Comparative Biochemistry and Physiology Part A 126 (2000) 415–434 www.elsevier.com/locate/cbpa

Review Brain regulation of feeding behavior and food intake in fish

Xinwei Lin, He´le`ne Volkoff, Yuwaraj Narnaware, Nicholas J. Bernier, Pierre Peyon, Richard E. Peter*

Department of Biological Sciences, Uni6ersity of Alberta, Edmonton, Alta., Canada T6G 2E9 Received 17 September 1999; accepted 24 May 2000

Abstract

In mammals, the orexigenic and anorexigenic neuronal systems are morphologically and functionally connected, forming an interconnected network in the hypothalamus to govern food intake and body weight. However, there are relatively few studies on the brain control of feeding behavior in fish. Recent studies using mammalian or fish homologs of mammalian neuropeptides indicate that brain orexigenic signal molecules include Y, , and b-endorphin, whereas brain anorexigenic signal molecules include , , corticotropin-releasing factor, cocaine- and amphetamine-regulated transcript, and . Tachykinins may also have an anorectic action in fish. The brain hypothalamic area is associated with regulation of food intake, while sites outside the hypothalamus are also involved in this function. There is correlation between short-term changes in serum growth hormone levels and feeding behavior, although possible mechanisms integrating these functions remain to be defined. © 2000 Elsevier Science Inc. All rights reserved.

Keywords: Feeding; Neuropeptide; Growth hormone; Brain; Fish

1. Introduction relatively little. Chronic imbalance between food intake and energy expenditure results in changes In mammals, stability of body weight and body in adipose tissue mass (Je´quier and Tappy, 1999). composition over long periods of time requires The ‘lipostatic model’ has been proposed to ex- that energy intake matches energy expenditure plain the well-regulated control of body weight (Je´quier and Tappy, 1999). There are mechanisms and food intake, and predicts that secretions from that tend to maintain energy intake and energy fat cells are the key signal to the brain to regulate expenditure in balance. In mature mammals, body feeding and body-fat deposition (Inui, 1999). A weight regulation mainly concerns adipose tissue large and rapidly growing literature supports this mass, as protein and carbohydrate stores vary hypothesis (Woods et al., 1998; Seeley and Schwartz, 1999). In particular, recent cloning of  Plenary lecture at the International Congress of Compara- the obese (ob) and identification of its en- tive Physiology and Biochemistry, August 1999, Calgary, coded protein leptin produced from adipose tissue Alta., Canada. (Zhang et al., 1994) is a major breakthrough in * Corresponding author. Tel.: +1-780-4924757; fax: +1- 780-4927033. the understanding of the neuroendocrine regula- E-mail address: [email protected] (R.E. Peter). tion of energy homeostasis. Leptin acts via hypo-

1095-6433/00/$ - see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S1095-6433(00)00230-0 416 X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434 thalamic receptors to inhibit feeding, decrease as a motivator for additional research on regula- body weight, and increase locomotor activity and tion of feeding in fish. thermogenesis in rodents (Campfield et al., 1995; Halaas et al., 1995; Pelleymounter et al., 1995). Leptin and its receptor system provide an afferent 2. Brain regions involved in feeding regulation negative feedback signaling system reflecting the amount of adipose energy stores to the brain In mammals, hypothalamic sites, such as the hypothalamic centers (Schwartz and Seeley, 1997). ventromedial nucleus (VMN), dorsomedial nu- Leptin targets in the hypothalamus include neu- cleus (DMN), paraventricular nucleus (PVN), and ropeptides, such as (NPY), the lateral hypothalamus (LH), have been previ- agouti-related (AGRP), a-melanophore- ously indicated as neural centers involved in the stimulating hormone (a-MSH), corticotropin-re- control of feeding behavior, largely based on the leasing factor (CRF), galanin, melanocyte numerous studies employing either discrete lesions concentrating hormone (MCH), and orexins or surgical transection of neural pathways (Kalra (Mercer et al., 1996; Cheung et al., 1997; et al., 1999). The dual center model for regulation Campfield et al., 1998; Ha˚kansson et al., 1998, of feeding hypothesized that the LH area served as 1999), that modulate food intake and energy ex- a ‘feeding center’ and the VMN as a ‘satiety penditure. Thus, a feedback regulatory loop with center’ (Anand and Brobeck, 1951). Over the past three distinct steps has been hypothesized, which few years, identification of a number of orexigenic include a sensor that