Regulatory peptides and control of food intake in non-mammalian vertebrates

Ž .Comparative Biochemistry and Physiology Part A 128 2001 471�479

Review

Regulatory peptides and control of food intake innon-mammalian vertebrates

Jorgen Jensen�¨Department of Zoophysiology, Goteborg Uni�ersity, P.O. Box 463, 405 30 Goteborg, Sweden¨ ¨

Received 1 April 2000; received in revised form 3 July 2000; accepted 4 October 2000

Abstract

The current view of the control of food intake involves a central feeding system in the hypothalamus receiving inputfrom peripheral systems. The presence of food in the gut stimulates the release of several regulatory peptides thatcontrol gut motility and secretion. Some of these peptides also act as feedback satiety signals, responsible fortermination of a meal. Among the regulatory peptides suggested as peripheral satiety signals are cholecystokinin andgastrin releasing peptide. A more long-term peripheral regulation of food intake has also been postulated and leptin hasbeen suggested as a regulator of food intake. Several regulatory peptides mediate orexigenic or anorexigenic effects inthe central feeding system. Neuropeptide Y and galanin both act centrally and stimulate the intake of food, whilecorticotropin releasing factor reduces food intake. At present, most information about the regulation of food intake isgained from mammalian studies and these findings are used as a base for a discussion on the current knowledge of howregulatory peptides control appetite in non-mammalian vertebrates. � 2001 Elsevier Science Inc. All rights reserved.

Keywords: Appetite; Bombesin; Cholecystokinin; CRF; Galanin; Neuropeptide Y; Satiety

1. Introduction

The control of food intake is highly complexand involves numerous external and internal fac-tors. This review will concentrate on the regula-tory peptides suggested to be involved in themediation of this control. Several reviews on thecontrol of appetite in mammals have been pub-lished during the last decade, but the purpose of

� Corresponding author. Tel.: �46-31-7733671; fax: �46-31-7733807.

Ž .E-mail address: [email protected] J. Jensen .

the present review is to give an overview of thecontrol in different groups of non-mammalianvertebrates. However, as most knowledge is basedon findings from mammals and the informationabout the control of food intake in other verte-brate groups is limited, especially when it comesto amphibians and reptiles, the knowledge frommammals will be used as a base for the discus-sion.

A current model of the control of food intakedescribes a central feeding system, which has theoverall control of the intake of food. This systeminvolves specific nuclei of the hypothalamus and

1095-6433�01�$ - see front matter � 2001 Elsevier Science Inc. All rights reserved.Ž .PII: S 1 0 9 5 - 6 4 3 3 0 0 0 0 3 2 9 - 9

( )J. Jensen � Comparati�e Biochemistry and Physiology Part A 128 2001 471�479472

receives input from two major peripheral systems.One short-term system, also called the peripheralsatiety system, which transmits meal-related sig-nals to the central system, and one long-termsystem giving information to the central feedingsystem on the amount of adipose tissue and theoverall energy balance of the body.

The major focus of this review is on the regula-tory peptides present in the short-term peripheralsatiety system and the central feeding system.However, the long-term peripheral system hasreceived a lot of attention the last few years,

Žfollowing the discovery of leptin Zhang et al.,.1994 . Leptin is in mammals suggested to be

released from adipose tissue in relation to theamount of adipose tissue present, and leptin thenacts on the central feeding system to reduce food

Žintake Considine and Caro, 1997; Friedman and.Halaas, 1998 . The chicken leptin gene has been

cloned and sequenced, and the deduced aminoacid sequence of the protein show a high degree

Žof similarity to mammalian leptin Taouis et al.,.1998 . Like in mammals, peripheral injections of

Žleptin reduce food intake in chicken Raver et al.,.1998 . Although the gene for fish leptin has not

been cloned, immunoreactive material similar insize to mammalian leptin was recently describedin tissues from several species of fish, using anti-bodies against mouse leptin. It was also demon-

Žstrated that fasted green sunfish Lepomis cyanel-.lus have reduced plasma levels of leptin com-

Ž .pared to fed fish Johnson et al., 2000 . On theother hand, long-term treatment of coho salmonŽ .Oncorhynchus kisutch with human leptin has no

Žsignificant effect on food intake Baker et al.,.2000 , and it is evident that structural characteri-

zation of a fish leptin and more physiologicalstudies are needed before the function of leptinin fish may be clearly established.

