reviews - Advances in Clinical and Experimental Medicine

REVIEWS
Adv Clin Exp Med 2007, 16, 4, 569–576
ISSN 1230−025X
© Copyright by Silesian Piasts
University of Medicine in Wrocław
MAŁGORZATA ŚMIAROWSKA1, MONIKA BIAŁECKA2, KAROLINA KORWIN−PIOTROWSKA1
Molecular Mediators in Control of Food Consumption
and Energy Balance in Eating Disorders
Molekularne mediatory kontroli poboru pożywienia
i równowagi energetycznej w zaburzeniach odżywiania
1
2
Department of Psychiatry Pomeranian University of Medicine, Szczecin, Poland
Department of Pharmacology Pomeranian University of Medicine, Szczecin, Poland
Abstract
Eating disorders are in fact civilisational problem. The analysis of recent studies shows that genetic background,
neuronal and endocrine transmission have wide and differential impact on eating pattern, behavior, emotions and
attitudes connected with personality profile. Despite intensive studies, the neuroregulation and psychic mecha−
nisms in eating disorders still remain unclear. It is an unresolved problem whether psychologic disturbances and
neuroendocrine disorders are primary or if they appear secondary – due to changes in nutrition habits. Defining the
typical “biological markers” of these processes would be of great importance for early prevention and more effec−
tive treatment. Actual knowledge on neurotransmitters responsible for the process of eating and energy balance is
presented in the paper. Authors consider the conceptions of hypothetical pathomechanism of regulations distinc−
tiveness, which may have an effect on revealing or supporting the improper nutrition behavior: anorexia nervosa,
psychic bulimia, binge eating and obesity (Adv Clin Exp Med 2007, 16, 4, 569–576).
Key words: neuropeptides, monoamines, leptin, anorexia nervosa, bulimia nervosa.
Streszczenie
Zaburzenia odżywiania są współczesnym problemem cywilizacyjnym. Jak wynika z dotychczasowych badań,
podłoże genetyczne, przekaźnictwo neuronalne i endokrynne wywierają szerokie i zróżnicowane działanie na
wzorce żywieniowe, zachowanie, emocje i postawy związane z profilem osobowości. Pomimo intensywnych ba−
dań, mechanizmy psycho− i neuroregulacyjne w zaburzeniach odżywiania nadal są niejasne, a zwłaszcza zagadnie−
nie, czy zaburzenia psychologiczne oraz neuroendokrynologiczne są zmianami pierwotnymi, czy też pojawiają się
wtórnie do zmienionego sposobu odżywiania. Istotne znaczenie dla opracowania wczesnej prewencji i skuteczniej−
szych metod leczenia zaburzeń odżywiania miałoby określenie „biomarkerów” tych procesów. W artykule przed−
stawiono aktualny stan wiedzy na temat neuroprzekaźnictwa odpowiedzialnego za proces odżywiania i utrzyma−
nie bilansu energetycznego ustroju. Autorzy odnoszą się do koncepcji wyjaśniających hipotetyczny patomecha−
nizm tych odrębności w regulacjach, które mogą mieć znaczenie w powstawaniu lub/i podtrzymywaniu
nieprawidłowych zachowań żywieniowych: jadłowstrętu psychicznego, bulimii psychicznej, napadów objadania
się typu binge eating oraz otyłości (Adv Clin Exp Med 2007, 16, 4, 569–576).
Słowa kluczowe: neuropeptydy, monoaminy, leptyna, jadłowstręt psychiczny, bulimia psychiczna.
Eating disorders such as anorexia nervosa (AN),
bulimia nervosa (BN), and obesity are in fact civi−
lizational problems. They are currently the subject of
great interest due to the threatening consequences
they pose, such as the development of cardiovascular
system disease, diabetes mellitus (metabolic syndro−
me), and the activation of particular neoplasms [1, 2].
The seriousness of this problem can be illustrated
by the fact that about 20% of patients with anorex−
ia die of cachexia [3]. Studies have confirmed the
relationship between anorexia and bulimia nervosa
on the one hand and affective disorders and alcohol
dependence syndrome on the other. This also might
support hypotheses of their common origin [4–6].
570
M. ŚMIAROWSKA, M. BIAŁECKA, K. KORWIN−PIOTROWSKA
Anorexia nervosa and bulimia afflict
0.3–0.7% and 0.7–2.5% of the total female popu−
lation; morbidity peeks between the ages of 15.7
and 18.1 years [3]. It is estimated that 25–30% of
women suffering from BN have a past history of
treatment for AN [4] and that 10–50% of adoles−
cent girls admit to dieting and having binge−eating
episodes, which may foreshadow the development
of typical illness in adulthood [3]. Thus there is the
possibility of phenotypic variation according to
the coincidence of environmental exposure, psy−
chological factors, and genetic predisposition,
which all lead to neuronal and humoral interac−
tions [4, 7, 8]. Previous studies have shown that
genetic background and neural and endocrine
transmission have a wide and varied impact on
nutritional behavior, emotions, and attitudes.
