21 - Aracne · tryptophan is made available according to Le Châtelier’s equilibrium (367,402)....

ACKNOWLEDGMENTSWe thank Michele Colletti for the assistence and we were grateful to the subjects who participated inthe study

ARACNE

Role of the Neurotransmitters and Peptides Involved in Feeding Behaviour Control

Maurizio La Guardia / Santo Giammanco / Marco Giammanco

UNIVERSITÀ DI PALERMOFISIOLOGIA E NUTRIZIONE UMANASezione del Dipartimento DIMPEFINU

ASSISTED BY THE FOLLOWING MEMBERS:Cecconi M. PHD – University of Palermo

Chiazzese F. – Graduated PharmacyDi Majo D. PHD – University of Palermo

Polidori P. – Graduated Pharmacy

Copyright © MMVIIARACNE editrice S.r.l.

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I edizione: febbraio 2007

Role of the Neurotransmitters and Peptides Involved in feeding behaviour control

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CONTENTS

I. INTRODUCTION pag. 7 II. CENTRAL FEEDING BEHAVIOUR CONTROL pag. 8 III. NEUROTRANSMITTERS

A. Tryptophan and Serotonin pag 10 B. Noradrenaline pag. 15 C. Dopamine pag. 16 D. γ-aminobutyric Acid pag. 17 E. Nitric Oxide pag. 18

IV. PEPTIDES 1- PEPTIDES ACTING AS PERIPHERAL SIGNALS A. Leptin pag. 21 B. Insulin pag. 24 C. Glucagon and Glucagon-like Peptides pag. 26 D. Cholecyistokinin pag. 27 E. Bombesin Homologous Peptides pag. 28 F. Amylin and Calcitonin Gene Related Peptide pag. 29 G. Ghrelin pag. 30


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2- ANOREXANT PEPTIDES FROM NEURONS IN THE CNS

A. Melanocytes Stimulating Hormone pag. 31 B. Cocaine and Amphetamine Regulated Transcript pag. 32 C. Corticotropin Releasing Factor and Glycocorticoids

pag. 33

D. Neurotensin pag. 37 E. Oxytoicin pag. 37 F. Thyrotropin-releasing hormone pag. 38

3- PEPTIDES INDUCING FOOD INTAKE

A. Neuropeptide Y pag. 39 B. “Agouti” Related Protein pag. 40 C. Endogen Opioids pag. 41 D. Orexins A and B (Respectively Hypocretin 1 and 2) pag. 42 E. Melanine Concentrating Hormone pag. 44 F. Growth Hormone Releasing Hormone pag. 45 G. Galanin pag. 45

V. OTHER FACTORS AFFECTING FOOD INTAKE IN DIFFERENT PATHOLOGIES: CYTOKINES

pag. 46

VI. CONCLUSIONS pag. 48 VII. REFERENCES pag. 49


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I. INTRODUCTION

Recently, researchers have invested greater interest in studies concerning body-weight, appetite, and feeding behaviour illnesses. The development of new theoretical models has rendered problems more complex, especially in relation to etiopathogenesis, nosographic classification and to therapeutic strategies. A great number of clinical and experimental studies have brought to light many scarcely known aspects of feeding behaviour, showing the essential neuropeptide and neurotransmitter role. In particular, the so called aminostatic mechanism has been widely accepted, highlighting the close relationship between the serotoninergic system and feeding behaviour, thus allowing an effective therapeutic approach to some clinical conditions. Also the role of hypothalamic peptides in food intake control and energy consumption has recently received greater attention. This work analyses the central regulation feeding behaviour mechanisms; the neurotransmitter and neuropeptide roles are treated in this context given that the great amount of data leads to the expectation of future developments of feeding behaviour regulating substances.


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II. CENTRAL FEEDING BEHAVIOUR CONTROL

As known, animals are able to control food intake according to their own energy requirements. Although not everything is known yet on the control mechanisms, it is commonly believed that such ability is part of the control mechanisms of the energy balance. Now classic experimental studies have shown that food intake is controlled by hypothalamic suprahypothalamic centers. There are hypothalamic areas in: the lateral area (LHA), ‘hunger center’ and the ventromedial nucleus (VMN), ‘satiety center’; inhibition of the hunger center after feeding causes ‘satiety sensation’ (6, 161). Researchers, concerning feeding behaviour, have not only focused their attention on the hypothalamus, but they have also studied the effects of electrical stimulations on limbic system structures. In particular electrical stimulations of the dorsal hippocampus induce, in experimental animals (rabbits or monkeys), both short term and long term increment of food intake and body weight as well as (124, 125, 126, 127, 129, 130, 131, 132, 133, 135, 136). The hippocampus is part of Papez’s emotional circuit (hippocampus, via fornix, mammillary bodies and hypothalamus, via Vicq D’Azyr’s mammillo-thalamic bundle, anterior thalamus, via thalamic projections to the limbic cortex, V temporal convolution, hippocampus) (302); such a circuit represents the anatomical substrate that explains the limbic system influences on the hypothalamus. On the other hand, also the hippocampus is sensible to glycemic levels: in fact this structure has shown electrical activity changes during hypoglycemia (128, 134). As said before, although neurophysiological studies have the great merit of having allowed to locate the anatomical structures involved in feeding behaviour control and to explain –though roughly, their functions, they could not shed any light on the finer food intake mechanisms. In particular it was not possible to find out how the hypothalamus is able to keep long-term energy reserve amounts fairly constant. Even before food is tasted, smell, food appearance, thinking about it, along with factors connected to the environment trigger reflexes (conditioned reflexes) that have noticeable effects on numerous functions of the gastro-intestinal apparatus. Subsequently even food taste and texture influence feeding behaviour (25, 77). Such factors add up to the responses –the nervous inputs, coming from the mechanoceptors and chemoceptors of the


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digestive system and are determined by metabolic and endocrine variations, which induce food intake or lead to it (31). Nervous inputs are sent to the central nervous system (CNS) through the glossopharyngeal, facial, trigeminal and vagus nerves; such information represents a first class of signals acting on the CNS, which, as reply, induces food intake reduction (‘post-ingestive’ control of feeding behaviour) (31,275,399). Food intake interruption is influenced by gastric wall distention, always through the vagus afferences, which are followed by the release of peptide intestinal factors (cholecystokinin, CCK), able to influence the CNS (31,275,343,399). During the ‘post-absorptive’ phase, the nutrients carried to the peripheral tissue constitute a second class of signals (metabolic signals) for the CNS. Here we have: glucose, free fatty acids (FFA), and several amino acids (AA) like tryptophan and large neutral AA (LNAA) (31,218,246). Glucose represents the most classical example. According to Mayer’s glycostatic theory, a large artero-venous difference in glycemic levels determines fullness sensation due to the VMN glycoceptor stimulations; instead its reduction induces hunger, independently of the absolute glycemic levels (246). The AA role in regulating food intake has been confirmed by experimental data supporting the hypothesis where variations in AA plasma levels can affect the availability of AA –cerebral neurotransmitter precursors, involved in feeding behaviour (218,401,402,403). Tryptophan –precursor of the neurotransmitter serotonin or 5-hydroxytriptamine (5-HT), is considered an anorexiant substance (56,218). We will see how the role covered by (essential) phenylalanine and tyrosine in feeding behaviour control is not as important as that carried by tryptophan, though these AA, being noradrenaline adrenaline and dopamine (DA) precursors, are also food intake regulating neurotransmitters. Also pancreas hormones as leptin, which will be discussed in the following pages, are to be considered as ‘post-absorptive’ signals. The CNS reacts to all these signals through peptide synthesis, inducing or inhibiting energy dispersion (through the vegetative nervous system) thus controlling food intake (199,230,318). In synthesis, nerve and humoral afferences produced in the ‘post-ingestive’ and ‘post-absorptive’ phase induce CNS synthesis and release of numerous neurotransmitters and neuropeptides involved in feeding behaviour control.