2. The peripheral satiety system

The presence of food in the gastrointestinalcanal stimulates the release of regulatory pep-tides involved in the control of gut motility andsecretion. Some of these peptides are also in-volved in the peripheral satiety system transmit-ting satiety signals to the central feeding system,thereby causing termination of the meal. Thesignals can be mediated by stimulation of afferentnerves or by endocrine pathways and arise from

receptors sensing factors such as gastric disten-sion and intestinal nutrient content. A high in-testinal nutrient content will also convey signalsto the stomach, reducing gastric emptying rateand thus further prolong the postprandial gastric

Ž .distension Morley, 1987 . Several regulatory pep-tides have been suggested to act as satiety signals,but cholecystokinin and bombesin described belowhave received most attention so far.

2.1. Cholecystokinin

Ž .Cholecystokinin CCK is a peptide occurringin several different molecular forms. In mammals,CCK8 and the N-terminally extended forms con-sisting of 22, 33, 39 or 58 amino acids representdifferential processing by proteolytic enzymes.The structure of the C-terminal octapeptide ofCCK has been well conserved during evolutionand is identical in mammals, chicken, turtle andfrog, and there is only one substitution in the fish

Ž .CCK8 described so far Johnsen, 1998 . CCK iswidely distributed in both nerves and endocrinecells of the gastrointestinal tract in both mam-mals and non-mammalian vertebrates and is in-volved in many gastrointestinal functions includ-ing gallbladder contraction, pancreatic enzymesecretion, stimulation of gastrointestinal motility

Žand inhibition of gastric emptying Crawley andCorwin, 1994; Grider, 1994; Jensen and Holm-

.gren, 1994 .CCK is probably the best studied of the pep-

tides suggested to be involved in the peripheralsatiety system. In mammals, the intake of foodwill stimulate the release of CCK from endocrinecells which in turn stimulates vagal afferents in-nervating the central feeding system causing aninhibition of further food intake. Studies haveshown that CCK may be a regulatory substancealso in the central feeding system acting on cen-tral receptors and causing a reduction in food

Žintake Silver and Morley, 1991; Reidelberger,.1994 .

Ž .Intraperitoneal i.p. injections of CCK8 pro-duce a dose-dependent suppression of food in-take in the goldfish, Carassius auratus, which sug-gests a role for CCK in the peripheral satiety

Ž .system also in fish Himick and Peter, 1994b .However, so far nothing is known about themechanism behind this satiety effect.

In the goldfish, nerve fibers showing CCK-likeimmunoreactivity have been demonstrated in the

( )J. Jensen � Comparati�e Biochemistry and Physiology Part A 128 2001 471�479 473

areas of the CNS known to be involved in feedingcontrol, and high-affinity binding sites for CCKare localized to areas corresponding to the dis-tribution of CCK-containing nerves. In addition,

Ž .intracerebroventricular i.c.v. injections of CCKproduce a reduction of the food intake in gold-fish, supporting the role of CCK as an inhibitoryfactor also in the central feeding system of fishŽ .Himick and Peter, 1994b; Himick et al., 1996 .

Several studies show that i.p. and intravenousŽ .i.v. injections of CCK produce a reduction of

Žfood intake in chicken Savory and Gentle, 1980;Covasa and Forbes, 1994b; Rodriguez-Sinovas et

.al., 1997 . In addition, peripheral injections ofCCK receptor antagonists stimulate food intakeŽCovasa and Forbes, 1994a; Rodriguez-Sinovas et

.al., 1997 . However, the antagonist does not blockthe inhibitory effect of exogenous CCK and therole of CCK as a peripheral satiety factor inchicken has been questioned. CCK induces aver-sive effects and it has been suggested that thereduction of food intake produced by exogenousCCK may be a result of abdominal discomfortŽ .Savory, 1987; Covasa and Forbes, 1994a,b . Onthe other hand, in a study of the white-crowned

Ž .sparrow Zonotrichia leucophrys gambelii it wasshown that suppression of food intake induced byexogenous CCK is abolished by a CCK-antagonistand it was concluded that peripheral CCK in-

Žduced satiety without causing malaise Richard-.son et al., 1993 . Similar to what has been found

in mammals and fish, i.c.v. injections of CCK inbirds suppress feeding, suggesting a role for CCK

Žalso in the central feeding system Denbow and.Myers, 1982; Rodriguez-Sinovas et al., 1997 .