monitors the level of energy, and anorexigenic signaling molecules and their hypothalamic centers that receive and integrate receptors in the hypothalamus, and the neuronal through leptin receptors the intensity of the signal, sites of their production, release, and receptive and effector systems that influence energy intake fields has redefined the hypothalamic pathways and energy expenditure (Je´quier and Tappy, involved in the regulation of feeding and body 1999). weight. In addition, evidence of morphological There are relatively few studies on the brain relationships among these signaling-molecule pro- control of feeding behavior in fish. From the ducing neurons, and co-localization or co-produc- 1960s to the early 1980s, a number of studies using tion of more than one signaling molecule in these electrical stimulation and lesioning of brain re- neurons has demonstrated an interconnected cir- gions demonstrated hypothalamic involvement in cuitry in the hypothalamus to regulate feeding the control of feeding behavior in fish (Peter, behavior (for a review, see Elmquist et al., 1999). 1979; Demski, 1983). From the 1980s to the 1990s, In LH, two neuropeptides, MCH and the orex- a large number of brain neuropeptides and their ins, also called hypocretin, were newly recognized receptors related to feeding regulation have been (Bittencourt et al., 1992; de Lecea et al., 1998; identified and characterized in mammals. Starting Sakurai et al., 1998). It is now well known that in the early 1990s, some of these mammalian MCH and orexins are orexigenic signaling neuropeptides or fish homologs of mammalian molecules, and their producing neurons represent neuropeptides were examined to assess their regu- the anatomic components for the lateral hypotha- latory effects on feeding behavior and food intake lamic feeding center (Qu et al., 1996; Sakurai et in fish. Goldfish have been used as a major model al., 1998). The central nervous system targeted for these studies, and neuropeptides and neuro- sites for MCH and orexins are similar, and in- transmitters, such as NPY, orexins, galanin, CRF, clude the paraventricular thalamic nucleus, central b-endorphin, cholecystokinin (CCK), bombesin gray, raphe nuclei, locus coeruleus, suprachias- (BBS), cocaine- and amphetamine-regulated tran- matic nucleus, PVN, arcuate nucleus (ARC) and script (CART), tachykinins and serotonin, have supraoptic nucleus (Date et al., 1999). On the been shown to be involved in the regulation of other hand, recent evidence has shown that neu- feeding in fish. These studies provide a framework ropeptides that decrease food intake and body for understanding mechanisms underlying the weight are also expressed in the LH area, and brain regulation of food intake in fish. The follow- these may play a counteregulatory role, opposing ing review will briefly describe these studies in the systems that increase food intake. These neu- comparison with what has been achieved in mam- ropeptides include CART and CRF, both of malian models. We hope that this review will serve which are expressed in LH and decrease X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434 417 food intake when centrally administered (Koylu et NPY levels in the ARC, PVN and DMN (Inui, al., 1997; Kristensen et al., 1998; Kelly and Watts, 1999). In addition, leptin receptors are coex- 1998). In ARC, a prominent hypothalamic site pressed with POMC neurons, which also produce associated with hypothalamic integration of en- CART peptides and POMC peptides (b-END and ergy balance, neurons produce orexigenic peptides a-MSH) in the ARC and retrochiasmatic area such as NPY, opioids, galanin (GAL), AGRP, (Cheung et al., 1997; Elias et al., 1998b). Recent , and the pro-opiomelanocortin anatomic studies have begun to illuminate the (POMC)-derived , b-endophin (b-END), connection between leptin-regulated neurons in and anorexigenic peptides such as CART peptides the ARC, and MCH and neurons in the and the POMC-derived peptide, a-MSH, and the LH area. There is intense innervation of both amino aicds, g-aminobutyric acid (GABA) and MCH and orexin neurons in the LH by axons glutamate (Kalra et al., 1999). The terminal fields containing NPY, AGRP, and a-MSH, probably of these orexigenic and anorexigenic producing from the ARC (Broberger et al., 1998; Elias et al., neurons in the ARC extend into various hypotha- 1998a). On the other hand, neural receptive sites lamic sites including the VMN, DMN, PVN, pre- for the anorexigenic signals overlap with sites optic area (POA) and perifornical hypothalamus. containing receptors and terminal fields of orexi- In addition, the ARC appears to be the site for genic signals (Kalra et al., 1999). Therefore, the