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III. NEUROTRANSMITTERS

A. Tryptophan and Serotonin

Tryptophan is a neutral, essential, monoamino, monocarboxyl, heterocyclic amino acid. Besides being needed for protein synthesis, it can be converted in nicotinic acid (PP vitamin) and in serotonin (5-HT). It’s mainly metabolized by the liver (therefore influenced by hepatocyte functionality) and to a lesser extent by the brain (19). Tryptophan concentration in plasma, along with other factors (see ahead) also depends on the hepatic activity of the tryptophan pyrrolase (TRPO) involved in the metabolism of tryptophan leading to kynurenine and nicotinic acid formation (19). In normal subjects, about 1-2% of the amino acid ingested with food is transformed in 5-HT. However such a quota can reach 60% in patients suffering from intestinal carcinoma (304). Drugs capable of increasing hepatic TRPO activity, such as glucocorticoids, or conditions where the secretionary increment of the latter occurs (stress), take tryptophan from the metabolic pathway leading to 5-HT synthesis to the one leading to kynurenine nicotinic acid formation (304). Circulating tryptophan binds through a non covalent-bound with plasma albumin in such a way that only 10% of the tryptophan is free and readily diffusible (152); the bounding is fairly specific, though some metabolites compete for it, e.g. FFA: a variation of the plasma levels of the latter is capable of changing the free tryptophan amount, which, in turn, can go in the brain to form 5-HT; it is then believed that FFA are, at least in part, intermediaries of the insulin effect on the plasma tryptophan levels (106, 321). After feeding, the increment of insulin plasma levels allows AA to enter muscle tissue; however being tryptophan the only albumin bound amino acid, it will be less liable to enter muscles tissue; this implies a relative increment of the total tryptophan proportion but not of the free tryptophan; furthermore insulin frees albumin from its FFA bounds (facilitating FFA entrance in the adipocytes) thus allowing free tryptophan molecules to bind with albumin. As the concentration of free plasma tryptophan decreases, it is partially reconstituted through other tryptophan molecules spreading from other tissues as the skeleton muscle; furthermore part of the albumin-bound tryptophan is made available according to Le Châtelier’s equilibrium (367,402). In any case the concentration of free and total tryptophan is


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greater than the other neutral AA, due to the fact that the latter goes in muscle tissue. Only the free tryptophan present in the blood is able to cross the hematoencephalic barrier (HEB). Tryptophan entrance in the brain is also influenced by the concentrations of other neutral amino acids: veline, leucine, isoleucine, phenylalanin, tyrosine and methiosine, which share in a competitive way with tryptophan the same specific transportation system across the HEB (106,322,401,402,403). The brain amino acid pool is very different than the plasma pool; not only some AA are only present in the brain (γ-aminobutyrric acid), but also other AA are present in the brain a remarkably greater concentration than in the plasma (glutamate, glutamine, aspartate). The brain captures plasma AA at a fast rate yet it discharges them at a similar rate, making sure that the pool composition remains constant. Amino acid uptake is an active transportation phenomenon; as far as the plasma secretion is concerned, although is an active mechanism, transportations is largely mediated by a carrier exchange in the uptake without energy consumption. Five AA transportation systems were identified on the basis of in vitro studies: one for acidic AA, one for basic AA, one for β-AA, two for neutral AA, in a similar way to what happens in the kidneys and intestine. As far as neutral AA are concerned, the systems are three but one of those (A-alanine system) involves only secretion not uptake (322). In the CNS, the tryptophan captured within the serotoninergic termination is hydroxylated to 5-OH-tryptophan and then decarboxylated to 5-HT (19). There are two different tryptophan hydroxylase (TRPH) isoforms –the enzyme considered the factor limiting 5-HT synthesis, the first isoform is found in the epiphysis, retina, stomach, spleen and thymus, the second (neuronal) is typical of the raphe (386). In physiological conditions, the 5-HT synthesis rate mainly depends on its cerebral precursor’s concentration. A controlling factor for cerebral 5-HT cerebral biosynthesis is the plasma ratio between tryptophan and LNAA –being competitors for the same carrier which transports them from the plasma to the brain (367,401,402,403). Tryptophan systemic administration increases of the cerebral concentration of 5-HT and its metabolite 5-OH-indolacetic acid (5-HIAA) (218). Summarizing, tryptophan cerebral levels are determined by at least three factors: 1. Plasma free tryptophan levels (not albumin bound); 2. Plasma molar ratio between free tryptophan and other LNAA competing

with tryptophan for access to the brain;


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3. Activity of the common transportation system across the HEB. Consequently changes may take place to the feeding behaviour when some clinical or experimental conditions, influencing one or more of the above factors, affect tryptophan availability to the brain (1,48,206,225,323). In fact the serotoninergic system seems to have the more relevant action of the two neurotransmission systems, the catecholaminergic and the serotoninergic, involved in hypothalamic feeding behaviour control (Table-1). The reason lies in the different characteristics of the serotoninergic hydroxylases which transform 5-HT and tyrosine respectively into 5-OH-tryptophan and DOPA. Unlike tyrosine hydroxylase, TRPH, due to its high dissociation constant, cannot be saturated to tryptophan physiological concentrations; this implies that the amount of 5-HT synthesis depends on the tryptophan available and, since the latter car vary remarkably, 5-HT levels undergo substantial variations even in physiological conditions (107). It has been known for sometime that 5-HT inhibits feeding behaviour (219,222,225). Tests carried through the central administration of exogenous 5-HT or drugs releasing endogenous 5-HT or one of its precursors –tryptophan or 5-OH-tryptophan, strongly support the idea that the serotoninergic system is able to reduce the amount of food intake by increasing the sensation of fullness (219). In particular it is known that 5-HT affects both the energetic balance and the circadian food intake rhythm activating satiety neurons sited in the medial hypothalamus (219,225). 5-HT reduces the amount of food intake, the length and speed of meals, while it does not influences the latency of the beginning of meals or the meal frequency (219,225); this suggests that 5-HT produces sense of satiety, rather than appetite inhibition, that is the beginning of the meal. Besides, the serotoninergic antagonists preferably reduce carbohydrates intake scarcely effecting protein intake (219,225,402). Actually, carbohydrate intake, through an increment of the insulinemia levels increases plasma tryptophan and then cerebral 5-HT inducing, in turn, meal cessation or, at least, guiding the next feeding choice towards proteins (222). On the contrary, protein ingestion lowers 5-HT cerebral levels. This can be explained since tryptophan is the least abundant of the amino acids among the proteins ingested as food so its relative plasma increment is less that the increment of the competitive amino acids (105).


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The aforementioned data support the so called ‘aminostatic hypothesis’ for feeding behaviour control; that is, besides glycemia, also changes in plasma amino acid concentration give rise to metabolic signals affecting feeding behaviour. However also the aminostatic hypothesis does not explain how the hypothalamus can regulate long term body composition. There is, as brought out by specific studies, a different action of 5-HT on feeding behaviour, according to the receptor subtypes set in different cerebral areas: in fact, there are presynaptic receptors 5-HT1A in the raphe median nucleus, which, when activated, determine hyperphagia (20,87,384), while receptors (5-HT1B/2C) responsible for food consumption reduction are to be found in the hypothalamus shown in Table 1 (32,81,87,216,222) . Mice –knockout for the gene of receptor 5-HT1B, eat and weigh more than the control group (28). The 5-HT effect on feeding behaviour must be understood as part of a wider influence of this neurotransmitter on energy balance. In fact, its administration in the VMN determines an increment of the orthosympathetic system activity with respect to the brown adipose tissue (328) and also increases O2 consumption (215). Besides the ‘classical’ hypothalamic control centers for food intake and energy consumption, there are other diencephalic structures involved in feeding behaviour control. The hippocampus is connected to the hypothalamus through the fornix –a nervous pathway that is part of Papez’s emotional circuit and is formed by the following structures: hippocampus, via fornix, mammillary bodies and hypothalamus, via Vicq D’Azyr’s mammillo-thalamic bundle, anterior thalamus, via thalamic projections to the limbic cortex, V temporal convolution, hippocampus (302). The electrical stimulation of one of these structures induces an increment of food consumption in experiment animals; in particular, electrical stimulation of the dorsal hippocampus in rabbits (125) and monkeys (124,130), as well as irritative alterations of the rabbit hippocampus (109), remarkably increase food intake and body weight. Posterodorsal amygdala damage induces food intake in rats; such a condition reduces the orexia effect of 5-HT1A agonists (72), implying that this structure can be considered a ‘satiety center’ activated by 5-HT pathways; if the center is damaged the orexia effect of the drug is reduced since it only acts on the hypothalamus ‘satiety center’. 5-HT inhibits food consumption also by integrating with feeding behaviour control systems; in fact serotoninergic receptors are present in several


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neurons that release other substance involved in feeding behaviour (66). Clinical studies showed that oral 5-OH-tryptophan administration can reduce food intake in obese patients not subject to caloric diets (56), can favour compliance to hypocaloric diets (48) and reduce carbohydrate craving in non insulin-dependent diabetic patients, thus confirming the 5-HT role in the choice of macronutrients (225). Finally, anorexia onset in cancer patients seems to be correlated to tryptophan increment of the plasma and the liquor (47,253,277).

