and
increased sympathetic activation with likely in-
crease in energy dissipation suggests that the
melanocortin system is well adapted to play a role
in decreases in body weight.
Since the main central effects of leptin are to
decrease food intake and body weight, and to in-
crease energy dissipation, it has been postulated
that this hormone could bring about these changes
by influencing the melanocortin system. It is thus of

interest to observe that the effect of leptin in de-
creasing food intake is blocked by a MC4 receptor
antagonist (SHU9119), and that pretreatment with
the antagonist is able to prevent the effects of leptin
in decreasing both food intake and body weight.
This effect is specific as the antagonist did not affect
the decreased food intake produced by another
peptide (GLP-1) (94). Thus, the MC4-receptor sig-
naling is important in mediating the effects of leptin.
In keeping with this finding is the observation that
the MC4 receptor agonist, MTII, which decreases
food intake in normal animals, also suppresses the
hyperphagia of the leptin-deficient ob/ob mice. This
suggests that leptin acts via MC4 receptors and that
in the absence of leptin, i.e. in ob/ob mice, the lack of
signaling through MC4 receptors would be respon-
sible for the increased food intake (95), a viewpoint
that remains to be fully validated (96).
When considering POMC (the precursor of
melanocortins, of -MSH) and AGRP (the antag-
onist of the MC4 receptor), it is of interest to ob-
serve that the lack of leptin in the ob/ob mouse (or
lack of leptin signaling in the db/db one) is accom-
panied by a decrease in POMC expression and an
increase in that of AGRP (97—99). Moreover, leptin
administration leads to an increase in POMC ex-
pression and a decrease in that of AGRP (100—103).
It may thus be concluded that leptin decreases food
intake and body weight, in part by favoring the
action of melanocortin neuropeptide(s) at the MC4

receptor, while concomitantly preventing the in-
hibitory influence of AGRP on this same receptor, a
concept excellently reviewed elsewhere (102). This
specific effect of leptin is probably additive to its
inhibitory one on hypothalamic NPY levels, NPY
being one of the most potent food stimulators as
described above, and being co-expressed with
AGRP within the arcuate nucleus of the hy-
pothalamus (104).
The Melanocortin System and Obesity
Obesity, as mentioned above, may result from alter-
ed functions of the MC4 receptors. This is illus-
trated in a global fashion by the observation that
when the melanocortin receptor agonist (MTII) is
administered i.c.v. to fasted—refed hyperphagic
mice, to obese ob/ob mice, to yellow (Ay) obese mice,
to NPY hyperphagic mice, their respective hyper-
phagia is largely canceled (95). In addition, it has
been recently demonstrated that mice lacking
POMC (hence lacking subsequent -MSH syn-
thesis and its inhibitory effect on feeding via its
binding to MC4 receptors) overeat and become
obese, a situation partly reversed by an -MSH
treatment (105).
The yellow obese mouse is an interesting animal
model that underlines the potential importance of
the melanocortin system. As reviewed recently, the
pigment produced by melanocytes in the skin is
under the regulation of -MSH and a paracrine
melanocyte signaling molecule called ‘agouti’ (from

American Spanish ‘aguti’, meaning alternation of
light and dark bands of colors in the fur of various
animals). Agouti binds to MC1 receptors and de-
creases their signaling, resulting in decreased cAMP
levels, thereby inducing melanocytes to synthesize a
yellow pigment (pheomelanin). -MSH binds to
MC1 receptors and increases their signaling, result-
ing in increased cAMP, thereby stimulating the syn-
thesis of a black pigment (eumelanin). The classical
agouti hair color of many species appears brown,
although the ‘brown’ hairs are in fact black-yellow-
107ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY
black banded hairs, due to the joint effects of agouti
and -MSH. The yellow mouse (A) is heterozygous
for a mutation in the agouti gene. This mutation
results in an ectopic expression of the agouti protein
throughout the body, while the non-mutated gene
induces the expression of the agouti protein only in
hair follicles. The ectopic expression of agouti is at
the origin of many different effects, i.e. yellow hairs,
increased linear growth, decreased fertility, obesity.
Within the brain, ectopic agouti functions as an
antagonist of the MC4 receptor (with little effect on
MC3-R), preventing the action of endogenous MC4
receptor agonists, with resulting obesity (102).
From a physiopathological viewpoint, the agouti
protein turns out not to be as esoteric as it may
sound. Indeed, a pathway very similar to that of the
agouti in the skin has been described in the hy-
pothalamus. Moreover, a novel gene called AGRP