integrating circulating metabolic signals, such as orexigenic and anorexigenic neuronal systems are the adrenal and gonadal steroids, leptin and in- morphologically and functionally connected, sulin (Kalra et al., 1999). In VMN, there is no forming an interconnected network in the hypo- evidence so far for production of orexigenic or thalamus to govern food intake and body weight. anorexigenic signals. However, it is suggested that In fish, there are relatively few studies dealing with the neural control of feeding. Information on VMN is a receptive field for a number of feeding the neural substrates involved in the regulation of regulatory signal molecules, and transfers the in- feeding are virtually all derived from studies using formation flow to the DMN–PVN for the release electrical stimulation and lesioning in the brain or of orexigenic signals (Kalra et al., 1999). DMH is transection of neural pathways, such as the olfac- one of the NPY-producing sites in the hypothala- tory tracts (for a review, see Peter, 1979; Demski, mus, and is suggested as a site of NPY and leptin 1983). Electric stimulation studies, carried out in interaction, and is thought to be involved in the bluegill sunfish (Demski and Knigge, 1971), cich- attenuation or inhibition of feeding by leptin lids (Demski, 1973) and goldfish (Savage and (Yokosuka et al., 1998). PVN is another NPY- Roberts, 1975; Roberts and Savage, 1978), producing site, and is thought to be one of the demonstrated the involvement of the inferior crucial sites for the release of orexigenic signals, lobes of the hypothalamus in the organization and also one of the sites for interaction of neuro- and control of feeding behavior. Feeding re- hormones that inhibit feeding by diminishing sponses have also been evoked in nurse sharks by NPY release (Kalra et al., 1991a; Dube et al., electrical stimulation of the inferior lobe of the 1992). hypothalamus (Demski, 1977). Feeding behavior Leptin controls energy balance through a nega- in teleosts could also be evoked by stimulation of tive-feedback loop that originates in adipose tis- locations in the telencephalon or reduced by ol- sue, enters hypothalamus via the median factory tract lesions (Grimm, 1960; Demski and eminence and acts on hypothalamic centers Knigge, 1971; Stacey and Kyle, 1983). It was (Elmquist et al., 1999). Leptin receptor mRNA is suggested that olfactory input and telencephalon highly expressed in the hypothalamic nuclei output can serve to activate or arouse feeding around the median eminence, such as ARC and behavior. The output from the telencephalon with parts of VMN, DMN and ventral premammillary regard to feeding behavior would presumably be nucleus, as well as in the LH area (Fei et al., 1997; via the medial forebrain bundle to the inferior Elmquist et al., 1998; Ha˚kansson et al., 1998). lobe of the hypothalamus (Peter, 1979). In addi- Leptin receptors are expressed in NPY neurons tion, electrical stimulation of the optic lobes in co-producing NPY and AGRP (Broberger et al., wrasse and sunfish has been shown to evoke 1998; Hahn et al., 1998). Leptin inhibits NPY-me- feeding behaviors, indicating that an input from diated neuronal activity in the hypothalamus, re- the optic tectum may also arouse feeding mecha- duces levels of NPY mNRA in the ARC, and nisms in the hypothalamus (Peter, 1979). 418 X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434

In fish, several feeding-related neuropeptides, synaptic contacts with GAL and POMC peptides such as NPY (Blomqvist et al., 1992), MCH (a-MSH and b-END) producing neurons in the (Baker et al., 1995), galanin (Anglade et al., 1994; ARC, with CART peptide perikarya in parvocel- Wang and Conlon, 1994), POMC-derived pep- lular PVN, and with orexin neurons in LH tides (Okuta et al., 1996; Arends et al., 1998), (Elmquist et al., 1999). CRF (Okawara et al., 1988; Ando et al., 1999; The presence of NPY in fish was first demon- Bernier et al., 1999) and CCK (Peyon et al., strated in goldfish by immunological and chro- 1988), have been identified in the brain by isola- matographic studies (Kah et al., 1989). In tion of the peptide or by cloning of their cDNA goldfish, NPY immunoreactive neurons are sequences. However, the studies on the potential present in the ventromedial-posterior hypothala- regulatory effects of these neuropeptides on food mus and hypothalamic inferior lobes (Pontet et intake are very limited. Generally, these studies al., 1989). Our previous studies have shown that indicate that the brain hypothalamic area is in- NPY binding sites are also localized in the feeding volved in the regulation of food intake by these regulatory center (Himick et al., 1995). The