B. Noradrenaline

As early as the 60’s, some studies showed food intake increments in sated rats that had been administered noradrenaline (NA) in the anterior lateral hypothalamus (142). Through successive pharmacological studies, the noradrenaline system has shown opposite effects on feeding behaviour control according to where it acts. NA promotes food intake when injected in the hypothalamus* paraventricular nucleus (PVN) (Table-1); such effect is linked to the activity of α2-postsynaptic adrenergic receptors; α2-adrenergic stimulation induces food intake during meals and determines a preferential ingestion of food rich of carbohydrates (224). Given these effects NA, through its α2-noradrenergic receptors, interacts antagonistically with 5-HT (225). α2-agonists drugs (clonidine) inhibit adenylate cyclase in the PVN neurons and such effect is counteracted by selective antagonists (54). Instead α-blocking drugs cause a

* After pharmacological studies on the administration of agonists and antagonists in the rat

intracerebro-venticular area or directly on the hypothalamus, many consider the PVN the ‘satiety center’ (45). Actually it is very difficult to establish whether the VMN or the PVN is the ‘satiety center’; in fact, it is true that VMN damage could be associated with the interruption of important nerve pathways and this could invalidate Heterington and Ranson remarkable results obtained in the 40’s, but it is true as well that neurotransmitter or drug central administrations do not demonstrate that the PVN is the ‘satiety center’ for at least two reasons: a) the drug or neurotransmitter administered dose could be excessive or, on the contrary, insufficient; b) drug diffusion to the nearby centers dare not avoidable no matter how skilled the researcher be, the observed effect could be caused by the activation or inhibition of other hypothalamus nuclei instead of the action of the substance on the PVN; in particular, this is relevant in rats, where the PVN is remarkably thin. Such limitations were highlighted by Leibowits herself (45) who sustained the importance of the realization of this type of experiments.


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reduction in carbohydrate ingestion (4). Then it is possible to hypothesize that PVN α-adrenergic receptors are involved in controlling diet composition and in particular carbohydrate percentages with respect to proteins, slowing down or inhibiting carbohydrate satiety rather then stimulating hunger or meal onset. The afferent pathways of this noradrenergic system come from the PVN level on dorsomedial direction, cross the thalamus preventricular area then descend to the central midbrain gray matter, through the pons and then continue towards the dorsal vagus complex (388). Moreover the very same NA causes the suppression of feeding behaviour in β-adrenergic mediated circuits set in the lateral hypothalamus; administering agonists on β2-adrenergic receptors reduces food intake in rats and such effect is blocked if these receptor antagonists are administered in the perifornix area (26). NA and adrenaline stimulate food intake when they act on the hypothalamus paraventricular nucleus, but they are anorexiant when they act on the adrenergic receptors in the hypothalamus perifornix area (219). Both 5-HT and NA, not only reduce food intake, but also they increase sympathetic activity (32). The relation ‘food intake – sympathetic activity increment’ suggests that effects of the neurotransmitters on feeding behaviour must be seen within the wider function of energetic balance regulation: the sympathetic activity increment following food intake aims at dispersing the introduced energy. Instead, when energy is low, sympathetic activity does not increase thus contributing to limit energy dispersion.

C. Dopamine

Up to now dopamine (DA) action on food intake control has not been well defined since DA researches are difficult because the neurotransmitter is also involved in animal motorial behaviour (272). It is fundamental to consider DA action site. Experimental trials carried by injecting DA in hypothalamus perifornix area have produced anorexia mainly for proteins, as well as a specific interference with meal onset (219,220,223). Initially experimental data indicated the receptor D2 as responsible for anorexia; in fact the administration of a D2 agonist led to food intake reduction; while a D1 agonist did not cause any effect on feeding


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behaviour; furthermore administrations of D2 antagonists (Table-1) in the perifornix area increased food intake (54, 303). Recently it has been shown D1-D2 cooperation in mediating the aforementioned effect (204). Finally, using knockout mice for the gene of the receptor D3, it was brought out that also this receptor has a function in food intake control, above all by inhibiting lipid ingestion (252). The DA function on the base nuclei and in the accumbens nucleus in particular has altogether a different meaning: this was shown by using knockout mice for the gene of tyrosine hydroxylase. These hypokinetic, aphagic and adipsic animals, after having been administered l-DOPA, temporarily acquired the motorial ability needed to feed themselves, however they ingested a definitely insufficient amount of food (366,411). Genic therapy restores the ability to normally feed (365). Furthermore DA turns out to be essential for animal survival.

D. γ-aminobutyric Acid

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is present in high concentrations in the lateral hypothalamic area (79). It stimulates food intake when injected in the VMN, and reduces it when injected in the LHA, as shown in Table 1 (187,188). Insulin induced hypoglycemia determines GABA reduction in the lateral hypothalamic area (thus disinhibiting the hunger center) and determines GABA increment in the vetromedial hypothalamus (increasing inhibition in the neuronal system) (188,194); thus it has been thought this GABAergic system could be the one that connects the hunger to the satiety center. Muscimol injections (GABAergic agonist) in the vetromedial nucleus lead to an increment of food consumption (219); bicuculline (GABAergic antagonist) antagonizes muscimol and also noradrenaline hyperphagic outcomes (189). Though partially, bicuculline antagonizes ß-endorphine induced hyperphagia (71). Given that there is specificity in removing inhibition on the satiety center from phentolone (α-adrenergic antagonist) for noradrenaline and from naloxone for ß-endorphine while the bicuculline effect is aspecific, it is supposed that GABA is the terminal neurotransmitter of an interconnection system between the hunger and the satiety center (53). Recently, a population was found with an association between the increment of activity of the gene encoding for the glutamic acid decarboxylase enzyme


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(GAD2) and favors obesity; it has been hypothesized that the increment in the hypothalamus GABA pool and its consequent orexia, could be responsible for changes in feeding behaviour and that GAD2 could be the obesity gene (27).

E. Nitric Oxide

More than 15 years ago it was shown that endothelial cells synthesize and release several factors, Nitric Oxide (NO) is among those (174). It is a highly labile gaseous substance with a short half-life (3-5”) and a powerful vasodilator and platelet-aggregator. Since then a wide array of data has shown how also cells from other tissues, neurons included, release this substance. The enzyme addressed to its synthesis is NO synthase (NOS) that is functional starting from the amino acid arginine (266). NO is not enclosed in vesicles, but being a gas is able to easily cross cell membranes and quickly spread without any specialized carriers and without the interaction of membrane receptors. This way, not needing a close anatomical juxtaposition, NO affects many nearby cellular elements. NO stimulates cyclic guanosine monophosphate (cGMP) synthesis, which, in turn, determines effects that depend on the cell in which it resides. The discovery that NO works as a CNS neurotransmitter (116) has changed the classical concept of chemical neurotransmission where information is passed from a presynaptic neuron to a postsynaptic neuron; in fact according to the most accredited hypothesis the postsynaptic cell releases NO in the CNS in reply to an intracellular Ca++ increment (113). In this context the glutamatergic receptors, N-metyl- D-aspartate (NMDA) exitors that have an ionic Ca++ gain a particular relevance. One of the functions ascribed to NO in the CNS is feeding behaviour control. NO is thought to induce food intake (274). In rats, lack of food increases nNOS activity (355) and administering nNOS inhibitors reduces food intake (357), even in fasting animals (45). NO anorexigenic activity can be mediated by several neurotransmitter systems. Administering nNOS inhibitors increases cerebral 5-HT (355,356). Furthermore NO irreversibly inactivates tryptophan hydroxylase (203). Experimental results show that high concentration of cerebral NO increase HEB permeability to GABA (351). It has been reported that NO stimulates GABA release through the increment of K+ (341) or through peroxynitrite


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formation, which, in turn is formed by a reaction of NO with a superoxide (292). Leptin, an anorexigenic peripheral peptide, inhibits NOS activity; L-arginine, a NO precursor, counteracts leptin effects on food intake and body weight, implying that it may modulate the serotoninergic function by inhibiting the activity of diencephalic nNOS. In fact L-arginine icv administrations counteract leptin action on 5-HT turnover, while peripheral L-arginine administrations do not alter leptin effect on food intake, indicating that leptin effects are mediated by the inhibition of NO formation in the brain. Furthermore both peripheral and central leptin administrations increase 5-HT turnover thanks to nNOS activity (44). In knockout mice for the nNOS gene, leptin inhibiting effects on food intake are less than in wild animals, implying that such inhibiting effects are partly mediated by the inhibition of NO synthesis in the brain (45).


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IV. PEPTIDES

In the last 10 years, a noteworthy amount of work has brought up the importance of several peptides in feeding behaviour control. The remarkable increase of knowledge in this field has brought numerous researches to individualize agonists and antagonists for these peptide receptors with the purpose of gaining new weapons for the treatment of feeding behaviour disorders; most likely in a near future, anorexia and bulimia therapy will employ these very same drugs. Many peptides are present in peripheral cerebral regions normally associated with feeding behaviour control. Some of the above are synthesized and released by peripheral structures above all in the digestive tract: the presence of food in the gastro-intestinal tract acts as a satiety signal and several indications suggest that hormones released by stomach and intestine could act as peripheral satiety signals CNS (30,31,275,343). Prevalently hypothalamic neurons synthesize and secrete several peptides; micro-inoculating some peptides in specific cerebral areas can cause feeding-behavioural changes (30). In synthesis, leptin, insulin, glucagon, CCK, bombesin, somatostatin, melanocyte stimulating hormone (α-MSH), the Cocaine peptide and Amphetamine Regulated Transcript (CART), corticotrophic releasing hormone (CRH), the thyrocotrophic releasing factor (TRH), neurotensin and oxyticin inhibit food intake; opiates, the neuropetide Y (NPY), the orexins, galamin, the melanin concentrating hormone (MCH), ghrelin and the growth hormone releasing hormone (GHRH) increase food intake. The interaction that the neuropeptides have among themselves and with neurotransmitters must be fully recognized in order to fully understand their functions in food consumption.


