J-STAGE Advance Publication Date: December 25, 2010 The Journal of Poultry Science doi: 10.2141/jpsa.010117

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Hypothalamic Melanocortin System on Feeding Regulation in Birds: A Review

Takashi Bungo*, Jun-ichi Shiraishi and Shin-ichi Kawakami

Department of Bioresource Science, Graduate School of Biosphere Science, Hiroshima

University, Higashi-Hiroshima 739-8528, Japan;

Running head: MELANOCORTIN SYSTEM AND FEEDING REGULATIONProofs

*Correspondence:

Dr. T. Bungo Laboratory of Animal Behavior and PhysiolViewogy, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan

E-mail: [email protected]

Advance

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Abstract

Regulation of feed intake in chickens represents a complex homeostatic

mechanism involving multiple levels of control. Understanding the regulation of

feeding behavior can be a very important theme in animal production. Recently, a

close evolutionary relationship between the peripheral and hypothalamic neuropeptides

has become apparent. In the infundibular nucleus (the avian equivalent of the

mammalian arcuate nucleus), the melanocortin system, which contains neuroendocrine

neurons that regulate endocrine secretions by releasing substances, is an essential site in

the brain for signals about the status of peripheral energy balance. The structure and

function of many hypothalamic neuropeptides, melanocortins, neuropeptide-Y (NPY)

and agouti-related (AGRP) have been characterized. ThisProofs review provides as

overview of the various effects and interrelationship of these central and peripheral

neuropeptides, and summarizes the role of the melanocortin system on feeding

regulation in chicks. View Key words: melanocortin system; pro-opiomelanocortin (POMC); neuropeptide-Y

(NPY); agouti-related protein (AGRP); feed intake; chick;

Advance

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Introduction

Feeding behavior in domestic chickens is the one of the greatest concerns of

animal scientists and producers because it not only establishes a healthy life but also

holds the key to improvements in productive efficacy for meat and eggs. Thus,

understanding the regulation of feeding behavior can be a very important theme in

poultry production. There are various factors which affect feeding behavior and the

information-processing network of those factors should operate accurately. In

particular, there is a vast amount of research on brain function because the central

nervous system (CNS) is thought to be a critical center of behavioral motivations.

From the initial findings, it is well known that the lateral hypothalamic area is the

feeding center that accelerates feed intake, and the ventromedialProofs nucleus of the

hypothalamus is the satiety center that decelerates feed intake. The hypothalamic

arcuate nucleus (ARC) has become the focus of much attention in recent years because

of its critical brain site, which is conveniently located at the floor of the third ventricle in an area without the blood brain barrier. View This facilitates signaling from the peripheral organs/tissues to reach the relevant nuclei via the ARC.

To regulate feeding, caloric intake must equal caloric expenditure over time.

Such an intricate process relies on the interactions of a number of physiological systems.

There is considerable evidence that the regulatory system signals from the peripheries

(e.g., intestines, pancreas and adipose tissue) inform the ARC about the status of

peripheral energy balance. Several observations suggest that the ARC contains neuroendocrineAdvance neurons, the so called melanocortin system which is an essential mediator for the peripheral signals such as leptin and insulin action in the CNS

(Schwartz et al., 2000; Benoit et al., 2002). In an expanded sense, the melanocortin

system consists of pro-opiomelanocortin (POMC) neurons inhibiting feeding, and

neuropeptide-Y (NPY) and/or agouti-related protein (AGRP) neurons stimulating

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feeding.

Previous reviews of the relevant neuropeptides and their comparative functions

in mammals on feeding regulation have discussed the role of the CNS in chicks (Furuse,

2002; Furuse et al., 2007). This review provides an overview of and discusses the role

of the melanocortin system on feeding regulation in birds, especially in chickens.