se- neuropeptides. However, little work has been car- quence of goldfish NPY cDNA has been deter- ried out on the precise mapping of these neu- mined and shows strong evolutionary ropeptides in the brain hypothalamic area in conservation among vertebrate species (Blomqvist regard to their feeding effects. Interestingly, our et al., 1992). The goldfish NPY has only five recent studies on postprandial CCK and NPY residues different from rat NPY (Blomqvist et al., gene expression have shown that sites outside of 1992). In situ hybridization and Northern blot the hypothalamus may also play an important studies have shown that NPY mRNA is mainly role in mediating regulation of feeding by these expressed in forebrain regions of goldfish, particu- neuropeptides (Peyon et al., 1999; Narnaware et larly in the nucleus entopeduncularis of the ven- al., 2000). tral telencephalon, POA, olfactory bulbs, and various thalamic regions (Peng et al., 1994). In the midbrain of goldfish, NPY mRNA is present in 3. Brain orexigenic signaling molecules the optic-tectum and locus coeruleus (Peng et al., 1994). A similar brain distribution of NPY 3.1. Neuropeptide Y mRNA has been described in coho salmon (Sil- verstein et al., 1998) by in situ hybridization using NPY is a 36-amino-acid peptide belonging to an antisense oligo probe corresponding to the the family (Tatemoto, goldfish NPY cDNA sequence. In addition, only 1982), and is the most abundant peptide yet dis- the pre-optic area of the hypothalamus demon- covered in the mammalian brain, widely expressed strated an increase in NPY gene expression with in the central and peripheral nervous systems fasting in this study, providing additional evi- (White, 1993). In mammals, NPY is the most dence for involvement of NPY in the regulation potent stimulator of appetite and food intake, and of food intake in fish (Silverstein et al., 1998). hypothalamic NPY-expressing cells represent an The direct action of NPY on feeding behavior important and critical site of integration of pe- and food intake has been examined in our recent ripheral hormonal signals with regulation of en- studies in goldfish (Narnaware et al., 2000). ergy homeostasis (Kalra et al., 1999). The effects Goldfish trained to eat daily on a scheduled regi- of NPY in stimulating food intake are mediated men (fixed time) for 10 days displayed a rapid and by NPY Y1 and Y5 receptor subtypes (Marsh et episodic elevation in NPY mRNA levels 1–3 h al., 1988; Wyss et al., 1998). In addition, NPY- before the scheduled feeding time. The elevated producing cells in the brainstem and hypothala- mRNA levels associated with the daily feeding mus (ARC, DMN) innervate various pattern suggest a physiological role for NPY in hypothalamic sites including the ARC, VMN, feeding in goldfish. Furthermore, brain intraven- DMN, PVN and surrounding regions, facilitating tricular administration (i.c.v.) of goldfish NPY the interaction of NPY with other orexigenic and (gNPY) increased mean food intake in goldfish, in anorexigenic signals in the hypothalamus (Sahu et a dose-dependent manner. The maximum stimula- al., 1988a). Indeed, NPY-producing neurons coex- tion of food intake by gNPY was observed at 2 press GABA and AGRP in the ARC, and have and4ng/g body weight (bw), while a higher X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434 419 dosage (8 ng/g bw) of gNPY suppressed food and human by two separate laboratories (Sakurai intake. The i.c.v. injection of the NPY Y1 recep- et al., 1998; de Lecea et al., 1998). Orexin-A, a tor antagonist, BIBP-3226, decreased basal food 33-amino-acid peptide, and orexin-B, a 28-amino- intake and also reduced food intake stimulated by acid peptide, are produced from a single protein gNPY in goldfish. These results indicate that precursor by proteolytic processing. In rodents, NPY is a potent stimulator of food intake and orexin-containing neuronal perikarya are local- feeding behavior in goldfish. The actions of the ized within and around the lateral hypothalamus, NPY Y1 receptor antagonist on feeding behavior and in the dorsomedial hypothalamus and the also indicate that the central regulatory action of perifornical nucleus (de Lecea et al., 1998; Sakurai NPY on food intake is, at least in part, mediated et al., 1998; Date et al., 1999; Nambu et al., 1999). by NPY Y1 receptors. The i.c.v. injection of orexin-A and orexin-B stim- The significance of endogenous NPY synthesis ulate feeding of the rat (Sakurai et al., 1998); in regulation of feeding has also been examined in however, the orexins are less effective than NPY goldfish. Food deprivation of goldfish for 24–72 in stimulating food intake. Orexin gene expression h resulted in time- and brain region-dependent