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1- PEPTIDES ACTING AS PERIPHERAL SIGNALS

A. Leptin

As said, body weight is controlled by counter-regulating physiological mechanisms determining reductions in food ingestions whenever increments in food assumption take place. Since animals, in normal conditions, are able to regulate their own body weight, a peripheral signal is needed to inform the CNS on the entity of the energy reserves of the organism. The glucostatic and the aminostatic hypothesis explain the reduction in food intake after feeding, but they cannot explain how peripheral signals inform the hypothalamus on the entity of the organism’s energy reserves. The answer to this fundamental problem came with the identification of leptin –protein produced by the mutated gene of the obese ob/ob mice (111) (gene also present in man) (232); in fact it brings this type of mice to reduce food ingestion and body weight (408). Such a peptide is secreted by the white adipocytes; it goes in the CNS through the HEB (46) and acts on CNS as a peripheral signal on the energy reserves, inhibiting food intake, reducing body weight and regulating energy balance (lipostatic hypothesis) (31,32,46,149,325,399). Leptin receptors are widely found in the VMN and the LHA as shown in Table 2 (31,257).


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Leptin administrations, besides reducing food intake and body weight in ob/ob mice, increase thermogenesis, physical activity and also normalize hyperglycemia and hyperinsulinemia (306); administrating icv leptin in normal rats reduces insulinemia and the ability to store lipids in adipose tissues, it also increases glucose availability and the tendency to oxidation; it favours uncoupling protein manifestation and then energy dissipation (318); body weight loss, more than anything else is tied to adipose tissue reduction (61), as it has also been demonstrated by leptin-treated animals (325); in vitro studies show also that leptin directly acts on adipocytes, increasing fat mobility (244). The above data suggest that food intake reduction is part of a more general leptin-induced tendency aiming to disperse the energy present in organisms and to prevent its further assumption (46,306,318) (catabolizing action); many of the above effects are mediated by the activations of the autonomous nervous system (32,46). Then, leptin regulates the individuals’ nutritional state (46, 318, 325). Gene mutations for leptin could also determine human obesity as it happens in ob/ob mice. Although such mechanism could theoretically be possible, very few mutations have been described for the homologous human ob gene: therefore it seems unlikely that it may occur in most of the human cases of obesity (51, 92, 267). In fact plasma leptin levels –far from being reduced in obese men (68), are correlated with adipose tissue reserves (232). The manifestations of the human ob gene have been studied through “in situ” hystochemical hybridizations techniques on subcutaneous and omental adipose tissue of thin and large obese subjects, highlighting a massive hyperconcentration in large obese. This fact introduces the concept of leptino-resistence at the hypothalamus level for some types of obesity. Under these circumstances, the abundant adipose tissue remarkably increases plasma leptin, probably in the attempt to carry out, at the hypothalamus level, metabolism adjustments towards some sort of energetic consumption and a reduced calorie input. In reality, the expected outcome does not take place in the hypothalamus due to a resistance towards the ob gene production (151,232). Therefore in obesity, the fault does not lie in the synthesis of adequate leptin amounts, but in the leptin receptor functionality or in alterations of the transductional postreceptor mechanisms of the message. For this matter, db/db mice, also genetically obese, but with high leptin levels, present a genetic alteration in leptin receptors (257,318); anyhow, other genetic leptin forms of obesity resistance are observed in rodents (173) that can also be induced by feeding (110), since hyperleptinemia induces leptin receptor down-regulation that


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initially only concerns peripheral receptors (382) and those for transportation in the CNS (52), and subsequently also the hypothalamic receptors (228). These obesity models get closer to human obesity. Leptin secretions, though being correlated to amounts of the adipose tissue, vary during the day; food intake, carbohydrates above all, increases it; furthermore plasma leptin levels seem to be correlated to insulin amounts (331); however, in this case, such variations cannot be easily related to the “short term” variations of the satiety sensations (305; 320). Then, according to the above data, leptin function is to reduce “long term” food intake (17, 158). Leptin acts on feeding behaviour inhibiting secretion and release of other orexiant peptides and increasing anorexiant factors. For example, leptin anorexiant effect in part depends on its action on the NPY system (the main orexiant central peptide: see ahead); in fact it has been observed that it inhibits hypothalamus NPY release (362). Several authors have noticed relationships between leptin and the serotoninergic system. 5-OH-tryptophan administrations increment plasma leptin levels in mice (405); icv or intraperitoneal (ip) leptin administrations increase diencephalic 5-HT metabolism (45) even in ob/ob mice (156); leptin affects 5-HT metabolism through a mechanism which involves nNOS activities; in fact icv leptin administrations reduce NOS diencephalic activity for a long time (44); the increment of leptin-induced diencephalic 5-HT is antagonized by L-arginin icv administrations; in knockout mice for the nNOS gene, the leptin anorexiant effect is reduced and no increment is observed in diencephalic 5-HT metabolism (45). Leptin receptors have been observed in the nuclei of the dorsal raphe for rats and in the caudal median and dorsal raphe for monkeys, being the raphe the well known origin serotoninergic pathways. In ob/ob mice, the 5-HT carrier levels in the neurons of the raphe dorsal nucleus are low (67), therefore 5-HT release towards the superior centres is reduced; the above is in agreement with the behavioural effects increasing food ingestion; furthermore, always in ob/ob mice, leptin ip administrations increase 5-HT metabolism in the midbrain and in the hypothalamus (Harris, et al, 1998). Other authors, instead, though they remark that both 5-HT and leptin reduce food intake, reject a relationship between the two systems (150). These data show how alterations concerning leptin and its complex mechanisms, which regulate its action, may actually be the primum movens for some obesity forms. On the other hand further research must be carried out before being able to think about using leptin clinically, at least in those


25

cases characterized by an insufficiency or structural alterations of the hormone produced in the adipocytes.

B. Insulin

The severe effects of insulin administrations mainly set this hormone as an appetite stimulator with a mechanism that involves both liver and CNS as shown in Table 2 (142). In reality this is due to its hypoglycemizing action rather than a proper orexiant action, since its peripheral administration, carried together with glucose-controlled administrations, so to keep glycemia constant (euglycemic clamp), determine reduction in food ingestion (398). Hypothalamic insulin release or its icv administrations inhibit food intake and produce permanent body weight loss in rodents (249, 338) and primates (398). Injections of anti-insulin anticorps in the rat ventromedial hypothalamus increases food intake and then body weight (249, 364); Furthermore knockout mice for the neuronal insulin receptor are hyperphagic, obese and show an imperfection in the reproductive central control (37,290). Then, like leptin, insulin is considered a satiety signal acting on the CNS and inhibiting those central systems that favour food consumption. Insulin can cross the HEB and directly interact with the CNS cells (17, 398, 399). A number of experiments suggests that insulin interacts in the brain with both orexiant and anorexiant peptides to regulate feeding behaviour, body weight and energy homeostasis. Insulin and leptin have a tight relationship; both are satiety signals and both are hyperexpressed in a state of obesity; Insulin increases leptin secretion (305), while leptin inhibits insulin secretion (103). A convergent mechanism mediating responses to cellular leptin and insulin in the hypothalamic neurons has been suggested on the basis of cerebral insulin and leptin similarities (55, 287,288, 291, 311, 409, 410). Insulin and leptin together regulate hypothalamus NPY synthesis (181, 339). NPY manifestations in the arcuate nucleus (ARC) neurons diminish after central or systemic administrations of insulin and leptin, while NPY hyperactivity is present when those hormones diminish (339, 352, 392). Furthermore cerebral insulin has been proposed as a neuromodulator involved in cognitive feeding processes (121,122). An in vivo a


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microdialysis technique showed hypothalamic insulin increments in rats accustomed to a specific “feeding-time” in the 30 minutes preceding mealtimes, while peripheral insulin levels remained unaltered (120,121; 298). Finally, other regulator peptides, such as leptin and galanin (2,361), interacting with insulin, revealed a possible involvement in such cognitive processes (122).