1. Characteristics of Feeding Regulation in the Melanocortin System

1.1. POMC

POMC is a precursor for the melanocortin peptides, α-, β- and γ-melanocyte

stimulating hormone (MSH) and the endogenous opioid, β-endorphin. To date, five

melanocortin receptors (MC1R to MC5R) have been identified (MounProofstjoy et al., 1992;

Adan and Gispen, 2000). MC3R and MC4R are highly expressed in the CNS, and

α-MSH released by POMC neurons in the ARC plays a key role in the control of feed

intake by acting on these receptors in mammals (Mountjoy et al., 1992, 1994; Roselli-Rehfuss et al., 1993). Central Viewinjection of α-MSH or MTII (a synthetic melanocortin agonist for MC3R and MC4R) inhibits feed intake in rodents, as well as in

primates (Poggioli et al., 1986; Fan et al., 1997; Rossi et al., 1998; Murphy et al., 2000;

Koegler et al., 2001; Wirth et al., 2001), and the intracerebroventricular (ICV)

administration of melanocortin antagonists, SHU9119 (both MC3R and MC4R

antagonists) and HS014 (a selective MC4R antagonist), stimulates feeding behavior in

rats (Seeley et al., 1997; Fan et al., 1997; Kask et al., 1998). α-MSH can also increase energyAdvance expenditure (Poggioli et al., 1986; Brown et al., 1998; Hillebrand et al., 2005). Genetic rodent models indicate the importance of the melanocortin system in the

maintenance of body weight (Huszar et al., 1997; Yaswen et al., 1999; Butler et al.,

2000).

The chicken POMC was found to be a single copy gene and shows the

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same structural organization as that of other species of different classes, suggesting that

melanocortins in chickens act in a paracrine and/or autocrine manner to control a variety

of functions in the central and peripheral tissues (Takeuchi et al., 1999). Additionally,

Phillip-Singh et al. (2003) revealed the presence of α-MSH-expressing neurons in the

infundibular nucleus (IN), the avian equivalent of the mammalian ARC (Figure 1). As

for the control of feeding behavior, the central injection of α- and β-MSH, which

non-specifically binds both MC3R and MC4R, suppresses feed intake in chicks

(Kawakami et al., 2000; Smith et al., 2008; Kamisoyama et al., 2009), and HS014

stimulates feed consumption in doves (Strader et al., 2003) and chicks (Bungo et al.,

unpublished data). Although MC3R and MC4R, which have potential roles in the

control of feed intake and body weight in mammals, are highly expressedProofs in mammalian

brains (Grantz et al., 1993; Mountjoy et al., 1994), MC3R expression is not detected by

RT-PCR in the chicken brain (Takeuchi and Takahashi, 1999). However, γ-MSH that

is highly selective for MC3R versus MC4R in chickens (Ling et al., 2004), reduces feed intake in chicks (Smith et al., 2009). Thus,View similar to mammals, the anorexigenic action of melanocortins by POMC neurons in birds seems to be mediated by both

MC3R and MC4R.

1.2. AGRP

AGRP is a 132 amino acid peptide with 25% homology to agouti (Fong et al.,

1997), and is produced in the ARC as a biologically active fragment of the endogenous

antagonist of α-MSH at the MC3R and MC4R (Ollman et al., 1997). In rodents, centralAdvance injection of AGRP potently increases feed intake (Hagan et al., 2000; Kim et al., 2000; Lu et al., 2001), and the anorexic effects of α-MSH and MTII can be blocked by

co-administration of AGRP (Rossi et al., 1998). In good agreement with these

pharmacological findings, genetic manipulations resulting in over expression of AGRP

lead to hyperphagia and obesity in mammals (Ollmann et al., 1997; Marks and Cone,

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2001). Marsh et al. (1999) reported that a targeted disruption of the MC4R gene in

mice eliminates the anorexic effects of MTII, suggesting that the anorexigenic effect of

α-MSH and the orexigenic effect of AGRP are integrated by MC4R. Taken together,

this system is unique in neuroendocrinology in having both agonistic and antagonistic

endogenous ligands that regulate stimulation and inhibition of feed intake depending on

the state of energy balance.