in rat hypothalamus was upregulated by fasting increase in NPY mRNA levels. In telencephalon- (Sakurai et al., 1998). These studies indicate that pre-optic and optic tectum-thalamus regions of the orexins are the new mediators of the lateral goldfish brain, NPY mRNA levels were not in- hypothalamic feeding response. There is no pub- creased by food deprivation until 72 h. In hypo- lished information on the presence and structure thalamus, NPY mRNA levels were significantly of orexins in nonmammalian vertebrates. increased by food deprivation from 24–72 h, in a Recently, the effects of orexin peptides on feed- time-dependent manner. Food deprivation for 48 ing behavior in goldfish have been examined and 72 h also resulted in an increase in mean food (Volkoff et al., 1999). The i.c.v. injection of hu- intake, which lasted for at least 45–60 min after man orexin-A or orexin-B in goldfish stimulated food deprivation. Finally, brain NPY gene expres- both appetite, as indicated by the number of sion was also modulated by the peripheral feeding acts, and food consumption, as indicated metabolic status of goldfish. Reduction in diet size by the total amount of food pellets consumed. by 50% of control levels (2% g bw) resulted in a Orexin-A was more potent than orexin-B, as significant increase in NPY mRNA levels in all orexin-A not only increased goldfish food intake brain regions examined (hypothalamus, telen- at lower i.c.v. dosages than orexin-B, but also had cephalon-POA, and optic tectum-thalamus). a greater stimulatory effect than that of orexin-B Taken together, these studies showed that NPY at similar dosages. This suggests a role for orexin plays a physiological role in stimulating food peptides in the regulation of feeding behavior and intake and feeding behavior through its specific food intake in goldfish, similar to that described receptors in goldfish brain, consistent with the in the rat. This also suggests the presence of findings in the mammalian models. orexin-like peptides in the goldfish brain. In the In mammals, it has been shown that gonadal rat, the effects of orexin-A are longer lasting than steroids modulate food intake and body weight those of orexin-B, although both orexins increase gain, probably via their direct action on the NPY food intake in a similar fashion (Sakurai et al., pathways in the ARC–PVN of the hypothalamus 1998). The longer lasting action of orexin-A might (Bonavera et al., 1994; Baskin et al., 1995). In be due to the structure of orexin-A, which renders goldfish, both estradiol and testosterone have it more resistant to inactivation. The higher po- been shown to induce a significant increase in tency of orexin-A might also be due to the fact NPY gene expression in the telencephalon-pre-op- that orexin-A binds to both orexin receptors tic area (Peng et al., 1994), implicating a possible (OX1-R and OX2-R), while orexin-B binds to regulation of feeding by gonadal steroids via NPY only the OX2-R receptors. pathways. 3.3. Galanin 3.2. Orexins/hypocretins GAL is a 29-amino-acid peptide originally iso- The orexin/hypocretin family of neuropeptides lated from porcine small intestine (Tatemoto et was recently discovered and characterized in rat al., 1983), shown to be widely distributed 420 X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434 throughout the gastrointestinal (GI) tract and also be blocked by a2-adrenergic receptor antago- central nervous system in mammals (Merchen- nist but not by a1 adrenergic receptor antagonist thaler et al., 1993). GAL has been studied exten- (De Pedro et al., 1995a), indicating that the a2- sively for its appetite-stimulating action in the adrenergic receptor pathway may be involved in brain of mammalian species (Kalra et al., 1999). the GAL regulation of food intake in fish; similar Microinjection of GAL in the PVN, LH, VMH results have been reported in mammals. and central nucleus of the amygdala stimulates feeding in rats, indicating the widely distributed 3.4. Pro-opiomelanocortin gene deri6ed peptides receptive sites for GAL in stimulating feeding (Kyrkouli et al., 1990; Schick et al., 1993). A close POMC mRNA encodes a large precursor anatomical and functional relationship exists be- protein, which is processed into g-melanophore- tween GAL and other orexigenic signal-producing stimulating hormone (g-MSH), adrenocorti- cells in the rat brain. For example, GAL may cotropin hormone (ACTH) and b- partially mediate the NPY-induced feeding re- hormone (b-LPH) (Nakanishi et al., 1979). Fur- sponse, as the NPY-producing neurons have di- thermore, ACTH and b-LPH contain small com- rect communication with GAL-producing ponent peptides with biological activity; a-MSH neurons in