(agouti-related protein) or ART (agouti-related
transcript) has been discovered in the hy-
pothalamus of rodents as well as humans (97,98). It
encodes a melanocortin (MC3, MC4) receptor an-
tagonist comprising 132 amino acid residues which,
as mentioned above, is the likely natural antagonist
of the brain melanocortin system (97,98). The im-
portance of the AGRP pathway is supported by the
observation that over-expression of human AGRP
in transgenic mice induces obesity without produc-
ing a yellow color of the fur, ARGP having no effect
on MC1 receptors and therefore on the coat color
(97,106).
CONCLUSION
From the description of the effects of the above-
mentioned orexigenic and anorexigenic neuropept-
ides and their relationships with leptin, it is obvious
that the regulation of food intake is complex, as is
the evolution toward overeating and obesity. This
complexity is even greater than described here, as
additional factors have not been mentioned. For
example, the role of glucocorticoids has not been
discussed, although these hormones favor the oc-
currence of obesity through many different mechan-
isms, one of them being to inhibit the thinning
action of leptin (107—109). Insulin, once within the
brain after its passage though the blood—brain bar-
rier, appears to participate in the regulation of en-
ergy homeostasis by decreasing food intake and
body weight gain in several animal species includ-

ing monkeys (2). The hypothalamic neuropeptide
galanin is associated with preference for dietary fats
(110). Other factors described as being able to
modulate food intake may, at the moment, be con-
sidered of lesser importance, although they may
reemerge as being essential. Several additional
neuropeptides will soon be discovered. Possibly the
strongest candidates among current perceptions of
the regulation of body weight homeostasis may be
perceived differently in the months or years to
come, and be superseded by others. Leptin appears
to regulate many of the orexigenic and anorexigenic
neuropeptides, and time will tell whether it can
regulate all of them. Its pivotal importance in the
modulation of food intake, body weight and energy
expenditure is illustrated by the observation that it
decreases the expression or content of many neur-
opeptides that favor food intake, while at the same
time favoring that of other neuropeptides that in-
hibit these processes. Leptin thus appears to be
strategically placed to modulate the dynamic equi-
librium between neuropeptides with opposing final
effects.
It should be noted that many of the genes and
neuropeptides involved in the regulation of body
weight homeostasis in animals mentioned above
are also encountered in humans. Thus, families have
been reported to have mutations in either the leptin
gene or the leptin receptor gene (111,112). Other
human mutations have an effect on orexigenic or

anorexigenic neuropeptides and lead to obesity.
These include mutation of the POMC gene
(113—115), as well as the MC4 receptor gene (116).
These rare cases provide support for the view that
many of the pathways described here are likely to be
present in humans. This is the basis of the view that,
by the development of various antagonists or agon-
ists, the correction of at least some aspects of human
obesity is within reach.
ACKNOWLEDGEMENTS
The present work was carried out with grant No
31-53719.98 of the Swiss National Science Founda-
tion (Berne), and by grants in aid of Eli Lilly and
Company (Indianapolis, Indiana, USA) and of
Novartis (Basle, Switzerland).
108 INTERNATIONAL TEXTBOOK OF OBESITY
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112 INTERNATIONAL TEXTBOOK OF OBESITY
8
Regulation of Appetite and the
Management of Obesity
John E. Blundell
University of Leeds, Leeds, UK
Appetite control implies a control over energy in-
take. Some researchers argue that it only requires a
habitual addition of 20—30 kilocalories per day to
lead over a number of years to significant body
weight increaseswhich, in turn, leads to an epidemic
of obesity. If human beings are the most intelligent
life force on this planet, why is it that they cannot
adjust their (eating) behaviour by the very small
amounts which would be required for weight stabil-
ity rather than weight escalation? Some explanation

for this may be found through an examination of
the processes involved in the regulation of appetite.
WHAT IS THE RELATIONSHIP
BETWEEN APPETITE AND OBESITY?
There are clear logical reasons for believing that the
expression of appetite—reflected in the pattern of
eating and overall energy intake—makes a large
contribution to the maintenance of a healthy
weight. The impact of appetite on obesity is a time-
dependent process and will occur at least over many
months and usually years. The relationship between
appetite and weight gain is therefore part of a devel-
opmental, or ageing, process and this perspective is
important (1).
Appetite fits into an energy balance model of
weight regulation but it is not necessary to believe
that appetite control is an outcome of the regula-
tion of energy balance. Appetite is separately con-
trolled and is relevant to energy balance since it
modulates the energy intake side of the equation.
This happens because appetite includes various as-
pects of eating patterns such as the frequency and
size of eating episodes (gorging versus nibbling),
choices of high fat or low fat foods, energy density of
foods consumed, variety of foods accepted, palat-
ability of the diet and variability in day-to-day in-
take. All of these features can play a role in en-
couraging energy intake to exceed energy
expenditure thereby creating a positive energy bal-
ance. If this persists then it will lead to weight gain.

However, there appears to be no unique pattern of
eating or forms of energy intake that will exclusively
or invariably lead to an excess of energy intake over
expenditure. Nevertheless, some characteristics of
the expression of appetite do render individuals
vulnerable to over-consumption of food—these
characteristics can be regarded as risk factors.
These risk factors and other modulating features of
the expression of appetite will be disclosed by an
analysis of how appetite is regulated.
CAN APPETITE BE CONTROLLED FOR
THE MANAGEMENT OF OBESITY?
It is widely accepted that body weight control and,
by implication, a lack of control arises from an
International Textbook of Obesity. Edited by Per Bjo¨ rntorp.
© 2001 John Wiley & Sons, Ltd.
International Textbook of Obesity. Edited by Per Bjorntorp.
Copyright © 2001 John Wiley & Sons Ltd
Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic)
interaction between biology and the environment—
particularly the food supply reflected in the nutri-
tional environment. The link between the two do-
mains is eating behaviour and the associated sub-
jective sensations which make up the expression of
appetite. It is this eating behaviour which transmits
the impact of biological events into the environ-
ment, and which also mediates the effects of the
nutrient environment on biology. Appetite is not
nutrition, rather it is the expression of appetite
which allows nutrition to exert an effect on biology,