Nothing has so far been published on the possi-ble function of CCK in appetite control in rep-

Ž .tiles or amphibians. However, Adrian et al. 1996reported that the plasma levels of CCK increased

Ž .50-fold in the Burmese python Python molurusafter food intake. This increase is considerablyhigher than what is generally found in mammalsand points to a potential role for CCK in gas-trointestinal and appetite control in reptiles.

2.2. Bombesin�gastrin releasing peptide

The 14 amino acid peptide bombesin, isolatedfrom the skin of the frog Bombina bombina, wasthe first peptide described from this peptide familyŽ .Anastasi et al., 1971 . The structurally related

Ž .gastrin releasing peptide GRP is a 27 amino

acid residue peptide isolated from several mam-malian species and closely related forms of thepeptide are also found in other vertebratesŽ .Holmgren and Jensen, 1994 . The group of pep-tides is characterized by a highly conserved C-terminal part, which is considered most importantfor the biological activity, while the N-terminalregion shows a higher degree of variability. Inmost physiological and immunohistochemicalstudies bombesin and antibodies against bom-besin have been used. However, GRP and notbombesin is the peptide that is expressed in thegut of vertebrates and the effects produced byexogenous bombesin most likely mimics the func-tion of endogenous GRP.

Bombesin-like immunoreactivity has been de-monstrated in the gastrointestinal canal of speciesfrom all the major vertebrate groups, althoughthe localization to nerves and endocrine cellsvaries. In fish and amphibians, bombesin-like im-munoreactivity is found in both nerves and en-docrine cells, while it appears to be exclusivelylocalized to nerves in mammals and to endocrinecells in birds. Bombesin�GRP stimulates gastricacid secretion, but several other functions for thepeptide have been indicated, including stimula-tion of gastrointestinal motility and inhibition of

Žgastric emptying Vigna and Thorndyke, 1989;.Jensen and Holmgren, 1994 .

The ability of bombesin�GRP to suppress foodintake after peripheral injections has been de-monstrated in several mammalian species, but themechanisms involved are not as clear as for CCKand it is currently not known exactly how thesatiety message of bombesin�GRP is mediated.Some studies have also indicated thatbombesin�GRP, especially in high doses, mayhave an aversive effect, which is responsible for

Žthe reduction in food intake McKoy and Avery,.1990; Lee et al., 1994 .

A function of bombesin�GRP as a mediator ofsatiety has been suggested also in fish. Peripheralinjection of bombesin in the goldfish produces asuppression of food intake, and in the carpŽ .Cyprinus carpio bombesin induces an initial de-lay in the onset of feeding, resulting in a reduc-tion of food intake during the experimental pe-

Ž .riod Beach et al., 1988; Himick and Peter, 1994a .A reduction of food intake is also observed

after central injection of bombesin in the goldfishand the presence of nerves showing bombesin�GRP-like immunoreactivity, as well as high-af-


finity binding sites for bombesin�GRP associatedwith the hypothalamic feeding center suggest afunction of bombesin�GRP in the central feeding

Žsystem Himick and Peter, 1994a, 1995; Himick et.al., 1995 .

In chicken and turkeys, i.v. injections of bom-Žbesin decrease food intake Savory and Hodgkiss,

.1984; Savory, 1987; Denbow, 1989 . However, Sa-Ž .vory 1987 suggests that the satiety response to

bombesin in the chicken is caused by effects ongastrointestinal motility, leading to abdominaldiscomfort.