The chicken AGRP gene was found to encode a 154 or 165 amino acid protein

with its C-terminal region showing high homology to mammalian counterparts, and

PT-PCR analysis detected the AGRP mRNA in the brain, liver and so on (Takeuchi et al., 2000). Administration of AGRP into the lateral ventricleProofs of chicks enhances feeding behavior and inhibits the anorexigenic action of α-MSH (Tachibana et al.,

2001). Collectively, α-MSH and AGRP produce opposing effects on feeding behavior

in chicks, comparable to those in mammals. In mammals, several pharmacological

studies have suggested a role for the central melanocortin system in the regulation of the activity of the hypothalamo-pituitary-adrenalView (HPA) axis (Calogero et al., 1988; Ludwig et al., 1998; Dhillo et al., 2002). In avians, ICV injection of α-MSH increases the

level of plasma corticosterone in chicks but the effect is not blocked by

co-administration of AGRP (Tachibana et al., 2007), suggesting that MCs related to the

feeding regulation or HPA axis might be different in the chick CNS. AGRP gene

expression in avians closely resembles that in mammals both in its exclusive

localization in the IN and also in the fact that the majority of neurons that express AGRPAdvance also co-express NPY, a potent appetite neuropeptide as mentioned below (Boswell et al., 2002; Phillips-Singh et al., 2003).

1.3. NPY

NPY contains 36 amino acid residues belonging to the pancreatic polypeptide

family (Tatemoto, 1982), and is one of the most abundant peptides in the brain of rats

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(Allen et al., 1983). In mammals, NPY is the most potent stimulator of feed intake

(Edwards et al., 1999) and NPY producing neurons are present in the hypothalamus and

brainstem (Gray and Morley, 1986). The ARC is the major site of expression for NPY

within neurons in the hypothalamus that projects to the paraventricular nucleus, the

ventromedial nucleus and other sites, facilitating the interaction of NPY with other

orexigenic and anorexigenic signals in the hypothalamus (Sahu et al., 1988). For

example, NPY and AGRP co-express in the ARC neurons and simultaneously repress

anorexigenic melanocortin signaling in the ARC (Kalra and Kalra, 2004). ICV

injection of NPY produces a powerful and prolonged increase in feed intake in rats

(Clark et al., 1984), while long-term administration results in decreased thermogenesis

and obesity (Stanley et al., 1986). The NPY stimulationProofs of feeding is in a

dose-dependent manner, although at higher doses feeding stimulation is less marked

(Clark et al., 1987). As for the receptors for NPY, fasting increases NPY Y1 mRNA

expression in the rat hypothalamus (Wyss et al., 1998), and Y1 receptor deficient mice show significant reduction of daily, fasting-View and NPY-induced feed intake (Pedrazzini et al., 1998; Kanatani et al., 2000). Mice lacking the Y5 receptor eat normally with

normal responses to exogenous NPY but demonstrate late onset of weight gain (Marsh

et al., 1988). Consistent with these findings, pharmacological studies prove that

appetite stimulation by NPY in mammals is mediated by receptors Y1 and Y5 (Kask et

al., 1998; Lecklin et al., 2002; 2003). In addition to Y1 and Y5, Y2 is also an

important receptor in the melanocortin system: POMC neurons in the ARC are inhibited by Advancethe administration of the Y2 receptor agonist PYY3-36 (Ghamari-Langroudi et al., 2005), and mice without Y2 receptors in the NPY neurons show increased NPY and

decreased POMC mRNA expression in the ARC (Shi et al., 2010).

The presence of NPY in the CNS of chickens was first demonstrated by the

NPY-like immunohistochemical study using antibodies against porcine NPY and avian

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pancreatic polypeptide (Kuenzel and McMurtry, 1988). Thereafter, the chicken NPY

gene was cloned (Blomqvist et al., 1992), and NPY was found to be synthesized within

the avian brain by in situ hybridization studies (Boswell et al., 1998; Wang et al., 2001;

Boswell et al., 2002). Similar to mammals, central administration of NPY robustly

stimulates feeding behavior in chickens and chicks in a dose-dependent manner

(Kuenzel et al., 1987; Kuenzel and McMurtry, 1988; Furuse et al., 1997; Bungo et al.,

2000). Fasting leads to increased NPY mRNA levels in the IN hypothalamus of birds

(Boswell et al., 2002). Six NPY receptors (Y1, Y2, Y4, Y5, Y6 and Y7) have been

identified in chickens and their binding characteristics have been investigated (Salaneck

et al., 2000; Holmberg et al., 2002; Lundell et al., 2002; Bromée et al., 2006).