The amine uptake system may help in revealing
a biological background in individuals exposed to
specific social stressors. Pathological neuropeptide
transmission takes part in creating and consolidat−
ing incorrect nutritional patterns [10]. According to
psychological studies, the personality profile of
patients with AN or BN is of great importance in
their body perception and in forming the incentive
mechanisms responsible for the vicious circle of
these disorders. This notion is supported by the high
rates of such personality features as perfectionism,
impulsiveness, and low self−esteem [4–6, 10].
Despite intensive investigations, the psycho−
and neuroregulatory systems in AN and BN remain
unclear [5, 11]. It has not yet been determined
whether the psychological disturbances and neu−
roendocrine disorders are primary or if they appear
secondarily to changes in nutritional habits. It is
a well−known fact that activities aimed at reducing
weight or provoking vomiting are not present in
every case of these illnesses [12]. Therefore an
important scientific question is whether specific
biomarkers can be used to select the group of indi−
viduals with a higher risk of eating disturbances,
which can lead to early prevention and more effec−
tive treatment of these patients. The current state of
knowledge concerning the neurotransmission
responsible for the nutritional process, with special
attention to the variety of mechanisms which play
roles in the pathogeneses of anorexia nervosa and
bulimia nervosa, is presented here.
Body mass and energy balance are regulated at
the central and peripheral levels by stimulating or
inhibiting consumption and by using up energy
factors. Among the central neuronal and humoral
mediators connected with controlling metabolic
processes are melanin−concentrating hormone
(MCH), neuropeptide Y (NPY), agouti−related pro−
tein (AGRP), adrenocorticotropic hormone (ACTH),
α−melanocyte−stimulating hormone (α−MSH),
thyrotopin−releasing hormone (TRH), corticotro−
pin−releasing hormone (CRH), urocortin (melano−
cortin family), cocaine− and amphetamine−regulat−
ed transcript (CART), brain−derived neurotropic
factor (BDNF), β−endorphin (β−EP), dynorphin A,
enkephalins, orexins A and B (OXA, OXB), nor−
epinephrine (NA), dopamine (DA), serotonin (5−
HT), neurotensin, glutamine, and gamma amino−
butyric acid (GABA). The activities of these neu−
Table 1. A distribution of mediators connected with the control of the organism energy balance including: the source, the
chemical building and the appetite
Tabela 1. Podział mediatorów związanych z kontrolą równowagi energetycznej ustroju z uwzględnieniem: źródła
pochodzenia, budowy chemicznej i wpływu na łaknienie
Influence on eating
behaviour
Centrally−derived mediators
(Syntetyzowane w o.u.n.)
Peripherally−derived mediators
(Syntetyzowane obwodowo)
(Wpływ
na łaknienie)
activating
(pobudzający)
inhibiting
(hamujący)
activating
(pobudzający)
inhibiting
(hamujący)
Peptides
(Peptydy)
MCH, NPY, AGRP
ACTH, α−MSH,
TRH, CRH, galanin,
urocortin, CART,
BDNF
ghrelin
GLP−1, CCK, galanin,
insulin, bombesin,
PYY, NPY
Opioids
(Opioidy)
β−endorphin, dynor−
phin A, enkephalins
Hypocretins
(Hipokretyny)
OXA i OXB
Biogenic amines
(Aminy biogenne)
norepinephrine
Amino acids
(Aminokwasy)
glutamate, NMDA,
GABA
Cytokines
(Cytokiny)
dopamine, serotonin,
neurotensin
serotonin
TNF−α, IL−1β, leptin
571
Molecular Mediators in Eating Disorders
apidose tissue
LEPTiN (cytokines IL−6 group), ADIPONECTIN
+
IL−1β
tkanka tłuszczowa
LEPTYNA (grupa cytokin IL−6), ADIPONEKTYNA
–
+
catabolic parhway of CNS:
anabolic parhway of CNS:
OREXIGENIC agents
ANOREXIGENIC agents
szlak anaboliczny o.u.n.:
szlak kataboliczny o.u.n.:
OREKSYGENICZNY
ANOREKTYCZNY
POMC, melanocorins (α, β MSH) CART
POMC, melanokortyny (α, β MSH) CART
neurotensin, GLP−1, CRH (CR1R, CR2R)
neurotensyna, GLP −1, CRH (CR1R, CR2R)
TRH, urocortin, insulin (IR)
TRH, urokortyna, insulina (IR)
CNTF
malonyl Co−A
DA (D1/D5, D2−D4), BDNF → 5−HT (5−HT2C)
NPY (Y1R, Y5R)
Agouti, AgRP,
mahogany syndecan
opioids: β−EP, MCH
opioidy: β−EP, MCH
OXA, OXB (hipocretins)
OXA, OXB (hypokretyny)
galanin
galanina
glutamate−NMDA, GABA
glutaminian−NMDA, GABA
NA
+
digestive tract
NPY, ghrelin
p. pokarmowy
NPY, grelina
+
suprarenal
glands
nadnercza
AGRP
–
n. X
n. X
digestive tract
GLP−1, GAL,
PYY, CCK,
insulin
p. pokarmowy
insulina
cytokines:
cytokiny:
TNF−α
Fig. 1. The neurotransmitters’ distribution according to a source of secretion and metabolic effect;
IL – interleukin, NPY – neuropeptide Y, Y1,Y5R – receptors for neuropeptide Y, AgRP – Agouti−related protein,
β−EP – β endorphin, OXA and OXB – A and B orexins, NMDA – glutamate N−methyl−D−aspartate receptors,
GABA – γ−aminobutyric acid, NA – norepinephrine, POMC – proopiomelanocortin, CART – cocaine− and ampheta−
mine−regulated transcript, α, β MSH – α, β melanocortins, GLP−1 – glucagon−like factor 1, GAL – galanin,
PYY – peptide Y, CCK – cholecystokinin, CNTF – ciliary neurotrophic factor, CRH – corticotropin−releasing hor−
mone, TRH – thyrotopin−releasing hormone, DA – dopamine, BDNF – brain−derived neurotropic factor,
5−HT – serotonin, D1–D4 – dopamin receptors, 5−HT2C – serotonin receptor, TNF−α – tumor necrosis factor α,
n. X – nervus vagus
Ryc. 1. Podział neuroprzekaźników ze względu na miejsce wydzielania i działanie metaboliczne;
IL – interleukina, NPY – neuropeptyd Y, Y1,Y5R – receptory dla neuropeptydu Y, AgRP – białko związane z Aguti,
β−EP – β−endorfina, OXA i OXB – oreksyny A i B, NMDA – receptor układu glutaminergiczego, GABA – kwas
γ−aminomasłowy, NA – norepinefryna, POMC – proopiomelanokortyna, CART – transkrypt regulujący dla kokainy
i amfetaminy, α, β MSH – α−melanotropiny α i β, GLP−1 – glukagono−podobny czynnik 1, GAL – galanina, PYY
– peptyd jelitowy Y, CCK – cholecystokinina, CNTF – rzęskowy czynnik neurotroficzny, CRH – kortykoliberyna,
TRH – tyreoliberyna, DA – dopamina, BDNF – czynnik neuroplastyczności mózgu, 5−HT – serotonina, D1–D4
– receptory dopaminy, 5−HT2C – receptor serotoniny, TNF−α – czynnik martwiczy guza α, n. X – nerw błędny
rotransmitters are diverse, as shown in Table 1.
The second group includes peripheral neurome−
diators and humoral factors involved in controlling
metabolic processes. These are glucagon−like pep−
tide 1 (GLP−1), cholecystokinin (CCK), galanin,
insulin, peptide Y (PYY), bombesin, leptin, inter−
leukin 1β (IL−1β), tumor necrosis factor alpha
(TNFα), ciliary neurotrophic factor (CNTF), and
grelin. Most of these mediators restrain appetite in
the central nervous system not only directly
through feedback, but also via the vagus nerve.
The only exception is grelin, which stimulates
food intake and is identified as a mediator of adap−
tation to malnutrition. Classifying these mediators
according to their central or peripheral origin is
imprecise because many of them can be synthe−
sized primarily both in the central nervous system
and peripherally, e.g. NPY, galanin, and serotonin.
However, the differences in their activity may be
caused not only by their source, but also by their
biochemical structures (Table 1). All interactions
between these mediators, along with their origin,
localization, and action, are shown in Figures 1
and 2.