3. The central feeding system

The hypothalamus has a key role in the inte-grated control of food intake in the central feed-ing system. Specific nuclei of the hypothalamus,including the paraventricular, ventromedial, dor-somedial and arcuate nuclei, relay neuronal sig-nals important in the initiation and terminationof a meal and in the control of energy balanceand body weight. Numerous regulatory peptidesand also monoamines are synthesized and re-leased from the hypothalamic neurons, producingorexigenic and anorexigenic signals. How theseneurons are interconnected and how they areaffected by peripheral signals have been workedout to some extent in mammals, while informa-tion about this is limited in other vertebrategroups. Neuropeptide Y, galanin and corti-

Ž .cotropin releasing factor CRF , presented in thefollowing sections, are regulatory peptides impli-cated in the central feeding system of both mam-mals and non-mammalian vertebrates.

3.1. Neuropeptide Y

Ž .Neuropeptide Y NPY is a 36 amino acidresidue peptide, originally isolated from the

Ž .porcine brain Tatemoto, 1982 . The peptide isstructurally characterized by the so called PP-foldwhich consists of two anti-parallel helices, onepolyproline helix and one �-helix held togetherby interdigitating proline and tyrosine residuesŽ .Blundell et al., 1981 . The primary structure ofNPY has been very well conserved during evolu-tion. Alligator NPY is identical to human NPY,and chicken and frog NPY differ by only oneamino acid. Fish NPYs show a few more substitu-tions but the C-terminal dodecapeptide is identi-

cal in all sequences known and they all containthe prolines important for the PP-fold structureŽ .Larhammar, 1996 . Five receptor subtypes forNPY, designated Y , Y , Y , Y and y , have been1 2 4 5 6cloned in mammals and there is also pharmaco-

Žlogical evidence for a Y receptor Michel et al.,3.1998; Wraith et al., 2000 . Several studies have

suggested that both Y and Y receptors are in-1 5volved in the feeding response produced by NPYŽ .Inui, 1999b .

NPY is probably the most studied peptide inthe central feeding system. Intracerebroventricu-lar and hypothalamic injections of NPY in mam-mals stimulate food intake and immunohis-tochemical studies demonstrate the presence ofNPY containing neurons projecting to the hy-pothalamic nuclei involved in appetite regulation.Several lines of further evidence support the roleof NPY as a peptide involved in the physiologicalcontrol of food intake. The expression and re-lease of NPY increase during starvation and thereis also an increase in NPY release before onset offeeding. Furthermore, specific NPY antagonistscause a reduction of feeding. NPY containingnerves interact with many of the regulatory sub-stances in the central feeding system and alsoreceive input from peripheral signals. For exam-ple both insulin and leptin are known to reduce

Žthe expression and release of NPY Schwartz and.Seeley, 1997; Inui, 1999a; Kalra et al., 1999 .

The potential role of NPY in appetite controlhas also been studied in non-mammalian verte-brates. In goldfish, i.c.v. injections of NPY inducea significant increase in food intake. The stimula-tory effect of NPY is abolished by the NPY-

� 27,36 32 � Ž .antagonist D-Tyr , D-Thr NPY- 27�36 , butthe antagonist has no effect on basal food intake.However, the increase in food intake observedafter 24 h of starvation is attenuated by the NPYreceptor antagonist, suggesting that hypothalamicNPY is released in response to starvationŽ .Lopez-Patino et al., 1999 . In accordance with

Ž .this, Silverstein et al. 1998 showed that NPYgene expression in the preoptic area of the hy-pothalamus, equivalent to the paraventricular nu-cleus in mammals, increased significantly in fasted

Ž .coho salmon Oncorhynchus kisutch and chinookŽ .salmon Oncorhynchus tshawytscha compared to

fed fish, giving further evidence for the involve-ment of NPY in appetite regulation in fish.