Although these reports demonstrate that the Y1 and Y5 receptorsProofs are expressed in the

hypothalamus containing the IN (Holmberg et al., 2002), in vivo pharmacological

studies have shown contradictory results: the Y1 receptor antagonist did not prevent

fasting- and NPY-induced feeding (Kawakami et al., 2001), while [Leu31, Pro34]-NPY, with a high affinity to the chicken NPY ViewY2 and Y4 receptors (Salaneck et al., 2000; Lundell et al., 2002), increased feed intake, comparable to NPY (Ando et al., 2001).

Because there are conflicting data between the receptor expressions and

pharmacological effects, further studies will be needed to understand the role of NPY

and its receptor subtypes in the melanocortin system.

1.4. Simplified Correlation between the Components on the Feeding Behavior

Based on the above-mentioned mammalian results, a schematic illustration of the hypothalamicAdvance melanocortin system for regulating feed intake is shown in Figure 2. Briefly, increased signals of a fasting condition (negative energy balance) from the

peripheries (intestines, pancreas and adipose tissue) to the ARC inhibits the POMC

catabolic pathway and stimulates the NPY/AGRP anabolic pathway, resulting in

accelerated feed intake (left diagram in Figure 2), while increased satiety signals inhibit

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the NPY/AGRP pathway and stimulate the POMC pathway, resulting in decelerated

feed intake (right diagram in Figure 2). As described above, the melanocortin system

in the IN of chickens resembles that in mammals, and the system has been

neuroanatomically and functionally conserved during long periods of vertebrate

evolution (Lin et al., 2000; Phillips-Singh et al., 2003; Boswell, 2005).

2. Factors Affecting the Melanocortin System

Increasing evidence suggests that peripheral signals from adipose tissue, the

pancreas and the intestines may communicate with the centers of feeding regulation in

the CNS through the melanocortin pathway. There have been a number of reviews

regarding the network in the mammalian melanocortin systemProofs (e.g., Schwartz et al.,

2000; Seeley et al., 2004; Cone, 2005; Garfield et al., 2009). However, it should be

noted that the network in the avian melanocortin system remains to be fully explored.

This section is a summary of the characteristics of major factors, which regulate the network in the hypothalamus of chicks, coViewmpared with the results in mammals. 2.1. Hypothalamic Signals

2.1.1. Cocaine- and Amphetamine-Regulated Transcript (CART)

CART was first identified as a major brain mRNA up-regulated by cocaine and

amphetamine and found to be co-localized with POMC, and expressed in the

hypothalamus (Douglass et al., 1995; Kuhar and Dall Vechia, 1999). In rodents, ICV

injection of CART fragments has been shown to suppress both normal and fasting-inducedAdvance feeding, and completely blocks the feeding response induced by NPY (Kristensen et al., 1998; Lambert et al., 1998). While CART antiserum administration

increases nighttime feeding, suggesting the role of CART as an endogenous satiety

factor (Lambert et al., 1998). There is a decrease in the ARC CART mRNA following

feed deprivation, demonstrating that CART mRNA regulation is related to the fuel

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availability and peripheral hormone status (Li et al., 2002).

Like mammals, central infusion of human CART induces anorexia in chicks

(Tachibana et al., 2003), and the CART mRNA expressions are changed by

anorexigenic and orexigenic peptide treatments (Honda et al., 2007; Bungo et al., 2009).

Although the chicken CART gene has not yet been fully identified, it can be predicted

that POMC neurons in the IN also resemble their mammalian counterparts in

co-expressing CART mRNA. Studies are therefore required to clone and characterize

the chicken CART gene.