the ARC and PVN of the rat brain and corticotropin-like intermediate-lobe peptide (Horvath et al., 1996). are derived from ACTH, whereas g-LPH, b- GAL was isolated and sequenced from rainbow MSH, b-END, and - are trout, and has 79% homology to the porcine form derived from b-LPH (Simth and Funder, 1988). of GAL (Anglade et al., 1994). GAL-like im- Within the hypothalamus of mammals, POMC munoreactive (IR) cell bodies and fibers were neurons are localized exclusively in the ARC, and found in the GI tract and brain of several fish innervate the VMN, PVN, DMN, and other areas species, with most abundant accumulation of of the hypothalamus (Khachaturian et al., 1985). GAL-like IR perikarya and fibers in the hypotha- b-END, along with and , lamo-hypophysial region, particularly in the nu- also produced by the hypothalamus, are members cleus pre-opticus periventricularis, nucleus of the hypothalamic opioid peptides, which have pre-opticus (NPO) and nucleus lateralis tuberis been shown to stimulate food intake in mammals (NLT) (Prasada Rao et al., 1996a, and references by activating the m-, d- and k-opiate receptor cited therein). In addition, GAL-like peptide subtypes, respectively (Kalra et al., 1999). Com- binding sites have been described in the brain of pared with NPY, feeding evoked by opioid pep- Atlantic salmon (Holmqvist and Carlberg, 1992), tides is generally short lived and relatively modest showing the highest density of binding sites in the (Levine and Billington, 1989). Anatomic studies posterior hypothalamus. These provide anatomic have shown morphological links between b-END, evidence for potential involvement of galanin in GAL, and NPY, and between b-END and GABA the regulation of food intake in fish. In goldfish, pathways in the hypothalamus, suggesting a role i.c.v. injection of GAL significantly stimulates of b-END in the operation of the interconnected food intake during the first 2 h after the injection, orexigenic network (Horvath et al., 1992, 1995, but has no effects during the rest of the food 1997). Indeed, NPY has been shown to stimulate intake period (2–8 h) (De Pedro et al., 1995a). b-END release in the hypothalamus (Kalra et al., Intraperitoneal (i.p.) injection of GAL in goldfish 1995), and pre-treatment with the opiate receptor was ineffective in stimulating food intake. These antagonist naloxone (NAL) attenuates feeding re- results suggest that GAL is involved in the central sponses to NPY (Levine and Billington, 1989). On regulation of feeding in fish. In addition, the the other hand, NPY decreases POMC mRNA GAL-induced food intake can be blocked by i.c.v. levels in the ARC, and NAL increases NPY administration of the GAL receptor antagonist mRNA levels in the ARC and NPY levels in the galantide in combination with galanin, while the DMH (Garcia de Yebenes et al., 1995; Lambert et antagonist itself does not affect food intake in al., 1994). goldfish, suggesting that galanin regulates food In teleosts, POMC cDNA was cloned from intake through its specific receptor pathways in chum salmon more than a decade ago (Kitahara fish (De Pedro et al., 1995a). The stimulatory et al., 1988). Since then, the POMC cDNA se- effects of galanin on food intake in goldfish can quence has been determined from several fish X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434 421 species, including sockeye salmon, common carp, pathways for energy homeostasis in mammals goldfish and rainbow trout (Salbert et al., 1992; (Flier and Maratos-Flier, 1998). Agouti protein, a Okuta et al., 1996; Arends et al., 1998; Hui et al., 131-amino-acid protein normally expressed in the 1999). Similar to its mammalian counterpart, fish skin, is a natural antagonist of MC-R (Klebig et POMC gene encodes a precursor potentially pro- al., 1995; Ollmann et al., 1997; for a review, see cessed into a-MSH, b-END and ACTH. How- Elmquist et al., 1999). Food intake and body ever, fish POMC lacks a coding region for weight are increased by administration of an g-MSH. Endorphin peptides have been isolated agouti protein analog, and animals that ectopi- from salmon (Kawauchi et al., 1980), and endor- cally overexpress the agouti protein are hyper- phin-like peptide immunoreactivity and binding phagic, obese and have yellow fur (Klebig et al., sites have been found in fish brain (Vallarino, 1995; Fan et al., 1997). In addition, agouti-related 1985; Rosenblum and Callard, 1988). In common protein, a homolog of agouti, is produced exclu- carp and goldfish, POMC mRNAs are expressed sively in the hypothalamus and acts as an antago- in hypothalamus and some other regions of the nist at the MC4-R, as one member of an apparent brain (Arends et al., 1998; Hui et al., 1999). In