and vice versa. Consequently, adjustments in the
processes regulating the expression of appetite
should have a significant impact on body weight
regulation.
Of course obesity can be managed by direct
changes in the environment itself—to enforce an
increase in physical activity or to coercively prevent
food consumption. Equally, pharmacological or
surgical interventions can be made directly in biol-
ogy to prevent the assimilation of food or to alter
the energy balance. In addition, adjustments in the
environment and biology have the potential to in-
fluence body weight indirectly by altering food in-
take—often by acting on the signals involved in
processes regulating appetite. The details of these
actions will be apparent as the regulation of appe-
tite is examined.
Consequently, in principle, appetite can be con-
trolled for the management of obesity. We can en-
visage interventions either in specific foods which
influence biology which in turn adjusts eating be-
haviour or through a direct and deliberate cognitive
control of behaviour. There are many reasons to
believe that an adjustment to the expression of ap-
petite is the best chance we have to prevent the
persistent surfeit of energy consumed over energy
expended which is currently characterizing much of
the world’s population. At the end of this chapter
we should be better informed about the possible
strategies for regulating appetite to prevent further

escalation of the obesity epidemic.
BASIC CONCEPTS IN APPETITE
CONTROL
As a first step to recognizing how appetite can
contribute to the prevention of obesity, it is useful to
outline some basic principles which explain how the
expression of appetite can be understood. This con-
ceptual approach will indicate how the detailed
mechanisms and processes contribute to the global
picture.
THE PSYCHOBIOLOGICAL SYSTEM
OF APPETITE CONTROL
It is now accepted that the control of appetite is
based on a network of interactions forming part of a
psychobiological system. The system can be con-
ceptualized on three levels (Figure 8.1). These are
the levels of psychological events (hunger percep-
tion, cravings, hedonic sensations) and behavioural
operations (meals, snacks, energy and macronut-
rient intakes); the level of peripheral physiology and
metabolic events; and the level of neurotransmitter
and metabolic interactions in the brain (2). Appetite
reflects the synchronous operation of events and
processes in the three levels. When appetite is dis-
rupted as in certain eating disorders, these three
levels become desynchronised. Neural events trig-
ger and guide behaviour, but each act of behaviour
involves a response in the peripheral physiological
system; in turn, these physiological events are trans-
lated into brain neurochemical activity. This brain

activity represents the strength of motivation to eat
and the willingness to refrain from feeding.
The lower part of the psychobiological system
(Figure 8.1) illustrates the appetite cascade which
prompts us to consider the events which stimulate
eating and which motivate organisms to seek food.
It also includes those behavioural actions which
actually form the structure of eating, and those
processes which follow the termination of eating
and which are referred to as post-ingestive or post-
prandial events.
Even before food touches the mouth, physiologi-
cal signals are generated by the sight and smell of
food. These events constitute the cephalic phase of
appetite. Cephalic-phase responses are generated in
many parts of the gastrointestinal tract; their func-
tion is to anticipate the ingestion of food. During
and immediately after eating, afferent information
provides the major control over appetite. It has
been noted that ‘afferent information from ingested
food acting in the mouth provides primarily posi-
tive feedback for eating; that from the stomach and
small intestine is primarily negative feedback’ (3).
114 INTERNATIONAL TEXTBOOK OF OBESITY
Figure 8.1 Diagram showing the expression of appetite as the relationship between three levels of operations: the behavioural pattern,
peripheral physiology and metabolism, and brain activity. PVN, paraventricular nucleus; NST, nucleus of the tractus solitarius; CCK,
cholecystokinin; FFA, free fatty acids; T:LNAA, tryptophan: large neutral amino acids; GLP-1, glucagon-like peptide 1. (See Blundell
(2) for detailed diagram)
SATIETY SIGNALS AND THE SATIETY
CASCADE

Scientifically important components of the appetite
system are those physiological events which are
triggered as responses to the ingestion of food and
which form the inhibitory processes that first of all
stop eating and then prevent the re-occurrence of
eating until another meal is triggered. These physio-
logical responses are termed satiety signals, and can
be represented by the satiety cascade (Figure 8.2).
Satiation can be regarded as the complex of pro-
cesses which brings eating to a halt (cause meal
termination) whilst satiety can be regarded as those
events which arise from food consumption and
which serve to suppress hunger (the urge to eat) and
maintain an inhibition over eating for a particular
115REGULATION OF APPETITE
Mediating processes
Sensory
Sensory
Cognitive
Post-absorption
Post-ingestive
Cognitive
Post-absorption
Post-ingestive
Late
early
Satiety
Food
Satiation
Figure 8.2 The satiety cascade illustrating the classes of events