2.1.2. μ- Agonists and β-Endorphin Fragments

The opioid system, β-endorphin, dynorphin and enkephalins are the three

biologically active peptides described in the hypothalamus (LevineProofs and Billington,

1989). Opioid peptides mediate the hunger component in the control of feed intake

(Baile et al., 1986), but in contrast to NPY-induced feeding, their effect is relatively

modest and short-lived. Among opioid peptides, β-endorphin (and its receptor) is one of the essential modulators in the melanocViewortin system because it is derived from β-, which in turn is derived from POMC (Mains et al., 1977). β-Endorphin

has affinity for both the μ- and δ-opioid receptors (MOR and DOR) in rats (Raynor et

al., 1994), but opioid antagonist analyses of β-endorphin feeding have shown reductions

induced by MOR, but not by DOR antagonists in mammals (Silva et al., 2001). It has

been recognized that β-endorphin acts in an autoreceptor manner to the MOR on POMC

neurons, diminishing the ARC POMC neuronal activity in response to elevated POMC-derivedAdvance melanocortin peptides that inhibit feed intake in mammals (Wardlaw et al., 1996; Cowley et al., 2001). NPY stimulates β-endorphin release in the

hypothalamus (Horvath et al., 1992), indicating a functional link between NPY and

β-endorphin in mammals. These results suggest that NPY may induce feeding directly

on its own and also by stimulating β-endorphin. The immediate actions of AGRP are

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blocked by non-specific opioid receptor antagonists but not the long-term effects

(Hagan et al., 2001). These findings suggest that the endogenous MOR ligands are an

important “system” modulator which may regulate not only the POMC but also

NPY/AGRP neuron activities.

Similar to that in mammals, central infusion of MOR agonist enhances feeding

behavior in chicks (Bungo et al., 2004; 2005; 2007), and the orexigenic effect is

abolished by MOR, but not by DOR antagonists (Yanagita et al., 2008a). Co-injection

of MOR antagonists are effective in reducing NPY-induced feeding, whereas DOR

antagonists had little effect, suggesting NPY stimulates β-endorphin release in the

hypothalamus in chicks (Dodo et al., 2005). Central MOR agonist infusion with

insulin prevents insulin-induced hypophagia, and attenuates increasingProofs POMC mRNA

expression in the brain of chicks (refer to “2.2.2 Insulin” below). β-Endorphin is

processed into N-terminal fragment peptides by enzyme, and its fragments having low

potency, attenuate β-endorphin-induced action in mammals (Hammonds et al., 1984; Suh et al., 1987; Plum et al., 2009).View In chicks, the fragment abolishes β-endorphin-induced feeding (Yanagita et al., 2008b), and accelerates insulin-induced

anorexia (Shiraishi et al., 2010). These findings imply that β-endorphin acts in an

autoreceptor manner to the MOR on POMC neurons in the IN of chicks, as in mammals.

Further histochemical studies will be needed to understand the role of MOR and MOR

ligands in the melanocortin system of chicks.

2.1.3. Nociceptin/orphanin FQ (N/OFQ) AdvanceNociceptin/orphanin FQ (N/OFQ) is an opioid-related heptadecapeptide identified as the endogenous ligand for the orphan Gi/Go-coupled opioid receptor-like 1

receptor (NOP1) (Meunier et al., 1995; Reinscheid et al., 1995). N/OFQ and NOP1 are

widely distributed in the brain (Mollereau and Mouledous, 2000; Reinscheid et al.,

2000), consistent with involvement in the control of a variety of biological functions

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including feeding regulation: N/OFQ has been shown to stimulate feeding behavior in

rats following ICV administration (Pomonis et al., 1996; Polidori et al., 2000;

Economidou et al., 2006). The ARC has been shown to be the most sensitive brain site

of action for N/OFQ in rats (Polidori et al., 2000). The orexigenic effects of N/OFQ in

the CNS are associated with changes in the hypothalamic AGRP, CART, catecholamines

and excitatory and inhibitory amino acids (Murphy et al., 1996; Murphy and Maidment,

1999; Schlicker and Morari, 2000; Marti et al., 2004; Bewick et al., 2005).

As in mammals, ICV injection of N/OFQ increases feed intake in chickens

(Abbasnejad et al., 2005; Tajalli et al., 2006). It also induces the increased AGRP and decreased CART mRNA expression in the CNS of chicks,Proofs and simultaneous administration of α-MSH completely blocks its orexigenic effect (Bungo et al., 2009),

suggesting that N/OFQ functions in chickens as one of the modulators in the

melanocortin system, as in mammals.