The regulation of body weight is a process
relying on the balance between central neurotrans−
mitters, which control food intake, and energy
expenditure, which is connected with substrate
oxidation and thermogenesis in adipose tissue and
skeletal muscle. The uncoupling proteins (UCPs),
572
M. ŚMIAROWSKA, M. BIAŁECKA, K. KORWIN−PIOTROWSKA
↑ PPM (UPC)
SNS (β rec)
CD4
IL−1,
TNF−α
insulin, ghrelin
insulina, grelina
starvation, exercise
głodzenie, wysiłek
+
+
+
PG
CRH, CART, POMC (α, β MSH)glutamate
CRH, CART, POMC (α, β MSH)glutaminian
leptin
leptyna
(IL−6: ObRa–e)
+
–
+
+
5−HT2C
–
–−
+
+
BDNF
+
MC4R
NPY (Y1, Y5R)
AGRP/GABA
–
SNS
↓ PPM (UPC)
+
PNS
hormones, digestive tract, insulin
hormony, przewód pokarmowy, insulina
↓ appetite
↓ łaknienie
Fig. 2. Regulations among neurotransmitters responsible for hunger and satiety arousing, their influence on autho−
nomic nervous system and energy expenditure;
PPM – basic metablism, SNS – sympathetic system, PNS – parasympathetic system, CD4 – limfocytes T helpers, PG
– prostaglandin; OBR a–e – leptin receptors, MC4R – melanocortin receptor
Ryc. 2. Schemat obrazujący regulacje między przekaźnikami odpowiedzialnymi za powstawaniem uczucia głodu
i sytości, ich wpływ na autonomiczny układ nerwowy i wydatkowanie energii;
PPM – podstawowa przemiana materii, SNS – układ współczulny, PNS – układ przywspółczulny, CD4 – limfocyty
T pomocnicze, PG – prostaglandyny, OBR a–e – receptory leptyny, MC4R – receptor dla melanokortyny
which are synergistically activated by the sympa−
thetic part of the autonomic system (ANS) and
such neuromediators as noradrenaline, triiodothy−
ronine, and leptin, are ascribed effector roles [14].
These mechanisms are directly controlled by the
autonomic nervous system and, simultaneously, by
neuropeptides characterized by sympatholytic,
parasympathomimetic (NPY/AGRP), and sympa−
thomimetic activity with affinity to β−adrenergic
receptors (CART/CRH/POMC) [7] (Fig. 1). Despite
their differences in structure, the actions of the
neuropeptides, monoamines, and cytokines in the
CNS are mutually conjugated and can be
described as agonistic−antagonistic. None of them
are one−dimensional.
The localization of the neurotransmitter−
releasing neurons plays a key role. The two main
centers contributing to appetite and energy expen−
diture control are located in the arcuate nucleus
(hunger center) and the subthalamic nucleuses, i.e.
the supraoptic, paraventricular, and nucleus tractus
solitarius (satiety center). The neurotransmitters
create common tracts with affinity to specific
receptors, and these are an important regulatory
element. These tracts are the starting points of
effector pathways which are polarized anabolical−
ly or directed to catabolism. A detailed description
of these mechanisms is presented below.
One of the strongest appetite stimulators is
NPY, which is especially directed towards carbo−
hydrate intake. In the central endocrine system,
NPY stimulates CRH release [15], which in turn
inhibits NPY [16]. Studies on animals confirm that
CRH activity is antagonist to NPY. In these stud−
ies, CRH injected was shown to support the feel−
ing of satiety, despite the fact of weight loss [17].
There is an hypothesis stating that feedback
between NPY and CRH at the hypothalamic level
is performed via amino−acid transmission [20].
Histochemical studies confirm the presence of
GABA in NPY−ergic neurons in the arcuate nucle−
us (ARC) [20]. Disturbance in the homeostasis
between CRH and NPY, as occurs in anorexia ner−
vosa, leads to CRH hyperactivity, activation of the
pituitary−adrenal axis [21], hypercortisolemia, and
consequently to clinical symptoms of depression
[22]. The above observations prompted several
hypotheses suggesting an interaction between
NPY or CRH release and emotions, mood, and the
ability to tolerate stressful situations [15, 22].
The orexigenic activity (connected with
appetite stimulation) of NPY might be reinforced
by the endogenous opioid system [16]. During
investigations with animals, direct synaptic con−
junctions between neurons releasing NPY,
enkephalins, and β−EP in the arcuate nucleus were
discovered [16]. Y1 receptors for NPY located on
pro−opiomelanocortin (POMC) neurons were indi−
cated [20]. POMC neurons are aroused by gluta−
mine, with a key role of the glutaminergic NMDA
573
Molecular Mediators in Eating Disorders
hypothalamus: AC, NTS
podwzgórze: AC, NTS
POMC
melanocortines
melanokortyny:
lipotropins
lipotropiny
β−endorphins (β−EP)
β−endorfiny (β−EP)
ACTH = α MSH = β MSH > γ MSH
homeostasis of body weight
the agonists of
homeostaza m. c.
agoniści
MC3,4R
blocade in mice
blokada u myszy
AGRP overexpression
nadmierna ekspresja AGRP
eating behaviour,
metabolism, energy
expenditure, satiety
zachowania żywieniowe,
metabolizm, wydatkowanie
energii, sytość
hiperglicaemia, hiperinsulinaemia
– obesity, the symptoms of diabetes
hiperinsulinemia, hiperglikemia
– otyłość, objawy cukrzycy
reduction of anorexia related with
neo hyperplasia (TNF),
reduction of the cancerous cachexia
zmniejszenie hipofagii związanej
ze wzrostem neo (TNF),
zmniejszenie kacheksji nowotworowej
Fig. 3. The melanocortin system and its influence on food consumption;
AC – arcuate nucleus, NTS – nucleus tractus solitari; other abbreviations see text
Ryc. 3. Układ melanokortyny i jego działanie metaboliczne;
AC – jądro łukowate podwzgórza, NTS – jądro pasma samotnego; pozostałe skróty mają objaśnienia w tekście
receptors in the lateral hypothalamus (LHA) [20].