which constitute satiety signals arising from food consumption
period of time. This characteristic form of an eating
pattern (size of meals, snacks etc.) is therefore de-
pendent upon the coordinated effects of satiation
and satiety which control the size and frequency of
eating episodes.
Initially the brain is informed about the amount
of food ingested and its nutrient content via sensory
input. The gastrointestinal tract is equipped with
specialized chemo- and mechano-receptors that
monitor physiological activity and pass informa-
tion to the brain mainly via the vagus nerve (4). This
afferent information constitutes one class of ‘satiety
signals’ and forms part of the pre-absorptive control
of appetite. It is usual to identify a post-absorptive
phase that arises when nutrients have undergone
digestion and have crossed the intestinal wall to
enter the circulation. These products, which accu-
rately reflect the food consumed, may be metab-
olized in the peripheral tissues or organs or may
enter the brain directly via the circulation. In either
case, these products constitute a further class of
metabolic satiety signals. Additionally, products of
digestion and agents responsible for their metab-
olism may reach the brain and bind to specific
chemoreceptors, influence neurotransmitter syn-
thesis or alter some aspect of neuronal metabolism.
In each case the brain is informed about some as-
pects of the metabolic state resulting from food
consumption.

It seems likely that chemicals released by gastric
stimuli or by food processing in the gastrointestinal
tract are involved in the control of appetite (5).
Many of these chemicals are peptide neurotrans-
mitters, and many peripherally administered pept-
ides cause changes in food consumption (6). There is
evidence for an endogenous role for cholecystokinin
(CCK), pancreatic glucagon, bombesin and
somatostatin. Much recent research has confirmed
the status of CCK as a hormone mediating meal
termination (satiation) and possibly early phase sat-
iety. This can be demonstrated by administering
CCK intravenously (the mouth cannot be used
since CCK would be inactivated as soon as it
reached the stomach) and measuring changes in
food intake and hunger. CCK will reduce meal size
and also suppress hunger before the meal; these
effects do not depend on the nausea that sometimes
accompanies an intravenous infusion (7). Food con-
sumption (mainly protein and fat) stimulates the
release of CCK (from duodenal mucosal cells)
which in turn activates CCK-A type receptors in the
pyloric region of the stomach. This signal is trans-
mitted via afferent fibres of the vagus nerve to the
nucleus tractus solitarius (NTS) in the brainstem.
From here the signal is relayed to the hypothalamic
region where integration with other signals occurs.
The components of this system are set out in Figure
8.3.
Other potential peripheral satiety signals include

peptides such as enterostatin (8), neurotensin and
glucagon-like peptide 1 (GLP-1) (9).
APPETITE AND THE DRIVE TO EAT
For years the focus of investigations of appetite
control has centred upon the termination of eating.
This is because the termination of an eating epi-
sode—being the endpoint of a behavioural act—
was perceived to be an unambiguous event around
which empirical studies could be organized. Conse-
quently satiety came to be the concept which for-
med the basis for accounts of appetite.
However, some 50 years ago there was an equal
emphasis on the excitatory or drive features of ap-
petite. This was embodied in Morgan’s ‘central mo-
tive state’ and in Stellar’s location of this within the
hypothalamus (10). One major issue was to explain
what gave animals (and humans) the energy and
direction which motivated the seeking of food.
These questions are just as relevant today but the
lack of research has prevented much innovative
thinking. In the light of knowledge about the physi-
ology of energy homeostasis, and the utilization of
different fuel sources in the body, it is possible to
make some proposals. One source of the drive for
food arises from the energy used to maintain
physiological integrity and behavioural adaptation.
116 INTERNATIONAL TEXTBOOK OF OBESITY
Paraventricular
hypothalamus
Decreased

feeding
Va gal
afferent
Receptor
stimulation
Stomach
Pylorus
Increased
contraction
Gallbladder
Increased
contraction
Liver
Pancreas
CCK*
Increased
protease
secretion
Figure 8.3 Peripheral—brain circuit indicating the postulated
mode of action of CCK (cholecystokinin) as a satiety signal
mediating the inhibition of eating
Consequently, there is a drive for food generated by
energy expenditure. Approximately 60% of total
energy expenditure is contributed by the resting
metabolic rate (RMR). Consequently RMR pro-
vides a basis for drive and this resonates with the
older concept of ‘needs translated into drives’. In
addition, through adaptation, it can be envisaged
that other components of energy expenditure would
contribute to the drive for food. The actual signals

that help to transmit this energy need into behav-
iour could be reflected in oxidated pathways of fuel
utilization (11), abrupt changes in the availability of
glucose in the blood (12) and eventually brain neur-
otransmitters such as neuropeptide Y (NPY) which
appears to be linked to metabolic processes. Leptin
is also likely to play a role via this system.
In turn this drive to seek food—arising from a
need generated by metabolic processing—is given
direction through specific sensory systems asso-
ciated with smell, but more particularly with taste.
It is logical to propose that eating behaviour will be
directed to foods having obvious energy value. Of
particular relevance to the current situation are the
characteristics of sweetness and fattiness of foods.
In general most humans possess a strong liking for
the sweet taste of foods and for the fatty texture.
Both of these commodities indicate foods which
have beneficial (energy yielding) properties.
Accordingly, appetite can be considered as a bal-
ance between excitatory and inhibitory processes.
The excitatory processes arise from bodily energy
needs and constitute a drive for food (which in
humans is reflected in the subjective experience of
hunger). The most obvious inhibitory processes
arise from post-ingestive physiological processing
of the consumed food—and these are reflected in
the subjective sensation of fullness and a sup-
pression of the feeling of hunger. However, the sen-
sitivity of both the excitatory and inhibitory pro-