2.1.4. Gamma-Aminobutyric Acid (GABA) It should be emphasized that in Viewthe hypothalamus, the key chemical mode of communication between neurons is via GABA. GABA, the most widely distributed

inhibitory neurotransmitter in the vertebrate central nervous system (Sivilotti and Nistri,

1991), is found in high concentrations in brain areas known to be involved in the control

of ingestive behavior (Decavel and Van den Pol, 1990). Hence, rather than functioning

as a directly acting facilitatory orexigenic agent, it is possible that GABA may exert an

inhibitory effect on an existing anorexigenic tone in the CNS, thus indirectly facilitating feedingAdvance behavior. This might be mediated by decreasing α-MSH release (Jegou et al., 1993) or by rendering crucial target sites highly responsive to NPY. Concerning the

melanocortin system, histochemical studies suggest that NPY neurons in the ARC

largely contain GABA (Horvath et al., 1997), and NPY/AGRP neurons contact and

inhibit adjacent POMC neurons by releasing the inhibitory neurotransmitter GABA

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(Acuna-Goycolea et al., 2005).

In chicks, GABA has been shown to exist in various regions of the brain

(Csillag et al., 1987; Stewart et al., 1988; Granda and Grossland, 1989), as it does in

mammals. Although there is considerable evidence that GABA in the CNS directly

and indirectly induces hyperphagia in chickens (Jonaidi et al., 2002; Takagi et al., 2003;

Bungo et al., 2003), little is known concerning the relationship with the components in

the hypothalamic melanocortin system. Further histochemical and mRNA expression

studies will be needed to understand the role of GABA in the melanocortin system.

2.1.5. Fatty Acid Synthase (FAS)

FAS, a critical enzyme in de novo lipogenesis, catalyzes the seven steps in the

conversion of malonyl-CoA and acetyl-CoA to palmitate in Proofsthe cytoplasm. FAS

inhibition has been shown to facilitate weight loss through increased peripheral

utilization of fat as well as reduction of feed intake in mammals (Ronnett et al., 2005).

Additionally, FAS is expressed in various sites of the brain, and co-localized with NPY in neurons in the ARC. ViewInhibitor experiments revealed that 3-Carboxy-4-alkyl-2-methylenebutyrolactone (C75), a specific inhibitor of FAS, alters

feed intake via interactions within the ARC-PVN pathway mediated by NPY in mice.

(Kim et al., 2002). C75 also prevents the hypophagia-induced increases in mRNA for

AGRP in the ARC of rodents (Aja et al., 2006), suggesting that FAS may be involved in

the mammalian melanocortin system.

Similar to mammals, FAS is found in a number of brain regions, including the IN, Advanceand peripheral administration of FAS inhibitor significantly reduces feed intake in chickens (Dridi et al., 2006). Dridi et al. (2006) also revealed that the inhibitor

decreased gene expressions of the MC1, MC4 and MC5 receptors, but not NPY, AGRP

and POMC in the brain of chickens. These results suggest that the central FAS in

chickens may participate in the regulation of feeding behavior through the melanocortin

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system. Although experiments aimed at determining the role of FAS in the

melanocortin system of neonatal chicks have not been performed, our recent research

shows that ICV injection of C75 reduces feed intake in chicks (Bungo et al.,

unpublished data), suggesting the central FAS in neonatal chicks may also be involved

in the melanocortin system, comparable to mammals.

2.1. Peripheral Signals to the CNS

2.2.1. Leptin

The discovery of leptin, the adipocyte-derived protein hormone providing this

signal (Zhang et al., 1994), plays an important role in defining the neuronal circuitry in

the hypothalamic controlling feed intake in mammals (Schwartz et al., 2000; Horvath et

al., 2004). Peripheral leptin administration results in activationProofs of hypothalamic

neurons expressing the leptin receptor (Håkansson et al., 1998), suggesting a

hypothalamic mediation of leptin effects on satiety. In the hypothalamic ARC, leptin

facilitates satiety through inhibition of the NPY/AGRP neurons while stimulating POMC neurons (Sahu, 2003) and CARTView (Kristensen et al., 1998). Leptin acutely suppresses NPY-induced feeding and on a long term basis in rats (Xu et al., 1998).