In this way the glutaminergic endogenous pathway
influences the craving stimulation in physiological
conditions as well as in pathological situations,
such as malnutrition [20]. The process of trans−
forming POMC into endogenous opioids and the
scheme melanocortin system activity are presented
in Figure 3.
The administration of exogenous opioid recep−
tor agonists, depending on the dose and period of
therapy, relieves eating disorders such as anorexia
nervosa, bulimia, and obesity. The majority of
exogenous and endogenous opioids, when used for
a short time, result in increasing food intake, in ani−
mals especially carbohydrates and fats and in
human beings mostly fats and proteins [16]. The
opioid system and the cannabin type 1 (CB1)
receptors connected with it are involved in control−
ling the energy balance in conjunction with subcor−
tical nucleuses from the reward system and the cor−
tical representation of memory. The CB1 receptors
have been detected in all key systems of peptide
neurons in the hypothalamus: CRH, POMC/CART,
MCH, and NPY/AGRP [2, 23]. Central stimulation
of CB1 results in increased appetite, while periph−
eral CB1 stimulation proceeds with the activation
of lipogenesis in adipose tissue [2, 23].
There are suggestions that endogenous canna−
binoids and their receptors may be of great impor−
tance in the pathogenesis of obesity, which also
explains the addictive aspect of eating [23, 24].
Furthermore, β−endorphins (β−EPs) are thought to
cooperate in reinforcing the vicious circle and
recurrence of symptoms in anorexia nervosa.
Among patients with anorexia nervosa, the mech−
anism of the β−EPs is not homogenous; a medium
concentration stimulates craving, whereas a high
level leads to increased tolerance of starvation.
Individuals with bulimia nervosa having high con−
centrations of β−EPs react as if their appetites were
increased; they have binge−eating episodes, pro−
voke vomiting, and all this consequently rein−
forces the pathological pattern of feeding [9].
Similarities in the circadian rhythm of β−EP secre−
tion in both anorexia nervosa and affective disor−
ders corroborate the hypothesis that β−endorphins
are endogenous antidepressants [25].
Satiety is connected with stimulation of the
receptor MC4R, which belongs to the melanocortin
system. MC4R agonists are POMC, α−MSH,
CRH, CART, leptin, serotonin, and interleukins
(IL−1, IL−6), while its strongest endogenous antag−
onist is AGRP. According to histochemical stud−
ies, AGRP is released together with NPY, because
they have a common origin in the ARC neurons.
Stimulation of NPY−related neurons in the hunger
center results in escalation of appetite due to inhi−
bition of satiety, which is connected with
AGRP’s direct influence on MC4R [13, 26]. With
regular feedback, the increase in NPY should esca−
late CRH secretion, connected with the satiety
center. Central transmission involving MC4R is
574
stimulated when the energy balance is positive.
Disturbances in the MC4R system lead to an
increase in appetite and a decrease in the expendi−
ture of cAMP−related energy, which contributes to
creating obesity. Melanocortin receptors have
been identified as playing a key role in the patho−
genesis of obesity [7, 27], binge−eating disorder
(BED) [28], and probably in reversing anorexia
[21, 26]. The regulatory mechanisms described
above are presented in Figures 2 and 3.
Other factors which, according to the latest
studies, also take part in generating satiety are
brain−derived neurotropic factor (BDNF), sero−
tonin, and CART. They are indicated as influenc−
ing not only eating disorders, but also depressive
episodes [29–31]. Experimental models have
demonstrated the significance of BDNF in neu−
ronal development, efficiency, and life span [32].
The secretion of BDNF is related to nutritional
conditions and exposure to stress [33]. Stressful
situations provoke an increase in glycocorticoid
secretion, which subsequently stimulates the
expressions of BDNF and neurotropin−3 (NT−3) in
the limbic system and hippocampal area [29].
Clinical observations corroborate a more intensive
release of BDNF during starvation, which is treat−
ed as prolonged stress for the organism. This
mechanism seems to be caused by the brain’s neu−
roplasticity, which is a barrier protecting against
atrophy in states of malnutrition [32, 34]. Mood
disturbances in the course of depression are
accompanied by a decreased level of plasma
BDNF [31]. Because of this, BDNF is suggested
to be not only a biological marker of depression
[31], bulimia, and anorexia nervosa, but also a fac−
tor predisposing to incorrect feeding patterns in
both anorexia and bulimia nervosa [30]. BDNF
activity proceeds via the serotoninergic system
(the 5−HT2C receptor) and melanocortin pathway
(MC4R) [33, 30]. This interaction might result in
alteration of serotonin release. A low concentra−
tion of serotonin is related to binge−eating
episodes in bulimic patients, restrictive and com−
pulsive behaviors in anorexia nervosa, and a pref−
erence for carbohydrates among obese individu−
als [9]. A well−known fact is serotonin’s influence
on mood, which has been demonstrated in phar−
macological studies.