yin–yang pair with a-MSH (Ollmann et al., 1997; goldfish, opioid peptides have been shown to be Shutter et al., 1997). The output from the feeding involved in regulation of several physiological and inhibitory MC4 receptor may be determined by behavioral responses, including feeding behavior the ratio of agonist (a-MSH) and antagonist (De Pedro et al., 1995b). The i.c.v. injection of (AGRP) at MC4-R receptor neurons (Flier and b-END induced an increase in food intake during Maratos-Flier, 1998). In fish, a-MSH has been the first 2 h postinjection, while no effects on intensively studied for its regulatory role in the feeding were observed in the next 6 h. In contrast, control of skin color (Baker, 1993). However, the i.p. injection of the same dose of b-END did not action of a-MSH on food intake and feeding affect food intake. The i.c.v. injection of NAL behavior remains to be defined. reduced food intake, and pre-treatment with NAL partially reversed the stimulatory effects of b- 3.5. Melanin-concentrating hormone END on food consumption (De Pedro et al., 1995b). These results indicate that b-END stimu- MCH was first discovered in chum salmon lates food intake via opioid receptors in goldfish pituitaries (Kawauchi et al., 1983). Salmon MCH brain. The m and k3 receptors, but not d or k1 regulates skin color by acting on melanosomes have been found in the goldfish brain by selective within pigmented skin cells (Baker, 1993). MCH radioligand binding studies (Brooks et al., 1994). and a-MSH are functional antagonists in the fish Recently, goldfish m-opioid receptor cDNA was scale system; MCH lightens skin by inducing ag- cloned and its mRNA detected in the hypothala- gregation of melanosomes, while a-MSH induces mus, olfactory bulbs and cerebellum (Hui et al., skin darkening by dispersal of melanosomes 1999). A further study by de Pedro’s group using (Baker, 1993). In mammals, MCH exists in the different opioid agonists and antagonists showed zona incerta and LH (Bittencourt et al., 1992), that the stimulation of feeding by b-END is medi- and i.c.v. administration of MCH stimulates feed- ated by m-opioidergic receptors in goldfish (De ing in rats (Qu et al., 1996). In addition, fasting Pedro et al., 1996). increased expression of MCH mRNA in both a-MSH, a nonopioid peptide encoded by the control and genetically obese ob/ob mice, and POMC gene, is distributed throughout the hypo- MCH mRNA was elevated in ob/ob mice (Qu et thalamus of rat (Jacobowitz and O’Donohue, al., 1996). Interestingly, MCH and a-MSH have 1978). Unlike b-END and other opiates, a-MSH been proposed, in models of auditory gating, inhibits food intake, probably through the type grooming and feeding, to have opposing actions four receptor (MC4-R), one of the in rat brain, as they do in the fish scale system five melanocortin receptor types cloned (Kalra et (Flier and Maratos-Flier, 1998). Notably, MCH al., 1999). MC4-R mRNA is widely distributed in has no affinity for melanocortin receptors, and the brain, including PVN, VMH, DMN and nu- MCH and a-MSH do not antagonize each other clei that occupy the medial zone of the hypothala- by acting on the same receptor, as in the case of mus (Tatro, 1990; Mountjoy et al., 1994). MC4-R AGRP and a-MSH. Recently, MCH has been has now been shown to be pivotal in the central recognized as a natural ligand for an orphan 422 X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434

G-protein-coupled receptor SLC-1 that is sequen- malian CCK8 sequence. In situ hybridization tially homologous to the receptors studies showed that CCK mRNA is expressed in (Chambers et al., 1999; Saito et al., 1999). SLC-1 the posterior ventrolateral hypothalamus of mRNA and protein are expressed in the VMN goldfish (Peyon et al., 1988), consistent with im- and DMN of the hypothalamus of rat brain, munocytochemistry findings. In addition, our re- consistent with a role for SLC-1 in mediating the cent studies showed a transient and acute effects of MCH on feeding (Chambers et al., postprandial increase in CCK mRNA levels in the 1999). Although MCH has been intensively stud- goldfish brain, supporting that CCK synthesis ied for its control of skin melanophores in fish, its and release occur following a meal in goldfish action on food intake and feeding behavior re- (Peyon et al., 1999). Notably, we have found that mains to be explored. the hypothalamus as well as areas including the olfactory bulbs, telencephalon-pre-optic region and posterior brain, also have a postprandial 4. Brain anorexigenic signaling molecules increase in CCK gene expression. This implicates that sites outside the hypothalamus may be in- 4.1. Cholecystokinin volved in the hypophagic actions of central CCK.