NPY-deficient mice demonstrated leptin-induced suppression of feeding, suggesting the

importance of other pathways in the action of leptin (Erickson et al., 1996). Blockade

of MC4R reduces the ability of leptin to inhibit feed intake, suggesting that the

melanocortin pathway has a major role in mediating leptin effects (Seeley et al., 1997).

The chicken leptin cDNA sequence that shares 95% and 97% sequence identity withAdvance mouse leptin at the nucleotide and amino acid level, was cloned (Taouis et al., 1998; Ashwell et al., 1999). The effect of central administration of mammalian or

recombinant chicken leptin is consistent with an inhibitory influence of the hormone on

feed intake in chickens (Denbow et al., 2000; Dridi et al., 2000). Continuous infusion

of chicken leptin down-regulates the expression of the MC4R, MC5R, leptin and NPY

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receptors but does not affect POMC or AGRP mRNA expression in the hypothalamus

(Dridi et al., 2005). There is evidence that the cloned chicken leptin receptor shows

conservation of the key motifs in the long form (Horev et al., 2000; Ohkubo et al.,

2000) and short form (Liu et al., 2007), and a leptin-like signaling system is present

(Adachi et al., 2008). On the other hand, several independent laboratories have been

unable to amplify the reported sequence by PCR (Friedman-Einat et al., 1999; Pitel et

al., 2000; Amills et al., 2003), and infusion of mouse leptin is ineffective in feeding

behavior in chicks (Bungo et al., 1999). Thus, the existence of a natural chicken leptin

gene and its encoded protein should be unequivocally established before progress can

be made in understanding the effects of leptin on energy balance in birds (Sharp et al.,

2008). Proofs

2.2.2. Insulin

Insulin is well recognized as the key glucostatic regulator. Recent data show

that in addition to the control of glucose uptake in peripheral areas, this role also encompasses powerful central effects, inView synergy with leptin. Insulin receptors and components of the insulin-signaling pathway are also widely distributed in the CNS,

and regulate vital physiological processes in mammals (Pagotto, 2009). Recently, it

has been suggested that impairment in brain insulin availability or signaling results in

serious problems such as metabolic, mental or reproductive disorders (Saltiel and Kahan,

2001; Obici et al., 2002; Gerozissis, 2004). Tschritter et al. (2006) reported that CNS

insulin resistance contributes to human obesity. It has been proposed that insulin resistanceAdvance may not only be a consequen ce of, but also involved in the etiology of obesity in humans (Pagotto, 2009). Insulin has been suggested to have anorexic

effects centrally (Woods et al., 1979), and notably, the ARC is one of the prominent

sites of insulin receptor expression in mammals (Corp et al., 1986; Marks et al., 1990).

Insulin down-regulates NPY and AGRP gene expression and increases POMC gene

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expression in the mammalian ARC (Schwartz et al., 1992; Benoit et al., 2002),

suggesting that the anorexigenic effects of insulin are associated with the melanocortin

system.

Like mammals, the insulin receptor is present in the CNS of chickens (Simon

and Le Roith, 1986). Injection of insulin into the lateral ventricle of chicks inhibits

feed intake, and increases expression of POMC mRNA and decreases that of NPY

mRNA (Shiraishi et al., 2008a; 2008b; 2009). Also, the melanocortin antagonists

prevent the anorexic effect of insulin. Recently, we found that the expression of

chicken insulin receptors in the CNS by nutrient conditions (Shiraishi et al., in press), to

be localized in the IN (Shiraishi et al., unpublished data). These findings suggest that

the central melanocortin system mediates the anorexia by central Proofsinsulin, as in mammals.

Further studies are therefore required for the insulin receptor to be co-localized with the

POMC or NPY neurons in the chicken IN.

2.2.3. Ghrelin Ghrelin, identified from rat stomachView as an endogenous ligand for the growth hormone secretagogue receptor, is unique as the first gut hormone (Kojima et al., 1999),

and is shown to stimulate feeding behavior (Strader and Woods, 2005). It further

stimulates feeding by its action on NPY/AGRP neurons and inhibition on POMC

neurons in the CNS (Cowley et al., 2003a; Greenman et al., 2004), suggesting the role

of the melanocortin pathway in transmitting gut hunger signals to the mammalian brain.