The neurotransmitters discussed above play
roles in the direct regulation of the hunger and
satiety centers and also have indirect influence on
the nutritional state, metabolic processes, and
mental status. Their neuroendocrine activities are
involved in modulation the activity of the hypo−
thalamus−pituitary−peripheral axis [8]. Former tri−
als have indicated that NPY stimulates the secre−
tion of luteinizing hormone (lutropin)−releasing
M. ŚMIAROWSKA, M. BIAŁECKA, K. KORWIN−PIOTROWSKA
hormone (LHRH) and inhibits growth hormone−
releasing hormone (GHRH) [15]. Endogenous β−EP,
similar to NPY, restrains CRH release and subse−
quently modifies hypothalamus−pituitary−gonad
axis activity. It also escalates the secretion of
insulin, which in turn inhibits the central secretion
of NPY [7]. Moreover, endogenous β−EPs impede
pituitary adrenocortical activity both directly and
indirectly, through modification of serotoninergic
and dopaminergic system activity [16].
The common link between the central neu−
ropeptide secretion system and the hypothalamus−
pituitary−peripheral axis is leptin, a protein hor−
mone secreted by adipose tissue cells [36]. It
belongs to the cytokine family, circulates by bind−
ing, and interacts with its receptors Ob−Rb in the
hypothalamus (ARC) with the neuronal n subcor−
tical neurons [37]. Leptin activity is connected
with most of the neurotransmitter systems in the
central nervous system, i.e. NPY, AGRP, MCH
[38], galanin [39], OXA and OXB [40], CRH,
TRH, BDNF, POMC, α−MSH, and CART [37, 41].
The anorectic activity of leptin (similar to BDNF
described above) is provided via 5−HT2C and
MC4R receptor activation [20]. Leptin’s dualistic
influence on MC4R receptors should be under−
lined: it is an agonist to CRH (induced by inter−
leukin−1α) and α−MSH (POMC product synthe−
sized by opioid neurons activated by leptin and
insulin) and an antagonist to the NPY/AgRP sys−
tem [38, 41, 42].
Based on a study of laboratory animals it was
suggested that mutation of leptin or its gene leads to
obesity [43]. This happens quite seldom among
humans, in contrast to MC4R mutation, which is
more frequent [28]. The states characterized by
adverse energy balance and a genetic defect in lep−
tin result in an alteration of appetite inhibition
which is connected with the effector pathway of the
neuropeptides having anorexic activity, i.e. CRH,
TRH, BDNF, and 5−HT2C, as well as decreased
influence of the autonomic nervous system [41, 42].
The release of leptin is related not only to
changes in body weight, but also to hormone con−
trol, especially in states of prolonged starvation
and binge−eating episodes [12, 44]. A negative
correlation was observed between leptin concen−
tration and psychopathological features typical of
anorexia nervosa, e.g. low self−esteem, distrust in
interpersonal relations, and disappointment in
body shape [12].
It remains unclear which of the above factors,
and now they modify genes’ expression and pene−
tration for hypothalamic neuropeptides. These
kinds of neuropeptides play key roles in the
process of adapting to malnutrition, and in the case
of anorexia nervosa, they rescue the sufferer from
Molecular Mediators in Eating Disorders
death. It is of great importance to be able to iden−
tify the risk group of individuals predisposed to ill−
ness prior to the first appearance of clinical symp−
toms. Unfortunately, examining neuropeptides and
monoamines in the human population is rather
problematic due to the inaccessibility of the cen−
tral nervous system. Measurements of plasma neu−
ropeptide levels are also unreliable as they are
related to the brain−blood barrier and the peripher−
al source of neuropeptide secretion located in the
575
gastrointestinal tract [10]. We should also not for−
get about laboratory misinterpretations. Taking all
these facts into consideration, one can state that
measurements of plasma neuropeptide levels do
not reflect their real central concentrations [15].
Cerebrospinal fluid examinations are connected
with a higher level of invasiveness. For all these
reasons, future studies on the pathogenesis of eat−
ing disturbances will search for new tools, such as
genetic methods.
References
[1] Fukumura D, Ushiyama A, Duda DG, Xu L, Tam J, Krishna V, Chatterjee K, Garkavtsev I, Jain RK: Paracrine
regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ Res 2003, 93, 88–97.