C. Glucagon and Glucagon-like Peptides

Glucagon ip administrations reduce the amount of food intake in rats, but it does not affect meal starting times or the other behavioural characteristics of postprandial normal satiety (118). Such effect could be due to hyperglycemia caused by increased hepatic carbohydrates mobilization, but that small icv injected doses of glucagon reduce food intake suggests a direct action on the CNS (142,176). Anyhow, more recent studies have reconsidered glucagon function in feeding behaviour; in fact, knockout mice for glucagon receptors have normal feeding behaviour and body weight, even though they show a smaller amount of fat mass and a thinner amount of thin mass (119). Glucagon comes from cleavage of a precursor 160 amino acid peptide precursor: pre-proglucagon. At the same time, such a peptide synthesises several other peptides called glucagon-like peptides (GLP), involved in many peripheral functions of the organism like glucose homeostasis, gastric emptying, insulin secretion and food intake (90, 368). The most important among the GLP’s is GLP-1 (Table-2). GLP-1 is released by L cells present in the digestive system; in man, such cells only release GLP-1 (166), while in other animals (rats, dogs, cats) they also release glucagon (85,210). Although they show 50% homology, GPL-1 and glucagon act through different receptors (372). As early as 1996, the discovery of specific GLP1 receptors and glucose sensible proteins (GLUT2 and glucokinase) supported the hypothesis that this peptide function is the hypothalamic regulation of macronutrients and water intake (280). GLP-1 works through specific receptors (GLP1-R) set in the temporal cortex, amygdala, ARC and PVN (164). It inhibits gastric emptying (279), glucagon secretion, stimulates biosynthesis and secretes


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glucose-dependent insulin (299), furthermore it has short-term effects on feeding behaviour control in the CNS of rats (379) and man (145). The exact mechanism through which GLP-1 influences feeding behaviour is not properly understood, however it seems its anorexiant effect is due to an influence on NPY (376). GLP-1 central administrations also activate neurons containing CRH and oxyticin; therefore this activation could be responsible for its anorexiant effect (209). GLP iv administrations not only diminish food intake but also lead to the dose-dependent inhibition of water intake (207). While CNS leptin and GLP-1 function synergically in the CNS, since leptin activates GLP-1 that, in turn inhibits food intake (139), those two peptides carry on opposite functions in the endocrine pancreas: in fact GLP-1 stimulates insulin biosynthesis and secretion (299), instead leptin inhibits the gene transcription for insulin and its glucose-dependent secretion (191). GLP-2 is a powerful neurotransmitter that inhibits feeding behaviour in rodents and has long-term effects homeostasis body weight homeostasis (368); this is important since any possible long-term effect of GLP-1 has been previously excluded (86). The GLP-2 effects are mediated by specific GLP-2R receptors present in the intestine, dorsal median hypothalamus, in the thalamic regions, hippocampus and cortex regions (276).

D. Cholecystokinin

Cholecystokinin (CCK) is a hormonal peptide produced by the gastrointestinal tract, affects the very same gastrointestinal tract and the CNS. Its ip administration inhibits food intake in rats (7, 137). Since CCK plasma concentrations are very low and its effects are abolished by vagotomy (115,233,315,353) and by damage in the nucleus of the tractus solitarius (95), it is thought that this peptide very likely acts through nervous pathways activating ascendant vagal fibers that synapse with the nucleus of the tractus solitarius, where fibers set off for the hypothalamus PVN and other higher centers (31,200,316,343). Such hypothesis is confirmed by the presence of CCK receptors in the afferent vagal neurons (269,270,271). Besides both gastric relaxation and CCK activate afferent vagal pathways (334). There are two types of receptors for CCK: A (or 1), mainly present at


28

the peripheral level, but also in the CNS; B (or 2), mainly present in the CNS and in the gastric mucous (Table-2) (73, 282). CCK-A receptors mediate feeding inhibition; CCK-B receptors carry an important function for anxiety (108). It is thought that CCK acts on feeding behaviour mostly by activating CCK-1 receptors present on the afferent neurons travelling along the vagus nerve (335). OLETF rats (Otsuka Long-Evans Tokushima Fatty), genetically lacking CCK-1 receptors, are hyperfagic, diabetic and obese (112). Even if CCK-2 receptors in the hypothalamic nuclei are involved in food intake control (258), their function in feeding behaviour is controversial. Ip administrations of antagonists for the latter receptors increase food intake in rats (88), agonist administrations affect only the motivational aspects of food intake (180); however ip administrations of CCK-2 receptor agonists determine the activation of hypothalamic neurons involved in food intake control not followed by the activation of cerebral trunk neurons (50). In spite that CCK is considered one of the earliest signals just after the occurrence of food intake leaving the periphery for the CNS (31,275,399); its function on feeding behaviour, as the one of the other peptides released by the digestive apparatus (bombesin, see ahead), is very different than leptin: mainly it informs the CNS that food intake has occurred but does not provide any information on the entity of the energy reserves (230), in so much that it controls meal size but not the total food intake (389). Anyway leptin and insulin increase CNS sensibility to CCK mediated information (17); in fact the lack of leptin (251) or of its receptors (78) annul CCK effect on feeding behaviour. In the end, administrations of icv leptin mixed with i.p CCK determine a meaningful body weight reduction, greater than the one produced by leptin alone (245). Several pharmacological studies show synergism between CCK and 5-HT; administrations of an antagonist of CCK-1 receptors inhibit the anorexiant effect of fenfluoroamine (a releaser and 5-HT reuptake inhibitor) and of the very same 5-HT (70). Furthermore an antagonist of the CCK-1 receptor partially antagonizes fenfluoroamine and metergolin (5-HT antagonist) antagonizes CCK administrations (141). In man, CCK has shown to be effective in reducing the amount of food intake in normal and obese subjects (31,32,343,399), while its high iv administrations do not have any effect on subjects suffering from nervous bulimia (262).


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E. Bombesin Homologous Peptides

It is a peptide group presenting noteworthy structural analogies with bombesin, a peptide extracted from the skin of a fog (Bombina bombina). The homologous in mammals are gastrin releasing peptide (GRP) and neuromedines B (NMB) (261, 297). Three different receptors have been identified for these peptides: a receptor for GRP, one for the neuromedines B and a third (with a 50% homology degree with the GRP receptors) for a still unidentified binder (orphan receptor) (18,140). Both gastric cells (248) and CNS neurons (261) synthesize GRP and NMB. Nerve fibers in the tractus solitarius nucleus (TSN) and in dorsal motorial nucleus of the vagus (DMV) have been immunoreactive to these peptides (240). Furthermore, their relative receptors were found in the same nervous centers (18). Peripheral administrations, mainly of GRP, reduce food intake both in experimental animals and man (101,138,146). The same can be held true for administrations in the rat fourth ventricle; actually central administrations produces better results (205). In the end, mice lacking the GRP gene do not show any glucose intake reduction when GRP has been peripherally administered (153). However at least two points must be clarified: 1) how do peripheral peptides act in the CNS, since they can hardly cross the HEB (13) and since the effect of peripheral administrations is not abolished by vagotomy as it happens for CCK (336) 2) Where from do the nerve fibers innervating zones of the TSN come, since the zones that receive projections from the digestive apparatus do not show any immunoreactivity to the above peptides (240) Several studies concerning the first point suggest that these peptides activate some capsaicin-sensible non-vagal nerves (260) instead they supply the celiac artery (196). Concerning the TSN afferences, it has been hypothesized that they may come from the PVN, the amygdala central nucleus and the stria terminalis, centers all involved in feeding behaviour control (227).


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F. Amylin and Calcitonin Gene Related Peptide

Amylin is a peptide released by the pancreas β cells together with insulin as response to feeding (42; 268). It reduces food intake in rats though in man its anorexiant effects is not as strong (12). They both act at the level of the last area (236,239,264) binding to a common receptor (69). These peptides’ anorexiant effect is synergic with CCK and GRP (23, 238). Amylin mechanism is still poorly understood. According to some authors, amylin mediates CCK and gene related peptide (GRP) anorexiant effect, since in mice lacking the amylin gene the effect of the aforementioned two peptides is not shown (265). However, if it were so, the amylin effect should be abolished by vagotomy as it happens for CCK (233) and/or the pharmacological destruction of the splanchnic vagal and non vagal afferences to the CNS and as it happens GRP (260); instead neither bilateral vagotomy (237) nor capsaicin treatment (236,239) reduce the peripherally administered amylin anorexiant effect.

G. Ghrelin

It is a 28 amino acid peptide released by the stomach that, unlike other gastrointestinal peptides, favours food intake increasing body weight through adipose tissue storage (377, 400). As it is logically expected, ghrelin plasma levels diminish after meals and increase during the inter-prandial periods (75). Ghrelin administrations activate neurons NPY and Agouti Related Protein (AGRP) secrete neurons in the ARC (183, 348). Reciprocal inhibition with leptin has been observed (15,74): on one hand leptin does not only acts centrally inhibiting orexiant peptide secretions like ghrelin; on the other hand ghrelin acts anorexiantly inhibiting leptin release.


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In agreement with the above hypothesis it has been observed that plasma ghrelin levels are high in anorexic individuals (9) and very low in the obese (344); variations related to food intake have been observed in the latter group (98). Some authors have observed that several polymorphisms of the ghrelin gene can contribute to genetic predisposition for obesity (380).