Ghrelin increases c-fos activity in the NPY/AGRP neurons but not in the POMC neuronsAdvance (Wang et al., 2002), and the hyperpolarization of POMC neurons thus induced by ghrelin might be mediated through GABA release by NPY/AGRP neuron

depolarization (Cowley et al., 2003b). While leptin might transmit energy balance

signals over a long term, the gut hormones might mediate short term signaling due to

rapid fluctuation with meals.

J-STAGE Advance Publication Date: December 25, 2010 The Journal of Poultry Science doi: 10.2141/jpsa.010117

Chicken ghrelin, containing a 26 amino acid peptide, has been cloned and

identified (Kaiya et al., 2002; Geelissen et al., 2003; Tanaka et al., 2003), and has a

various physiological functions, as in mammals (see Review, Kaiya et al., 2007a). The

levels of ghrelin and its mRNA in chicks are changed by nutritional condition, like in

mammals (Kaiya et al., 2007b). However, dissimilar to mammalian results, central

administration of ghrelin or its agonist has the opposite effect on feeding: it prevents

fasting- and NPY-induced hyperphagia (Saito et al., 2002; 2005; Khan et al., 2006).

Also the expression of NPY mRNA in the CNS is not altered by ghrelin infusion (Saito

et al., 2005). Interestingly, recent data show that peripheral injection of chicken

ghrelin has a short acting orexigenic effect, and acutely up-regulated hypothalamic FAS

mRNA levels in chicks (Buyse et al., 2009). This finding indicatesProofs that the effects of

ghrelin in the melanocortin system in chicks remain to be fully explored.

3. Conclusion Figure 3 shows a schematic diagramView for the predicted melanocortin system in the IN of chickens. Population of first-order NPY/AGRP and POMC neurons, which

are mutually connected with synapses, are regulated by peripheral hormonal and

nutrient/metabolic signals, and project to second-order hypothalamic neuropeptide

neurons involved in the regulation of feed intake. Although details for the receptors

are not indicated, some receptors for the numbers of hormones, neuropeptides and

neurotransmitters (e.g., MOR, NPY Y1, and GABA receptors) known to regulate the networkAdvance are assumed to exist in the hypothala mic melanocortin system, as in mammals. Furthermore, detailed second-order hypothalamic neuropeptide neurons (e.g.,

corticotropin-releasing hormone, galanin, melanin-concentrating hormone and so on)

are not described in this review due to lack of space. Some of the studies described in

the present review are only initial studies, and more work remains to be carried out with

J-STAGE Advance Publication Date: December 25, 2010 The Journal of Poultry Science doi: 10.2141/jpsa.010117

regard to the precise mapping in the CNS of the synthesis and release of neuropeptides

related to their feeding regulatory activities, and the innervation and localization of their

receptors in the CNS. A better understanding of feeding regulation may aid the

selection of chickens for production and animal welfare.

Acknowledgements

The authors are deeply indebted to K. Yanagita for his great help in preparation

of the manuscript. The authors further wish to thank M. Fujita, M. Tsudzuki and Y.

Yoshimura for their encouragement. The author, T. Bungo, was awarded the 2009

Scientist Prize of Japan Poultry Science Association for central feeding regulation in

chicks. Proofs

View

Advance

J-STAGE Advance Publication Date: December 25, 2010 The Journal of Poultry Science doi: 10.2141/jpsa.010117

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Legends

Figure 1. Location of the hypothalamic infundibular nucleus (IN) in which the

melanocortin system may exist in the chick brain. Coronal (transverse)

sections through the chick brain are depicted.

Figure 2. Schematic illustration of hypothalamic melanocortin system for regulating

feed intake. See text for details. NPY, neuropeptide Y; AGRP, agouti-related

protein; POMC, pro-opiomelanocortin; α-MSH, α-melanocyte-stimulating

hormone; ARC, arcuate nucleus; (+); activate; (-), inhibit.

Proofs

Figure 3. Schematic diagram depicting the predicted hypothalamic infundibular

nucleus (IN) neuronal network. See text for details. NPY, neuropeptide Y; AGRP, agouti-related protein; POMC,View pro-opiomelanocortin

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