[2] Lichtman AH, Cravatt BF: Food for thought: endocannabinoid modulation of lipogenesis. J Clin Invest 2005,
115, 5, 1130–1133.
[3] Grange D, Loeb K KL, Van Orman S, Jellar CC: Bulimia Nervosa in Adolescents. A Disorder in Evolution?
Arch Pediatr Adolesc Med 2004, 158, 478–482.
[4] Kaye WH, Klump KL, Frank GKW, Strober M: Anorexia and Bulimia Nervosa. Annu Rev Med 2000, 51,
299–313.
[5] Halmi KA, Sudany SR, Strobel M, Kaplan A, Fichter M, Treasure J, Berrettini WH, Kaye WH:
Perfectionism in Anorexia Nervosa, Variation by Clinical Subtype, Obsessionality, and Pathological Eating
Behavior. Am J Psychiatry 2000, 157, 1799–1805.
[6] Fichter MM, Quadflieg N, Hedlund S: Twelve−Year Course and Outcome Predictors of Anorexia Nervosa. Int
J Eat Disord 2006, 39, 2, 87–100.
[7] Devaskar SU: Neurohumoral regulation of body weight gain. Pediatr Diabetes 2001, 2, 131–144.
[8] Inui A: Eating behavior in anorexia nervosa – an excess of both orexigenic and anorexigenic signaling? Mol
Psychiatry 2001, 6, 620–624.
[9] Ericsson M, Poston WSC, Foreyt JP: Common biological pathways in eating disorders and obesity. Addict
Behav 1996, 21, 6, 733–743.
[10] Gendall KA, Kaye WH, Altemus M, McConaha CW, La Via MC: Leptin, neuropeptide Y, and peptide YY in
long−term recovered eating disorder patients. Biol Psychiatry 1999, 46, 2, 292–299.
[11] Polivy J, Herman CP: Causes of Eating Disorders. Ann Rev Psychol 2002, 53, 187–213.
[12] Brambilla F, Monteleone P, Bortolotti F, Dalle Grave R, Todisco P, Favaro A, Santonastaso P, Ramacciotti C,
Paoli R, Maj M: Persistent amenorrhea in weight−recovered anorexics: psychological and biological aspects.
Psychiatry Res 2003, 118, 3, 249–257.
[13] Inui A, Meguid MM: Ghrelin and cachexia. Diabetes Obes Metab 2002, 4, 431.
[14] Dulloo AG, Samec S: Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism recon−
sidered. Br J Nutr 2001, 86, 2, 123–139.
[15] Heiling M, Widerlov E: Neuropeptide Y: an overview of central distribution, functional aspects, and possible
involvement in neuropsychiatric illnesses. Acta Psychiatr Scand 1990, 82, 95–114.
[16] Lambert PD, Wilding JPH, Al−Dokhayel AAM, Gilbey SG, Ghatei M A, Bloom SR: Naloxone−Induced
Anorexia Increases Neuropeptide Y Concentrations in the Dorsomedial Hypothalamus: Evidence for
Neuropeptide Y – Opioid Interactions in the Control of Food Intake. Peptides 1994, 15, 4, 657–660.
[17] Heinrichs SC, Menzaghi F, Pich EM, Hauger RL, Koob G: Corticotropin−releasing factor in the paraventricu−
lar nucleus modulates feeding induced by neuropeptide Y. Brain Res 1993, 611, 18–24.
[18] Hamson ES, Dallman MF: Neuropeptide Y (NPY) May Integrate Responses of Hypothalamic Feeding Systems
and the Hypothalamo−Pituitary−Adrenal Axis. J Neuroendocrinol 1995, 7, 273–279.
[19] Rohner−Jeanrenaud F: A neuroendocrine reappraisal of the dual−centre hypothesis: its implications for obesity
and insulin resistance. Int J Obes 1995, 19, 517–534.
[20] Broberger C: Brain regulation of food intake and appetite: molecules and networks. J Intern Med 2005, 258:
301–327.
[21] Adan RA, Vink T: Drug target Discovery by pharmacogenetics: mutations in the melanocortin system and eat−
ing disorders. Eur Neuropsychopharmacol 2001, 11, 6, 483–490.
[22] Westrin A, Engstom G, Ekman R, Traskman−Bendz L: Correlations between plasma – neuropeptides and tem−
perament dimensions differ between suicidal patients and healthy controls. J Affect Disord 1998, 49, 1, 45–54.
[23] Horvath TL: Endocannabinoids and the regulation of body fat: the smoke is clearing. J Clin Invest 2003, 112, 3,
323–326.
[24] Davis C, Claridge G: The eating disorders as addiction: a psychobiological perspective. Addict Behav 1998, 23,
4, 463–475.