cesses can be modulated by signals arising from the
body’s energy stores.
It should be noted that the drive system probably
functions in order to ensure that energy intake at
least matches energy expenditure. This has implica-
tions for the maintenance of obesity since total en-
ergy expenditure is proportional to body mass. This
means that the drive for food may be strong in
obese individuals in order to ensure that a greater
volume of energy is ingested to match the raised
level of expenditure. At the same time whilst there is
a process to prevent energy intake falling below
expenditure, there does not seem to be a strong
process to prevent intake rising above expenditure.
Consequently, any intrinsic physiological disturb-
ance which leads to a rise in excitatory (drive) pro-
cesses or a slight weakening of inhibitory (satiety)
signals would allow consumption to drift upwards
without generating a compensatory response. For
some reason a positive energy balance does not
generate an error signal that demands correction.
Consequently the balance between the excitatory
and inhibitory processes has implications for body
weight regulation and for the induction of obesity.
SIGNALS FROM ADIPOSE TISSUE:
LEPTIN AND APPETITE CONTROL
One of the classical theories of appetite control has
involved the notion of a so-called long-term regula-
tion involving a signal which informs the brain
about the state of adipose tissue stores. This idea

117REGULATION OF APPETITE
Figure 8.4 Diagram indicating the proposed role of the OB
protein (leptin) in a signal pathway linking adipose tissue to
central neural networks. It has been postulated that leptin inter-
acts with neuropeptide Y in the brain (see text) to exert effects on
food intake (and indirectly on adipose tissue) and on the pan-
creas (release of insulin). The leptin link between adipose tissue
and the brain is only a part of a much more extensive periph-
eral—central circuit. EE, energy expenditure; EI, energy intake
has given rise to the notion of a lipostatic or pon-
derstatic mechanism (13). Indeed this is a specific
example of a more general class of peripheral appe-
tite (satiety) signals believed to circulate in the
blood reflecting the state of depletion or repletion of
energy reserves which directly modulate brain
mechanisms. Such substances may include satietin,
adipsin, tumour necrosis factor (TNF or cachec-
tin—so named because it is believed to be respon-
sible for cancer induced anorexia) together with
other substances belonging to the family of neural
active agents called cytokines.
In 1994 a landmark scientific event occurred with
the discovery and identification of a mouse gene
responsible for obesity. A mutation of this gene in
the ob/ob mouse produces a phenotype character-
ized by the behavioural trait of hyperphagiaand the
morphological trait of obesity. The gene controls
the expression of a protein (the OB protein) by
adipose tissue and this protein can be measured in
the peripheral circulation. The identification and

synthesis of the protein made it possible to evaluate
the effects of experimental administration of the
protein either peripherally or centrally (14). Because
the OB protein caused a reduction in food intake (as
well as an increase in metabolic energy expenditure)
it has been termed ‘leptin’. There is some evidence
that leptin interacts with NPY, one of the brain’s
most potent neurochemicals involved in appetite,
and with melanocortin-4 (MC4). Together these
and other neuromodulators may be involved in a
peripheral—central circuit which links an adipose
tissue signal with central appetite mechanisms and
metabolic activity (Figure 8.4).
In this way the protein called leptin probably acts
in a similar manner to insulin which has both cen-
tral and peripheral actions; for some years it has
been proposed that brain insulin represents a body
weight signal with the capacity to control appetite.
At the present time the precise relationship be-
tween the OB protein and weight regulation has not
been determined. However, it is known that in ani-
mals and humans which are obese the measured
amount of OB protein in the plasma is greater than
in lean counterparts. Indeed there is always a very
good correlation between the plasma levels of leptin
and the degree of bodily fattiness (15). Therefore
although the OB protein is perfectly positioned to
serve as a signal from adipose tissue to the brain,
high levels of the protein obviously do not prevent
obesity or weight gain. However, the OB protein

certainly reflects the amount of adipose tissue in the
body. Since the specific receptors for the protein
(namely OB receptor) have been identified in the
brain (together with the gene responsible for its
expression) a defect in body weight regulation could
reside at the level of the receptor itself rather than
with the OB protein. It is now known that a number
of other molecules are linked in a chain to transmit
the action of leptin in the brain. These molecules are
also involved in the control of food intake, and in
some cases a mutation in the gene controlling these
molecules is known and is associated with the loss
of appetite control and obesity. For example, the
MC4-R mutation (melanocortin-4 receptor) leads
to an excessive appetite and massive obesity in
children, just like the leptin deficiency (16).
These findings lead to a model of appetite control
based on the classic two-process idea involving the
stimulation (drive) to eat, and a quick-acting short-
term inhibition of food consumption which decays
118 INTERNATIONAL TEXTBOOK OF OBESITY
rapidly. The drive for food would be reflected in
high levels of hunger which are normally subjected
to episodic inhibitory (satiety) signals. There are
strong logical reasons why the drive (need) for food
should be related to energy expenditure of metab-
olism and physical activity. Evidence suggests a role
for NPY (which produces excessive food intake in
animal studies) and leptin (whose absence releases
the hunger drive in humans). This interpretation of