Intracerebroventricular injections of NPY sti-mulate food intake also in chicken, white-crowned


sparrow and in a reptile, the red-sided garterŽsnake, Thamnophis sirtalis parietalis Kuenzel et

al., 1987; Morris and Crews, 1990; Richardson et.al., 1995 . In white-crowned sparrows, birds sub-

jected to long day lengths showed a higher sensi-tivity to exogenous NPY compared to birds onshort day length, possibly because of higher en-dogenous levels of NPY in the long day adapted

Ž .group Richardson et al., 1995 . Although theknowledge about the function of NPY in non-mammalian vertebrates is limited, the studies re-ported so far supports the role of NPY as anorexigenic peptide in the vertebrate central feed-ing system.

3.2. Galanin

Galanin is a 29 amino acid residue peptideoriginally isolated from the pig intestine and wasnamed galanin from the presence of an N-termi-

Žnal glycine and a C-terminal alanin Tatemoto et.al., 1983 . Galanin has later been isolated from

several non-mammalian vertebrates and thesestudies show that the primary structure of galaninis highly conserved. The 14 N-terminal aminoacids are identical in all sequences of galanin

Žknown so far except for the yellow fin tuna,.which has one substitution in this region pointing

to the importance of the N-terminal part for theŽbiological activity of the peptide Habu et al.,

.1994; Wang and Conlon, 1994 .Immunohistochemical studies have demon-

strated the presence of galanin containing nervesin both the peripheral and central nervous system

Žof vertebrates Bishop et al., 1986; Lazar et al.,1991; Jozsa and Mess, 1993; Karila et al., 1993;

.Merchenthaler et al., 1993; Anglade et al., 1994 .In mammals, galanin is suggested to be involvedin a wide range of physiological functions, includ-ing control of gastrointestinal motility, inhibitionof pancreatic insulin release, stimulation of pitu-itary hormone release and stimulation of feedingŽ .Crawley, 1995 .

Intracerebroventricular and hypothalamic in-jections of galanin in mammals stimulate foodintake and studies of the mechanisms involvedsuggest that at least part of the stimulation iscaused by a release of other stimulatory sub-

Ž .stances Lee et al., 1994; Kalra et al., 1999 .Morphological evidence show that galanin nervesmake synaptic contact with hypothalamic �-endorphin containing nerves and galanin has also

been found to stimulate the release of nora-drenaline from the paraventricular nucleus of the

Žhypothalamus Kyrkouli et al., 1992; Horvath et.al., 1995 . Immunohistochemical studies also show

that NPY-immunoreactive axons surroundgalanin-containing cells in the hypothalamus andit is suggested that NPY in part may act through

Ž .a release of galanin Horvath et al., 1996 .The information on the function of galanin in

appetite control in non-mammalian vertebrates isconfined to two studies on fish. Central injectionsof galanin produce a significant increase in foodintake in both goldfish and tench, Tinca tinca,while peripherally injected galanin has no effect

Žon feeding behavior De Pedro et al., 1995a;.Guijarro et al., 1999 . In the goldfish, injection of

the galanin-antagonist, galantide, abolished thestimulatory effect produced by exogenous galanin,but had no effect on the basal feeding. It was alsoshown that the effect of galanin, like in mammals,probably is mediated by a release of noradrenalin

Žacting on adrenergic � -receptors De Pedro et2.al., 1995a . A role for galanin in the central

feeding system in fish is further supported by thepresence of galanin containing nerves and theautoradiographic demonstration of galanin bind-

Žing sites in the hypothalamus Batten et al., 1990;Moons et al., 1991; Olivereau and Olivereau,

.1991; Anglade et al., 1994 .

3.3. Corticotropin releasing factor

Corticotropin releasing factor or hormoneŽ .CRF, CRH is a 41 amino acid residue peptideoriginally isolated and structurally characterized

Ž .from the ovine hypothalamus Vale et al., 1981 .Determination of the primary structures of addi-tional mammalian and non-mammalian CRFsshow that the structure has been well conserved

Ž .during evolution Lovejoy and Balment, 1999 .CRF is known for its ability to release adrenocor-

Ž .ticotropin ACTH from the anterior pituitary,and several studies show that i.c.v. injections andinjections into the paraventricular nucleus of CRF

Žpotently reduce food intake in mammals Rivier.and Plotsky, 1986; Glowa et al., 1992 . CRF-con-

taining neurons interact with other neurons in thecentral feeding system and it has been suggestedthat CRF has an inhibitory control over NPY-