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2- ANOREXIANT PEPTIDES FROM NEURONS IN THE CNS

A. Melanocytes Stimulating Hormone

The discovery that α-MSH, deriving from the cleavage of proopiomelanocortin (POMC) and being secreted in the arcuate nucleus, reduces food intake, comes from studying a particular line of genetically yellow and obese mice: the agouti mice (346). These animals produce excessive amounts of the peptide AGRP, normally present in healthy animals (see ahead), which counteracts α -MSH both in the skin, interacting with melanocortin-1 (MC1) receptors, and in the hypothalamus, interacting with melanocortin-4 (MC4) receptors (Table-3) (102,293,350). AGRP hyperexpression counteracts excessively with α -MSH in the skin (yellow hair) and in the CNS (obesity). Mice with mutations for MC4 receptors or knockout mice for the same receptor are obese but not yellow (171,374). In rats, α -MSH icv administrations reduce food intake while AGRP icv administrations block α -MSH anorexiant effect (93). α -MSH also increases the orthosympathetic system activity (32); then it produces, as all the other food intake-reducing factors, a negative effect on energy balance, where food intake inhibition is only a single aspect (399). Endogen agonist and antagonist expression for α -MSH receptors in the CNS is controlled by energy balance variations and by signals coming from adipose tissues (21). Leptin icv administrations increase POMC expression in the hypothalamus ARC (17,263,327); in fact, leptin receptors, in the ARC neurons synthesize POMC and other anorexiant peptides (256). When leptin is lacking (fasting or ob/ob mice), α -MSH expression drops (263). However, unlike ob/ob mice, knockout mice for MC4 receptors turn out obese only when fed with lipid-rich diets (41,197); this suggests that α-MSH could be more than just a simple “effector” for leptin action. Furthermore a gene mutation for MC4 receptors has been found in 3.8% of a group 209 obese subjects (381). Finally, it must be pointed out that α-MSH-releasing neurons also have 5-HT2C receptors and that the anorexiant effect of the serotoninergic drugs needs the functional integrity of melanocortin neurons and receptors (160).


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Then α-MSH can be considered not only an effector for leptin but also for 5-HT.

B. Cocaine and Amphetamine Regulated Transcript

This protein, the peptide CART, inhibits feeding behaviour and stimulates the orthosympathetic system (Table-3) (32,202,374). CART and its mRNA are found in hypothalamic sites as the paraventricular nucleus, the supraoptic nucleus, the LHA, the hypothalamus dorsomedial nucleus, the ARC, the periventricular nucleus and the premammillar ventral nucleus. The CART neurons in the magnocellular paraventricular nuclei and in the supraoptic area (SON) express also dynorphin; those in the LHA and in the posterior periventricular area express also the Melanin-Concentrating Hormone; many CART neurons in the ARC express also mRNA for neurotensin; those in the parvicellular paraventricular area, in the dorsomedial hypothalamus and in the anterior periventricular area express also mRNA for TRH. Then CART neurons produce neuropeptides involved in energy homeostasis (Melanin-Concentrating Hormone, TRH, dynorphin and neurotensin) (96). CART affects feeding behaviour at lower doses than α -MSH (93). As shown for α -MSH, CART-secreting neurons also express leptin receptors (257); since CART genic expression is increased by leptin and reduced in ob/ob mice and by fasting, also in this case, this peptide can be considered a leptin intermediary (257; 202). However, CART and α -MSH act through different pathways since AGRP does not contrast CART anorexiant effects (93). CART also acts on lipid metabolism: in fact both normal and obese rats –chronically administered with icv CART, have a lower body weight and food intake as well as lower insulin and leptin plasma levels; besides it increases lipid oxidation –in obese rats above all (317). Several experimental results lead to the hypothesis that leptin may increase CART expression. In fact, due to lipid-rich diets, hypothalamic CART increases (317) while its mRNA is almost absent in obese and hyperleptinemic rats (202). Furthermore, animals, undergoing food restrictions, show a decrement for CART and its mRNA in the ARC, while peripheral leptin administrations increase their expression in obese mice (202).


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How CART functions on feeding behaviour is still not properly understood. In fact, in spite of its effects, CART knockout mice have normal body weight and food intake, but appear less sensible to pain (14). CART icv administrations activate neurons releasing CRH, as well as oxitonergic neurons in the magnocellular and parvocellular PVN. In particular, CART effects on its CRH neurons make the epinephral gland secrete corticosterone; at least in part, this could explain CART inhibition on feeding behaviour (385). Besides it seems that CART effects on locomotion and feeding could be mediated by a direct or indirect neuronal dopaminergic activity, on the ventral tegmental area (76). In the end, it also has been hypothesized that CART role on feeding could be tied, in part, to its role mediating CCK-induced postprandial satiety. In fact, several experimental results suggest that CART could be the neuropeptide released to tractus solitarius nucleus by afferent vagal neurons (33, 34).

C. Corticotropin Releasing Factor and Glycocorticoids

CRH is a powerful anorexiant agent whose mechanism seems to be related to the one of the neurotransmitters (32; 215; 374; 39); in fact, 5-HT inhibits food consumption and stimulates CRH release; instead, NA increases food intake and inhibits CRH release (39). CRH receptors are present in the ventromedial hypothalamus (286). There are two types of CRH receptors called CRH1 and CRH2; both receptors show some homologies, though they have a different anatomic distribution. CRH2 has two variants: CRH2α and CRH2β (Table-3). CRH2α seems to be involved in the effects produced by CRH on food intake (360). Also urocortin, a 40 amminoacid peptide strictly linked to CRH, found in many brain regions as well as other organs, is an appetite suppressor (22, 211); central and peripheral urocortin administrations influence satiety and modify the amount of introduced food (22,211,354). Urocortin binds to both CRH receptors; in particular, it is a very powerful binder for CRH2-R, more than for CRH (Table-3) (354). Since according to the animal nutritional state, leptin can increase (fed state) o diminish (fasted state) CRH expression and the activity of the neurons


35

containing it, it has been hypothesized that CRH is a leptin effector (170,286), attributing it an analogous role as the one of α -MSH and CART. Anyway, CRH mechanism, as seen also for CART, is not related with α -MSH, since AGRP does not contrast CRH anorexiant effects (93); instead, paradoxically, α -MSH administrations attenuate CRH anorexigenic effects (296). Other authors hypothesize antagonism between CRH and NPY. In fact, it has been observed that diabetic insulin-deficient rats –fed with hyperglycidic diets, increase NPY expression in the ARC nucleus and diminish CRH in the paraventricular nucleus; besides, such rats are hyperphagic. On the contrary, in insulin-deficient diabetic rats –fed with hyperlipidic diets, NPY and CRH expressions have opposite profiles; these animals feed normally. These observations support hypothesis that food intake normalization seen in diabetic rats fed with hyperlipidic diets could be, at least in part, mediated by a drop in NPY and by an increase in CRH (60). The antagonism between CRH and NPY has also been shown by pharmacological studies (159).


36


37

While dealing with CRH, it seems proper to briefly discuss glycocorticoid effects on feeding behaviour. The description of feeding behaviour outcomes in patients affected by both Cushing and Addison disease is classical. Glycocorticoids increase food intake, carbohydrates above all, reduce hypothalamic CRH levels and increase NA activity in the PVN; in turn, PVN α-adrenergic stimulations increase circulating glycocorticoids (224). Other authors have stressed how elevated glycocorticoids levels reduce leptin anorexiant effects and determine leptin-resistance (407). Several observations suggest that glucocorticoids stimulate hypothalamic NPY secretions (163,208,250), also in ob/ob mice (62). Epinephrectomy reduces NPY in the paraventricular nucleus and preproNPY in the ARC nucleus (390); it also reduces NPY receptors in the VMN (395). Furthermore, glucocorticoids have a stimulating action on the levels of the mRNA for receptors Y1 (208). Finally, epinephrectomy compromises the orexiant effect caused by icv NPY administrations, (359). Since central NPY administrations stimulate glucocorticoid secretions (154,319), it may be possible that there is a positive feedback between hypothalamus NPY and glucocorticoid plasma levels. Furthermore there is a correlation between the glucocorticoid circadian rhythm and the NPY circadian rhythm and this could explain the circadian rhythmical choice of carbohydrates normally observed also in animals (3). These data are certainly important for their possible clinical outcomes since they may show central pathogenetic mechanisms determining and supporting overweight in pathologies caused by glucocorticoid overproduction, although the peripheral effects from hypercortisolism on body fat distribution and from insulin-resistance must be taken in consideration. Besides they could explain the different attitudes towards food observed in the pathologies caused by the excess and from the defect of glucocorticoid production.


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D. Neurotensin

Neurotensin, a neurotransmitter known as an antinociceptive (281), inhibits food consumption (235). In rats, it interferes with NA release when administered in the PVN and in the LHA (216). According to some authors, neurotensin is a leptin mediator (327); in fact, its genic expression, reduced in ob/ob mice (394) and in neurotensin-releasing neurons, present in hypothalamic nuclei involved in feeding behaviour regulation (172), expresses leptin receptors (148). In the end, a study, carried out using homozygote mice lacking the gene for neurotensin-receptors1 (NT-1R), showed that this subtype of neurotensin receptors is implied in feeding behaviour control but not in the antinociceptive effect.