leptin action is consistent with the suggestion of a
dual role of leptin (24). Within the interaction be-
tween excitatory (drive) and inhibitory (satiety) pro-
cesses there is ample room for the operation of a
large number of mediating ‘orexic’ or ‘anorexic’
neuro-modulators (2).
LEPTIN DEFICIENCY AND APPETITE
CONTROL
It seems clear that for the majority of obese people,
the OB protein (leptin) system is not a major cause
of rapid or massive weight gain.
However, for certain individuals very low levels
of leptin (or the absence of leptin) may constitute a
major risk factor. Recently a number of individuals
have come to light. For example, two young cousins
have been studied who displayed marked hyper-
phagia from a very early age. This hyperphagia
took the form of a constant hunger accompanied by
food cravings and a continuous demand for food
(17). The eldest of the two cousins had reached a
body weight of more than 90 kg by the age of 9. Her
serum leptin level (like that of the cousin) was very
low, and subsequently a mutation in the gene for
leptin was revealed. This finding seems to implicate
leptin (OB protein) in the control of the drive for
food; that is, in the expression of hunger and active
food seeking rather than with satiety or the short-
term inhibition over eating. Leptin therefore ap-
pears to modulate the tonic signal associated with
the translation of need into drive; when leptin levels

are low or absent then the drive is unleashed and
results in voracious food seeking. The MC4 recep-
tor is also part of the same system and the absence
of this receptor also abolishes restraint over appe-
tite leading to massive hyperphagia. This phenom-
enon is quite different from the removal of a single
satiety signal which would lead only to an increase
in meal size or a modest increase in meal frequency.
FAT PREFERENCE AS AN APPETITE
RISK FACTOR
It is clear that the expression of appetite—the will-
ingness of people to eat or to refrain from eating—
reflects an interaction between biology and the en-
vironment (particularly the presence of salient food-
related stimuli). The tendency of this eating to lead
to a positive or negative energy balance will be
strongly influenced by the energy density of the
foods selected. Considering over-consumption, the
high energy density of fatty foods means that die-
tary fat intake is likely to lead to a positive energy
(and fat) balance, and in turn to weight gain (18,19).
Evidence for the effect of dietary fat on appetite
and weight gain arises from many different forms of
investigation including epidemiological surveys,
nutrient balance studies in calorimeters, short-term
interventions on food intake and experiments on fat
substitutes (20). One important issue in assessing
the effects of fat ingestion is the difference between
satiation and satiety (see Figure 8.1). Satiation is the
process in operation while foods are being eaten;

satiety is the state engendered as a consequence of
consumption. In considering dietary fat as a risk
factor in over-consumption, the effect on satiation is
likely to be much more important than that on
post-ingestive satiety.
The experimental evidence has led to the dis-
closure of two phenomena—termed ‘passive over-
consumption’ and the ‘fat paradox’. Use of an ex-
perimental procedure called concurrent evaluation
has indicated that, when people eat to a state of
comfortable fullness from a range of either high fat
or high carbohydrate foods, they consume much
greater quantities of energy from the fatty diet. This
has been termed high fat hyperphagia or passive
over-consumption. The effect is almost certainly
due, in large part, to the high energy density of the
high fat foods; hence it can be regarded as passive
rather than active eating. However, the term passive
means only that there is no deliberate intention on
the part of the eater to over-consume, and does not
mean that the phenomenon occurs without the me-
diation of mechanisms. Evidence indicates that
people can consume very large amounts of fat in
single meals and over a whole day (20). This is due
to a weak effect of fat on satiation and a dispropor-
tionately weak effect of fat on satiety (21). Some
studies have shown that human subjects obliged to
119REGULATION OF APPETITE
Table 8.1 Postulated interactions between behavioural risk factors and the obesigenic environment which generate a tendency for
over-consumption

Biological vulnerability (behavioural risk
factor) Environmental influence Potential for over-consumption
Preference for fatty foods
Weak satiation (end of meal signals)
Oro-sensory responsiveness
Weak post-ingestive satiety
Abundance of high fat (high energy-dense)
Large portion size
Availability of highly palatable foods with
specific sensory-nutrient combinations
Easy accessibility to foods and presence of
potent priming stimuli
! fat intake
! meal size
! amount eaten
! frequency
! frequency of eating
! tendency to re-initiate eating
eat a high fat diet for 3 weeks actually increased
their hunger and decreased feelings of fullness be-
fore a test meal (22). This finding resonates with
animal studies showing that when mice are fed a
high fat diet there is a consequent decrease in leptin
signalling in the hypothalamus. Therefore a high fat
diet may weaken any inhibition over the tonic sig-
nal which translates needs into hunger drive.
The capacity of some people to consume very
large quantities of fat creates a paradox. On one
hand fat in the intestine generates potent satiety
signals (5). On the other hand, exposure to a high fat

