Abstract

M

Ś

, M

B

, K

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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_{Department of Psychiatry Pomeranian University of Medicine, Szczecin, Poland} 2_{Department of Pharmacology Pomeranian University of Medicine, Szczecin, Poland}

Adv Clin Exp Med 2007, 16, 4, 569–576 ISSN 1230−025X

REVIEWS

© Copyright by Silesian Piasts University of Medicine in Wrocław

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 eatingoraz 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].

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 Centrally−derived mediators Peripherally−derived mediators behaviour (Syntetyzowane w o.u.n.) (Syntetyzowane obwodowo)

(Wpływ activating inhibiting activating inhibiting

na łaknienie) (pobudzający) (hamujący) (pobudzający) (hamujący)

Peptides MCH, NPY, AGRP ACTH, α−MSH, ghrelin GLP−1, CCK, galanin,

(Peptydy) TRH, CRH, galanin, insulin, bombesin,

urocortin, CART, PYY, NPY

BDNF Opioids β−endorphin, dynor−

(Opioidy) phin A, enkephalins Hypocretins OXA i OXB (Hipokretyny)

Biogenic amines norepinephrine dopamine, serotonin, serotonin

(Aminy biogenne) neurotensin

Amino acids glutamate, NMDA,

(Aminokwasy) GABA

Cytokines TNF−α, IL−1β, leptin

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),

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 – βendorphin, 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, βMSH – α, βmelanocortins, 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, βMSH – α−melanotropiny αiβ, 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

suprarenal glands nadnercza

AGRP digestive tract

NPY, ghrelin p. pokarmowy

NPY, grelina

digestive tract GLP−1, GAL,

PYY, CCK, insulin

insulina p. pokarmowy anabolic parhway of CNS:

szlak anaboliczny o.u.n.: OREXIGENIC agents

OREKSYGENICZNY

NPY (Y R, Y R)1 5 Agouti,AgRP, mahogany syndecan opioids: β−EP,MCH

OXA, OXB (hipocretins)

galanin galanina

glutamate−NMDA, GABA

NA

catabolic parhway of CNS: ANOREXIGENIC agents szlak kataboliczny o.u.n.:

ANOREKTYCZNY

POMC, melanocorins (α,βMSH) CART

neurotensyna, GLP −1, CRH (CR R, CR R)1 2 TRH, urocortin, insulin (IR)

CNTF malonyl Co−A

DA(D1/D5, D2−D4),BDNF −HT(5−HT2C)

tkanka tłuszczowa

LEPTYNA (grupa cytokinIL−6), ADIPONEKTYNA IL−1β

–

– +

+

+

n. X

cytokines: cytokiny:

TNF−α n. X apidose tissue

LEPTiN (cytokinesIL−6 group), ADIPONECTIN

opioidy: β−EP,MCH

OXA, OXB (hypokretyny)

glutaminian−NMDA, GABA

POMC, melanokortyny(α,βMSH) CART neurotensin, GLP−1, CRH (CR R, CR R)1 2

TRH, urokortyna, insulina (IR)

+

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

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

SNS (βrec)

CRH, CART, POMC (α,βMSH)glutamate

IL−1, TNF−α

MC4R

↓appetite

+

+ BDNF

5−HT2C +

NPY(Y1, Y5R)

AGRP/GABA

−

SNS PNS

hormones, digestive tract, insulin hormony, przewód pokarmowy, insulina

+ –

+

↑PPM (UPC)

+

+

+

insulin, ghrelin insulina, grelina

↓PPM (UPC)

+

CD4

PG

–

+ – –

starvation, exercise głodzenie, wysiłek

CRH, CART, POMC (α,βMSH)glutaminian

↓łaknienie )

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

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

POMC

melanocortines melanokortyny:

ACTH =αMSH =βMSH >γMSH homeostasis of body weight the agonists of

homeostaza m. c. agoniści

reduction of anorexia related with neo hyperplasia (TNF),

reduction of the cancerous cachexia zmniejszenie hipofagii związanej ze wzrostem neo (TNF),

zmniejszenie kacheksji nowotworowej

MC3,4R

blocade in mice blokada u myszy

eating behaviour, metabolism, energy expenditure, satiety zachowania żywieniowe, metabolizm, wydatkowanie energii, sytość

AGRP overexpression nadmierna ekspresja AGRP

β

−endorphins

endorfiny

( −EP) ( −EP)

β β

β

−

lipotropins lipotropiny

hypothalamus: AC, NTS podwzgórze: AC, NTS

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

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].

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