Ž .induced feeding Heinrichs et al., 1993 . Experi-mental evidence also indicates a possible involve-ment of CRF in the mediation of the anorectic


effect induced by leptin. Leptin stimulates theexpression of the CRF-gene and the release ofCRF in the hypothalamus, and the CRF receptorantagonist, �-helical CRF , blocks the re-9 � 41

Ž .sponse to leptin see Inui, 1999a .Two other peptides belonging to the same

family of peptides as CRF are urocortin andurotensin I. Urocortin was recently identified inthe rat brain and is found to be more potent than

ŽCRF in reducing food intake Vaughan et al.,.1995; Spina et al., 1996 . Urotensin I has been

isolated from several fish species and has in ratbeen found to be equally potent to urocortin in

Žreducing food intake Spina et al., 1996; Lovejoy.and Balment, 1999 .

No studies have so far been reported on thepossible appetite controlling effect of urotensin Iin fish. However, central injections of ovine CRFproduce an inhibition of food intake in both

Ž .tench and goldfish De Pedro et al., 1995c, 1997 .In the goldfish, the feeding inhibition producedby exogenous CRF is attenuated by the antago-nist �-helical CRF and further studies indi-9 � 41cate that the inhibitory effect of CRF is partlymediated by an action on adrenergic and dop-

Žaminergic systems in the hypothalamus De Pedro.et al., 1997, 1998 . Like the situation with galanin,

the knowledge about the role of CRF in thecentral feeding system in other non-mammalianvertebrates is very limited.

3.4. Other peptides

In addition to the peptides described above,several more regulatory peptides are suggested tobe involved in the control of appetite in thecentral feeding system of mammals. Among thesesubstances are, e.g. the anorexigenic peptides:cocaine and amphetamine-regulated transcriptŽ .CART and �-melanocyte-stimulating hormoneŽ .�-MSH , and the orexigenic peptides: melanin-

Ž .concentrating hormone MCH , opioids and orex-Ž .ins Inui, 1999a; Kalra et al., 1999 . So far, the

functions of only a few of these peptides havebeen investigated in non-mammalian vertebrates.The opioid peptide, �-endorphin, promotes feed-ing in mammals and has also been shown to

Žstimulate food intake in fish and birds Devicheand Schepers, 1984; Morley, 1987; De Pedro etal., 1995b; Maney and Wingfield, 1998; Kalra et

.al., 1999 . Similarly, the recently discovered pep-tides orexin A and orexin B have, as the name

implies, an orexigenic effect in mammals and thisŽhas also been demonstrated in goldfish Sakurai

.et al., 1998; Volkoff et al., 1999 . It is likely thatfuture studies will show that additional regulatorypeptides, implicated in mammalian food intakeregulation, will prove to be involved in feedingcontrol also in non-mammalian vertebrates.

4. Conclusions

The current knowledge about regulatory pep-tides in the regulation of food intake indicatesthat there are great similarities in the way differ-ent regulatory peptides are involved in the con-trol in different groups of vertebrates. Althoughthe information from other groups than mammalsis restricted, the basic patterns seem to be verysimilar in this complex control system and suggesta high degree of conservation of the system dur-ing evolution.

CCK and GRP both seem to be involved in theperipheral satiety system transferring the satietymessage from the gastrointestinal tract to thecentral feeding system. In the central feedingsystem, NPY and galanin are both involved in thestimulation of feeding, while CRF exerts an in-hibitory effect. The function of leptin as a media-tor of signals relating to the adiposity stores hasso far only been recognized in mammals andbirds, although evidence has also been put for-ward for a similar function of leptin in fish. How-ever, as mentioned this is a very simplified pictureand many more substances are known to be in-volved in the control of feeding. Future studieswill hopefully be able to clarify how the neuronscontaining regulatory peptides are interconnectedin the central feeding system and how these neu-rons are interconnected with the peripheral sys-tems in the integrated control of feeding.

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Regulatory peptides and control of food intake in non-mammalian vertebrates