diet leads to over-consumption (of energy) suggest-
ing that fat has a weak effect on satiety (21). The
resolution of this paradox is revealed by the evi-
dence that although individuals—in the experimen-
tal situation—eat greater energy from the high fat
foods, they may consume a smaller volume or
weight of food. Since the function of a satiety signal
is to limit the amount of food people put into the
mouth, the signal has done its job but is overwhel-
med by the speed with which the large amount of
energy (from the high fat foods) can be delivered to
the stomach. This dietary override of physiological
satiety signals has a number of implications.
However, although there is a compelling correla-
tion between dietary fat and obesity, the relation-
ship does not constitute a biological inevitability.
Some people eat a habitual high fat diet and remain
lean.
RISK FACTORS FOR APPETITE
CONTROL
Most researchers do not have any trouble accepting
the idea that the state of a person’s metabolism
constitutes a major risk for developing weight gain
and becoming obese. However, as obesity develops,
metabolic characteristics change so that the state of
obesity itself is associated with a different metabolic
profile to that accompanying the process of weight
gain. This makes it important to do longitudinal
studies (whilst weight is increasing) as well as cross-
sectional studies (comparing lean and obese sub-

jects). Recently, Ravussin and Gautier (23) have
drawn attention to this issue and have outlined
those metabolic and physiological factors asso-
ciated with weight gain and with the achievement of
obesity.
The tendency to gain weight is associated with a
low basal metabolic rate, low energy cost of physi-
cal activity, a low capacity for fat oxidation (rela-
tively high respiratory quotient—RQ), high insulin
sensitivity, low sympathetic nervous system activity
and a low plasma leptin concentration. In the state
of obesity itself many of these risk factors (or pre-
dictors of weight again) are reversed.
Just as certain metabolic variables (risk factors)
can lead to a positive energy balance, so we can
envisage certain behaviourally mediated processes
which themselves constitute the risk factors leading
to hyperphagia or ‘over-consumption’ (high energy
intake leading to a positive energy balance). These
processes may be patterns of eating behaviour, the
sensory or hedonic events which guide behaviour,
or sensations which accompany or follow eating.
For convenience this cluster of events can be refer-
red to as behavioural risk factors. These events may
include a preference for fatty foods, weakened sati-
ation (end of meal signals), relatively weak satiety
(post-ingestive inhibition over further eating),
strong oro-sensory preferences (e.g. for sweetness
combined with fattiness in foods), a binge potential,
and a high food-induced pleasure response. In turn,

120 INTERNATIONAL TEXTBOOK OF OBESITY
Table 8.2 Characteristics of male high and low fat phenotypes
High fat
phenotype
(HF)
Low fat
phenotype
(LF)
Age (years) 20.5 20.6
Body Mass Index 22.6 22.1
% body fat 9.9 9.8
Dietary fat (g/day) 158.8 80.8*
(% energy) 44.3 32.0*
Basal metabolic rate (kcal/day) 1624 1455*
Resting respiratory quotient 0.84 0.89*
Plasma leptin (ng/ml) 2.92 1.79*
* Significant difference between HF and LF, P:0.05 (2-tail).
these events may be subdivided to describe more
specific components leading to a risk of over-con-
sumption.
These behavioural risk factors can be regarded as
biological dispositions which create a vulnerability
for weight gain and which manifest themselves
through behavioural acts themselves, or through
physiological processes which promote or permit
changes in behaviour.
However, such risk factors alone would be un-
likely to lead to a positive energy balance in a
benign environment, i.e. one in which the food
supply and the cultural habits worked against ex-

cessive consumption. In most of today’s societies,
however, the food environment exploits biologi-
cally based dispositions and this promotes the
achievement of a high energy intake. This concep-
tualization is set out in Table 8.1.
INDIVIDUAL VARIABILITY IN
APPETITE CONTROL: THE HIGH FAT
PHENOTYPE
The concept of fat as an environmental risk factor is
reflected in a general agreement that the increased
energy intake which occurs on high fat diets is
reflected in body weight gain and increasing obes-
ity. When individuals in a large national survey
were classified according to dietary fat intake, obes-
ity (BMI 930) among high fat consumers was 19
times that found in the low fat consumers (25).
Consequently, this supports the view that, in gen-
eral, a high intake of dietary fat tends to increase the
likelihood of weight gain. However it is also clear
that obesity resulting from a high fat diet is not a
biological inevitability. In all databases we have
examined, some high fat eaters remain normal
weight or lean. This observation has led to a charac-
terization of people based on the nature of their
habitual dietary intake.
Comparisons between groups characterized by
the amount of fat consumed in the diet has revealed
quite diverse responses to nutrient challenges and
to energy loading. The degree of hunger experi-
enced and the behavioural responses were different