[25] Müller EE, Cavagnini F, Panerai AE, Massironi R, Ferrar E, Brambilla F: Neuroendocrine measures in anorex−
ia nervosa: comparisons with primary affective disorders. Adv Biochem Psychopharmacol 1987, 43, 261–271.
576
M. ŚMIAROWSKA, M. BIAŁECKA, K. KORWIN−PIOTROWSKA
[26] Yang YK, Hormon CM: Recent developments in our understanding of melanocortin system in the regulation of
food intake. Obes Rev 2003, 4, 239–248.
[27] Slopień A, Robakowski F, Dmitrzak−Weglarz M, Czerski P, Hauser J, Komorowska−Pietrzykowska R,
Rajewski A: TNF−α and intPLA2 genes’ polimorfizm in anorexia nervosa. Acta Neuropsychiatr 2004, 16, 290–294.
[28] Branson R, Potoczna N, Kral JG, Lentes KU, Hoehe MR, Horber FF: Binge eating as a major phenotype of
melanocortin 4 receptor gene mutations. N Engl J Med 2003, 348, 12, 1096–1103.
[29] Garcia R: Stress, metaplasticity, and antidepressants. Curr Mol Med 2002, 2, 7, 629–638.
[30] Ribases M, Gratacos M, Fernandez−Aranda F, Bellodi L, Boni C, Anderluh M, Cavallini MC, Cellini E, Di
Bella D, Erzegovesi S, Foulon C, Gabrovsek M, Gorwood P, Hebebrand J, Hinney A, Holliday J, Hu X,
Karwautz A, Kipman A, Komel R, Nacmias B, Remschmidt H, Ricca V, Sorbi S, Wagner G, Treasure J,
Collier DA, Estvill X: Association of BDNF with anorexia, bulimia and age of onset of weight loss in six
European populations. Hum Mol Genet 2004, 13, 12, 1205–1212.
[31] Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H,
Shinoda N, Okada S, Iyo M: Alterations of serum levels of rai−derived neurotrophic factor (BDNF) in depressed
patients with or without antidepressants. Biol Psychiatry 2003, 54, 1, 70–75.
[32] Hashimoto K, Koizumi H, Nakazato M, Shimizu E, Iyo M: Role of brain−derived neurotrophic factor in eating
disorders: recent findings and its pathophysiological implications. Prog Neuropsychopharmacol Biol Psychiatry
2005, 29, 4, 499–504.
[33] Baoji Xu, Gouldig EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt LF: Brain−derived neu−
rotrophic factor regulates energy balance downstream of melanocortin−4 receptor. Nat Neurosci 2003, 6, 7, 736–742.
[34] Lee J, Seroogy KB, Mattson MP: Dietary restriction enhances neurotrophin expression and neurogenesis in the
hippocampus of adult mice. J Neurochem 2002, 80, 3, 539–547.
[35] Nakazato M, Hashimoto K, Shimizu E, Kumakiri C, Koizumi H, Okamura N, Mitsumori M, Komatsu N,
Iyo M: Decreased levels of serum brain−derived neurotrophic factor in female patients with eating disorders. Biol
Psychiatry 2003, 54, 4, 485–490.
[36] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese
gene and its human homologue. Nature 1994, 372, 6505, 425–432.
[37] Harvey J, Ashford MLJ: Leptin in CNS: much more than satiety signal. Neuropharmacology 2003, 44, 845–854.
[38] Cummings DE, Schwartz MW: Genetics and pathophysiology of human obesity. Ann Rev Med 2003, 54,
453–471.
[39] Wrenn CC, Crawley JN: Pharmacological evidence supporting a role for galanin in cognition and affect. Prog
Neuropsychopharmacol Biol Psychiatry 2001, 25, 283–299.
[40] Burdakov D, Liss B, Ashcroft FM: Orexin excites GABAergic neurons of the arcuate nucleus by activating the
sodium−calcium exchanger. J Neurosci 2003, 23, 12, 4951–4957.
[41] Flier JS: Obesity Wars: Molecular progress confronts an expanding epidemic. Cell 2004, 116, 337–350.
[42] List JF, Habener JF: Defective melanocortin 4 receptors in hyperphagia and morbid obesity. N Engl J Med 2003,
348, 1160–1163.
[43] Lonnqvist F, Nordfors L, Schalling M: Leptin and its potential role in human obesity. J Intern Med 1999, 245,
643–652.
[44] Monteleone P, Martiadis V, Colurcio B, Maj M: Leptin secretion is related to chronicity and severity of the ill−
ness in bulimia nervosa. Psychosom Med 2002, 64, 6, 874–879.
Address for correspondence:
Małgorzata Śmiarowska
Broniewskiego 26
71−460 Szczecin
Poland
Tel.: +48 91 45 40 701
Conflict of interest: None declared
Received: 18.06.2007
Revised: 28.06.2007
Accepted: 28.06.2007