E. Oxytoicin

Oxyticin (OT) is a 9 amino acid peptide expressed in the SON, magnocellular hypothalamic neurons and hypothalamus parvocellular neurons (PVN) (Table-3). Magnocellular neurons come out on the posterior part of the pituitary gland, where OT secretion takes place; projections from the parvocellular neurons reach out to the brain central regions and external parts of the median eminence (212). OT, besides the well known effects on milk ejection and on uterine motility, has anorexiant effects (10, 11, 294); also it controls centrally and peripherally the electrolytic balance and amount of fluids (383). Ip or icv OT administrations reduce liquid and food intake and the time spent in eating both in fat and fasting animals for 21 hours; besides OT increases the latency period to the next mealtime. The effect is not observed if vasotocin, an OT antagonist, is icv injected. This shows that OT effects are mediated by specific cerebral receptors (11). However, anorexiant effects are not observed in non-fasted animals (231). A drop in food intake characterizes the OT inhibitory effect, which is not associated to plasma level alterations of hormones involved in caloric homeostasis or changes of the glycemic levels. OT agonists, administered in doses able to meaningfully inhibit food intake, have only a slight effect on water intake (294). Lack of food does not modify OT content in the SON


39

and in the PVN, while OT is reduced in the median eminence; the latter effect is not modified when feeding starts up again (40). The oxytoninergic system appears to be linked to CRH, as shown by the presence of CRH1-R and CRH2-R in the OT neurons of the PVN and SON (8) and by OT secretions in the pituitary gland right after CRH icv administrations (36); besides, pre-treating with oxytoninergic antagonists blocks the CRH effects on food intake, suggesting that OT is a mediator for CRH-induced hypophagia (295).

F. Thyrotropin-releasing hormone

Thyrotropin-releasing hormone (TRH) is an anorexiant peptide, whose main function is stimulating thyroid-stimulating hormone (TSH) release, but also it has other effects on the CNS. Such effects are mediated by two receptors with different anatomic distributions: TRH-R1 and TRH-R2. TRH-R1 is mainly found in the hypothalamus, while TRH-R2 is found in the thalamus, in the cerebral and cerebellar cortex and through the reticular formation (Table-3). In particular the latter is involved in pain perception and in some superior cognitive functions (162). TRH inhibits food intake acting in concomitance with leptin and melanocortin. Low leptin levels lead to a drop of the thyroid hormones as a consequence of a reduction of TRH synthesis and TSH secretion; while, in rats, TRH hyperexpression reduces leptin plasma levels (114). Not only leptin but also the melanocortins, as α-MSH, affect TRH expression and secretion (342) both in a direct way (64,143,284), and through POMC fibers linked to the TRH neurons in the PVN (155,217). In particular, the melanocortins increase TRH release, while antagonists of MC3/MC4 receptors block it (193). Instead, NPY has an inhibitory effect on TRH synthesis (64,104) and, consequently, even through this pathway, it carries out its orexiant action.


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3- PEPTIDES INDUCING FOOD INTAKE

A. Neuropeptide Y

NPY, polypeptide extracted for the first time in 1982 from pig brain (369), is one of the most natural orexiant agents ever obtained. In fact, its icv administrations in the hypothalamus determine hyperphagia and even food intake in already sated rats; it also determines ponderal increment (as in the syndrome from VMN damage) (32,289,317,358); on the contrary, anti-NPY antibody administrations in the paraventricular nucleus, reduce carbohydrates intake (Shibasaki, et al, 1993). NPY is synthesized by ARC neurons and produces its effects on food consumption by acting on the CNS sites responsible for body weight and energetic consumption control, in particular in the paraventricular nucleus and the dorsomedial hypothalamus (182,256). Besides, it diminishes the orthosympathetic system activity (32,199), thermogenesis (289,362), and increases insulinemia, corticosteroid plasma levels (318,362) and leptin release from the adipose tissue (318); studies in vitro show that NPY also directly affects both white adipocytes, reducing fat mobility (244), and brown adipocytes, inhibiting the effects of the orthosympathetic stimulation (Table-4) (24). Such reasons make it the most important CNS anabolizing peptide (32,318,399). At least six different NPY receptors are known; initially, the one considered responsible for the orexiant effect was the Y1 receptor (221); instead, according to more recent studies also the Y5 receptor induces food intake (184). Leptin (17,318,362) or insulin (17) central administrations reduce the expression of NPY mRNA in those nuclei where leptin (257) and insulin (406) receptors are present. It is thought that, at least in part, leptin (17,362) and insulin (17) act through the inhibition of the biosynthesis and release of NPY. Lack of leptin (ob/ob mice) or alterations of its receptors (db/db mice) determine disinhibition of NPY-releasing neurons (393). NPY-secreting neurons also have glucoreceptors; lack of glucose activates NPY release (393). In any case, NPY secretion depends from food intake: its hypothalamic levels increase during fasting and decrease after feeding (326); besides, stimulating the ARC–PVN pathway through catabolic signals (fasting, physical exercise, glicosuria) induces food intake, orthosympathetic activity and energetic consumption reduction and, parasympathetic activity


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increment (199). It is thought that the effect of the catabolic signals on NPY synthesis is mediated by leptin levels reduction (337); the inverse connection between leptin and NPY is confirmed by the fact that anorexia induced by some α-MSH receptor antagonists (that, as said before, is considered the main leptin effector) is mediated by NPY (185). Therefore the studies, undertaken by administering NPY centrally or peripherally, have highlighted the orexiant effects of this peptide; on the contrary, lack of NPY, obtained in mice through inactivation of the gene producing it, does not determine any behavioural or metabolic alteration (99,301); a partial improvement of the obesity and the metabolic syndrome is observed (100, 301) only if the mice also lack leptin (ob/ob). This leads to think that the role of NPY is to have a tonically inhibitory action on the anorexiant leptin effects and/or that other orexiant peptides have the aforementioned function (243,301). These data lead to view NPY as a peptide useful in times of shortage: an increment of its secretion, induced by the lack of energetic substrates, determines metabolic effects, mainly aiming to limit energetic consumption, and behavioural effects, aiming to seek out food. The remarkable amount of data concerning the hypothalamic peptide effects on feeding behaviour starts to give shape to an adipocyte-hypothalamus axe; leptin and insulin plasma levels, somewhat directly proportional to the white adipose mass, are seen as signals informing the CNS on the entity of the energetic reserves; the hypothalamus synthesizes stimulator and inhibitor peptides affecting - energy consumption (through sympathetic activity, then to be considered, as an efferent pathway) and feeding behaviour in a direct or inverse way to leptin and insulin plasma levels (199,230,318,327); in turn, the orthosympathetic nervous system, through β3 receptors, activates the brown adipocytes inducing thermodispersion and reducing leptin expression (242).

B. “Agouti” Related Protein

As said before, the peptide AGRP antagonizes α-MSH at its receptor level. ARC neurons secrete this peptide; to be specific, 90% of the NPY-releasing neurons also release AGRP (35). Then, these neurons’ role is really relevant;


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in fact they release both an orexiant peptide (NPY), and a peptide that inhibits α-MSH anorexiant activities (AGRP). Leptin reduces AGRP synthesis while fasting increases it in ob/ob mice (350). The AGRP/α-MSH system is considered one of the most important mechanisms through which leptin reduces food intake (230).

C. Endogen Opioids

In rats, central administrations of opioid peptides increase food intake, while their antagonists reduce it (226). In man, opiate antagonists reduce food intake in bulimic patients during crises (262); they are also effective in obese patients and those having a normal weight (82). Anyhow opiate orexiant effects are not as marked at NPY (226). They involve the µ receptors (186,313) and, according to some authors, also the δ (313), even if initially also κ (226) seemed involved in this action. The effects of the opioid system on feeding behaviour show some differences when compared to neuropeptide effects. While strong antagonist administrations reduce food intake, chronic administrations have shown to be ineffective in controlling body weight (226). According to some authors, more than controlling food intake as source of energy and nutrients, opioids are linked to the pleasing/displeasing sensation associated with food (89). Although the nervous centers involved in the opioid effects on feeding behaviour are different than those of other peptides, numerous experimental data show that their action site is the accumbens nucleus (313). According to some authors such a neural network involves LHA, the dorsomedial hypothalamus, the tegmental ventral area and the intermediate region of the tractus solitarius nucleus (391), all nuclei that co-ordinate metabolic, motivational, motorial and vegetative activities (Table-4). According to other authors, endogen opiods carry on a stimulating action with respect to feeding behaviour thanks to a mechanism interacting with the NPYergic pathways; this is suffraged by the fact that in sated rats, naloxone reduces NPY-induced food intake (332) and that there are anatomical relationships between NPY nervous immunopositive fibers and neurons containing β-endorphin (169).