(26). These features are present in individuals (in this
case young male adults) indistinguishable in terms
of their BMIs, percentage body fat, age and general
lifestyle. In an extension of these investigations cer-
tain physiological features have been examined.
The outcome indicates that the high fat (high en-
ergy) consumers with similar body weights to low
fat consumers have lower respiratory quotients
(RQs—the respiratory quotient reflects the oxida-
tion of fat or carbohydrate), as expected, but also
have higher resting metabolic rates (Table 8.2).
Taken together these two features would consti-
tute physiological processes offering protection
against the weight-inducing potential of a high fat
diet. This cluster of behavioural and physiological
features suggests the existence of a distinct pheno-
type. That is, a particular type of individual with the
physiological capacity to retain a stable lean body.
A further interesting feature of the high fat pheno-
type is the presence of a high level of plasma leptin.
However, it is possible that the high circulating
leptin may not be translated into an effective hy-
pothalamic signal.
In addition, the investigation of the consequences
of the habitual consumption of a particular diet has
drawn attention to the interplay between biology
and the environment. The relationship is not 100%
predictable. In general it is clear that a high fat diet
will favour the generation of a positive energy bal-
ance and weight gain, but some individuals who are

physiologically protected (through genetic disposi-
tion or adaptation) will respond differently. The fact
that the relationship between dietary fat and body
weight is not a biological inevitability means that
correlations from epidemiological studies (between
dietary fat and obesity) can be expected to be weak.
The interpretation of these weak correlations is
made even more confusing because of the huge
121REGULATION OF APPETITE
problem of mis-reporting food intake in large-scale
surveys (27).
FAT INTAKE AND ADIPOSITY IN
CHILDREN
Exposure to a diet containing high fat foods consti-
tutes a risk factor for body weight gain but this
relationship does not constitute a ‘biological inevi-
tability’. How does this relationship manifest itself
in children?
First, evidence suggests the existence of a rela-
tionship between parental obesity and obesity in the
offspring (28). In a retrospective cohort study of 854
subjects born between 1965 and 1971, obesity (de-
fined as a BMI of 27.8 for men and 27.3 for women)
in later adulthood was compared with the medical
records of the parents. Among those who were
obese during childhood, the chance of obesity in
adulthood ranged from 8% (for 1- to 2-year-olds
without obese parents) to 79% (for 10- to 14-year-
olds with at least one obese parent). Therefore obese
children under 3 years of age without obese parents

are at low risk for obesity in adulthood, but among
older children, obesity is an increasingly important
predictor of adult obesity. In this study, parental
obesity more than doubled the risk of adult obesity
among children under 10 years of age.
One mediating factor (and possibly a mechanism)
in the development of adult obesity from childhood
involves the so-called ‘adiposity rebound’ (AR).
This is the name given to the second augmentation
of BMI after birth, and there is an inverse relation-
ship between adult BMI and the age of AR. In a
longitudinal study of Czech children, followed from
1 month of age to adulthood, the heaviest adults
had an AR around 5 years and the leanest at 7.6
(29).
A number of studies have also examined the die-
tary fat intake of children and both the diet compo-
sition and adiposity of the parents. In one study, a
high-risk group of children (one or two overweight
parents) was compared with a low-risk group (no
parent overweight) at 4.5 years of age. The high-risk
group was consuming a higher percentage of fat in
their diet and a smaller percentage of carbohydrate
(30). In an unselected sample of 4- to 7-year-old
children (35 girls, 36 boys) there was an influence of
maternal adiposity on dietary fat intake in the
children, and, for the boys a correlation between
their own fat mass and fat intake (31). These data
suggest that mothers may contribute more strongly
than fathers to the development of obesity in

children by influencing their dietary fat intake.
Moreover, it is known that young children’s prefer-
ences for particular foods are powerful predictors of
consumption when self-selection is permitted (32).
Interestingly, it has been demonstrated that the fat
preferences (and fat consumption) of 3- to 5-year-
old children are related to parental adiposity (33).
The fat intake from 18 children was obtained from
30 h weighed food intake records and compared
with the body composition measures of children
and parents. Children’s fat intakes were correlated
with preferences for high fat foods and to their
triceps skinfold measurements. In addition, there
were strong correlations between the children’s fat
preferences and fat intakes and the BMIs of the
parents. Children of heavier parents had stronger
preferences for (and higher consumption of) fatty
foods. In a further study of 9- to 10-year-old
children, the fattest children consumed significantly
more energy from fat than the lean children (34).
These findings strongly support an environment-
al impact of the habitual diet upon the development
of weight gain and obesity. However, the data could
also suggest a biological influence over the prefer-
ences for those high fat foods which form part of the
habitual diet. This scenario, which focuses attention
on the energy intake side of the energy balance
equation, should not obscure the role of physical
activity and energy expenditure. One major factor
in the ever-increasing frequency of sedentary behav-

iours is television viewing. In a representative co-
hort of 746 youths aged 10—15 years there was a
strong dose—response relationship between the
prevalence of overweight and the hours of television
viewed (35). The incidence of obesity was 8.3 times
greater in those youths watching more than 5 hours
of television per day compared with those watching
0 to 2 hours. As is the case with adults (36), over-
weight in children appears to be strongly influenced
by the environmental factors of low physical activ-
ity (high frequency of sedentary activities) and expo-
sure to a high energy-dense (high fat) diet. However,
we should be wary of assuming that the effect of TV
watching is necessarily due to sedentarism since
viewing also provides an opportunity for further
eating. Consequently, in children appetite control
can play a significant role in weight gain and obes-
122 INTERNATIONAL TEXTBOOK OF OBESITY