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D. Orexins A and B (Respectively Hypocretin 1 and 2)

They are orexiant peptides (32,80,374) deriving from the same gene, whose product (preprohypocretin) cleaves in a different way, originating the two orexins. They interact with 2 different receptors (1 and 2); orexin A has greater affinity for receptor 1, orexin B for receptor 2 (Table-4) (329). Of the two orexins, A is more effective on feeding behaviour (94). Their intracerebroventricular administrations increase food ingestion (91), while fasting increases these proteins’ genic expression (241). The orexins are secreted by lateral hypothalamic neurons (177,256); ARC neurons releasing NPY innervate orexin-releasing neurons containing NPY1 and NPY5 receptors (167). These substances are supposed to interact with NPY (80,91,178).


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All the orexin-secreting neurons also secrete dynorphin (63), some also galanin (147) and, in man, also CART (307). The link with the opioid system is also supported by the fact that orexin administrations induce animals to choose tastier food (65). Orexin A reduces the activity of VMN glucosensible neurons (349) and increases the activity of the lateral hypothalamic neurons (229); these neurons contain receptors for orexin A (277). Orexinergic neurons, besides innervating the hypothalamus, they also innervate the tractus solitarius nucleus that receives vagal information on gastric distention (371). The presence of food in the stomach reduces neuronal orexinergic activity (42). Finally (but not for this less important) orexins are involved in the regulation of the sleep-awake rhythm and of locomotory activity (330). The reduction of their secretion favours sleeping (192). This could explain why is harder to fall asleep when fasting: fasting increases orexin release, in turn, making subjects more awake. Narcolepsy in man is attributed to the destruction of hypothalamic orexinergic neurons (285). Anyhow the effects on the sleep-awake rhythm and locomotory activity, at least in part, put in discussion the physiological role of the orexins on feeding behaviour. The increased ingestion of food, determined by these peptides, could be tied to a more general increment of the locomotory activity rather than a real orexiant action. In fact increments in orexin synthesis caused by fasting is not rapid, furthermore lack of orexins determines narcolepsy rather than anorexia (375). Furthermore, total fasting, not the simple reduction of food intake, increases orexin expression (42); at least in part, this could be due to the presence of food in the stomach. Finally, a single icv orexin administration is not sufficient in order to manifest hyperphagia and, chronic administrations do not induce obesity (157).

E. Melanine Concentrating Hormone

Strong MCH icv administrations transitorily increase food intake in rats; chronic administrations keep food intake constant and produce ponderal increment (83). Instead MCH knock-out mice show a drop in food intake and


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body weight but an increase in energy consumption (345). Also in this case, MCH-secreting neurons are found in the lateral hypothalamus and express leptin receptors (257); these neurons also release CART peptides (76). The control of MCH synthesis is prevalently carried out by the interaction between leptin and its receptors; in fact MCH synthesis is high in ob/ob mice (312) and obese Zucker rats (363), while leptin administrations make it drop in ob/ob mice (198). MCH is considered a α-MSH antagonist, then it increases food intake and promotes energy reserve conservation (234, 374). More recent studies suggest that MCH main function is to increase energy consumption, rather than reduce food intake; in fact, ob/ob mice also lacking the MCH gene are thin but their food intake is always high; these animals show increased oxygen consumption, body temperature, resistance to cold and expression of uncoupling proteins typical of the brown adipose tissue (UCP-1) (340). According to some authors, MCH action on energetic consumption is tied to its inhibitory action on the hypothalamus- hypophysis -thyroid axis (190). MCH is also found in the plasma and its receptors are also present in the adipose tissue, where it increases leptin (29).

F. Growth Hormone Releasing Hormone

GHRH administrations intake in the hypothalamus pre-optic medial area stimulate food (84); such an effect presents a U inverted dose-response curve, since higher doses inhibit food consumption (175). GHRH favours food intake of proteins more than carbohydrates (84). According to some authors, the GHRH effect is related to opioid system effect (84). Since both GHRH, and ghrelin increase somatotrophic hormone release, it could be hypothesized that both hormones act just through the growth hormone (GH). Instead the action mechanisms are independent, because ghrelin favours food intake also in rats lacking the GH gene (348). Besides, the body weight increment caused by ghrelin is tied for a good part to its inhibition of fat utilization (377), while, as known, the somatotrophic hormone acts catabolically on adipose tissues.


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G. Galanin

Galanin is a peptide isolated in the gastrointestinal tract, found in high concentrations also in the hypothalamus, and in particular in PVN neurons also expressing leptin receptors (259). It stimulates food intake, above all fat (32,327,370,374). Anyway galanin seems not to be as effective on feeding behaviour as other neuropeptides; in fact, body weight, both in galanin knockout rats and in those hyperexpressing it, is not different from the control groups (165). According to some authors, also galanin effects would be mediated by the opioid system, since considerable synaptic connections are found in the hypothalamus among galanin immunopositive nervous fibers and β-endorphin-containing neurons (168).


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V. OTHER FACTORS AFFECTING FOOD INTAKE IN DIFFERENT PATHOLOGIES: CYTOKINES Several severe pathologies, etiopathogenetically different among themselves (tumors, cirrhosis, uremia, cardiac insufficiency, chronic obstructive lung disease), have anorexia as common symptomatologic characteristic. The consequent food intake reduction leads to severe malnutrition states co-responsible for the hypercatabolic conditions that, in turn, contribute to meaningfully increase the disease morbidity and mortality (123,300,324,333,396). Also, a poor nutritive state, besides worsening the quality of life, can limit the use therapeutic tools, retarding or impeding an adequate treatment. The above show how important is to know the relationships among these pathologies and the mechanisms controlling feeling behaviour. The aforementioned relationships are nowadays still very controversial. Initially, researchers mainly focused their attention on two different factors: free tryptophan plasma levels and cytokine actions on the hypothalamus nervous centers. According to some authors, the increment of CNS tryptophan availability (expressed by the ratio free plasma tryptophan/LNAA), followed by cerebral 5-HT increment, represents the common pathogenic anorexic mechanism in different diseases (1,48,49, 206, 323); when considering 5-HT action on feeding behaviour, is comprehensible how reducing tryptophan transportation in the CNS, with the consequent reduction of cerebral 5-HT synthesis and activity, could alleviate anorexic states (49). The cytokines released by the immune system cells inhibit food intake in some pathologies (1,179,397). Following interferon treatment (144), anorexia onset has been observed for sometime but the first cytokines to be specifically studied for this purpose were the Tumor Necrosis Factor (TNF) (57) and interleukin (IL)-1 (247). Successivly, anorexia onset was also liked to IL-6 (310) and IL-2 (58). Knowing how cytokines affect feeding behaviour has a considerable importance since it can be the physiopathologic base for the development of new specific drugs able to contrast anorexia onset and, then, increase the effectiveness of specific therapies, improve the quality of life reducing morbidity and mortality rate in numerous chronic diseases (213). For example, the use of anticorps IL-6 alleviates anorexia and malnutrition in patients affected by some cancer types (373). Up to now, it is not completely clear how cytokines induce anorexia. It is obviously supposed that they may act by interfering with some of the peptidergic mechanisms described above (314).


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IL-1 and Ciliary Neurotropic Factor determine the reduction of hypothalamic NPY synthesis and of its post-receptor effects (117,195,404). Besides, over-regulations of the cerebral receptors for IL-1 has been observed in murine tumors (309, 378). It has been hypothesized that TNF and IL-2 reduce the responsivity of the α-MSH/AGRP system (59); in practice, these cytokines constantly activate α-MSH release and consequently inhibit NPY (214). According to other authors, cytokines also act on the serotoninergic system controlling feeding behaviour (1,49,255,308). TNF induces the oxidation of the ramified chain AA, which compete with tryptophan for HEB crossing; this way, more tryptophan reaches the CNS and more 5-HT is formed. In the end, it has been hypothesized that cytokines may also act by activating afferent vagal fibres that inform the CNS of the occurrence of food intake (38,97,283). Anyhow, given the close relationships among the different mechanisms of feeding behaviour control, it can be supposed that all these different hypothesis may not be valid, and at the same time that they may also be integrating among themselves. The results from different studies support such supposition (16,49,254, 347, 387).


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VI. CONCLUSIONS Knowing the exact mechanisms through which neuropeptides and cytokines as well as the respective receptor antagonists and agonists can increase or reduce food intake represents the first step for the development of new pharmacological interventions to be used in feeding behaviour disorders. Today ulterior studies are needed on the matter, not only to know more on food intake control systems, but also to evaluate the affects that the administrations of agonists and antagonists of neuropeptides and cytokines may have on other functions. The amount of commitment that today is being applied in merit is prevalently aimed to the treatment of obesity and primary feeding behaviour disorders, but the results of these researches will certainly have important consequences not only on the treatment of obesity and on feeding behaviour disorders, but also on the treatment for anorexia that is manifested in pathologies such as cancers, chronic kidney insufficiency and hepatic cirrhosis.


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