CCK and constitute a family of peptides 4.2. Bombesin characterized by the common C-terminus of Trp-

Met-Asp-Phe-NH2 (Crawley and Corwin, 1994). BBS is a tetradecapeptide that was first isolated In mammals, CCK exists in endocrine cells of the from skin extracts of the fire bellied toad, Bom- GI tract and within the central and peripheral bina bombina (Anastasi et al., 1971). In mammals, nervous system (Vanderhaeghen et al., 1980). both BBS and gastrin-releasing peptide (GRP), a CCK acts as a satiation factor at the levels of the 27-amino-acid peptide sharing a similar decapep- gut and centrally in specific brain regions in mam- tide C-terminal sequence as BBS, are widely dis- mals (Silver and Morley, 1991). CCK/gastrin-like tributed in the GI tract and central nervous IR perikarya and fibers are widely distributed in system (McCoy and Avery, 1990). BBS-related the forebrain, midbrain and hindbrain of goldfish peptides have been shown to be potent in sup- (Himick and Peter, 1994a). A highly concentrated pressing food intake when administered either i.p. and extensive CCK/gastrin-IR perikarya and fiber or centrally within specific areas of the hypothala- system is prominent in the posterior ventromedial mus and/or the hindbrain in mammals (Gibbs et and vertrolateral hypothalamus, and the hypotha- al., 1979; Flynn, 1991). lamic inferior lobes of goldfish. A similar brain In fish, BBS-like peptides have been detected distribution of CCK-like IR has been described in within neurons and endocrine cells of the GI the green molly and rainbow trout (Notenboom et tract, cardiovascular system, and brain (Himick al., 1981; Batten et al., 1990). Specific CCK/gas- and Peter, 1994b, and references cited therein). trin binding sites are found in these same brain BBS-like peptide has also been shown to be in- regions in goldfish (Himick et al., 1996). Specific volved in the regulation of gut motility and vis- binding sites for [3H]CCK have been described in ceral activity in several fish species (Holmgren and the hypothalamic feeding area of the sea bass Jonsson, 1988; Bjenning et al., 1991). In goldfish, (Moons et al., 1992). Importantly, i.p. or i.c.v. BBS/GRP-like IR are present in nuclear areas of injection of the sulfated form of CCK-8 acutely the ventro-posterior hypothalamus and the hypo- suppresses food intake in goldfish, supporting the thalamic inferior lobes, associated with the hypo- action of CCK as a satiety factor in fish (Himick thalamic feeding center in fish (Himick and Peter, and Peter, 1994a). 1995a). High-affinity and specific BBS/GRP bind- Recently, we reported the complete nucleotide ing sites are also found in the same brain regions sequence of cDNA encoding CCK precursor from (Himick et al., 1995). Preliminary studies showed goldfish brain by molecular cloning and sequence that BBS decreases feeding in carp following i.p. analysis (Peyon et al., 1988). The deduced CCK injection (Beach et al., 1988). In goldfish, BBS precursor contains CCK8 near its C-terminus, acts to acutely suppress food intake when admin- with only one substitution (Met to istered either i.p. or i.c.v. (Himick and Peter, Lys at position 5 of CCK8) relative to the mam- 1994b). Recently, we have isolated and sequenced X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434 423 a cDNA-encoding BBS/gastrin-releasing peptide in fish, as increased plasma cortisol levels induced from goldfish brain (Volkoff et al., 2000). Studies by i.p. administration of cortisol does not affect are being conducted to examine the significance of feeding (De Pedro et al., 1997). In addition, a1- gene expression and synthesis of BBS-related pep- adrenergic receptors and both D1 and D2 do- tide in regulation of food intake in goldfish. paminergic receptors have been shown to be involved in the anorectic effect of CRF in goldfish 4.3. Corticotropin-releasing factor family of (De Pedro et al., 1998a). peptides Urotensin-I is a member of the CRF peptide family in fish, and urotensin I peptide has been CRF is the primary hypothalamic hormone isolated and sequenced from several fish species stimulating pituitary ACTH release, which in turn (Lovejoy and Balment, 1999). Complementary stimulates cortisol secretion from the adrenal DNA encoding urotensin I has been determined glands (Antoni, 1986). In addition to the involve- from white sucker (Morley et al., 1991) and ment of CRF in regulation of the pituitary– goldfish (Bernier et al., 1999). Goldfish urotensin- adrenal axis, CRF has been shown to be a potent I has 62% sequence homology with rat urocortin, anorectic substance in mammals. CRF inhibits but only 45% homology with rat CRF. Phyloge- food intake, increases energy expenditure, and netic analysis shows a close relationship between produces sustained weight loss (Inui, 1999). The urocortin and urotensin-I (Lovejoy and Balment, sites of anorectic action of CRF are within the 1999). Therefore, the fish urotensin-I could be the PVN, possibly mediated by CRF R1 or CRF R2 homolog of mammalian urocortin. The action of receptor types (Monnikes et al., 1992; Heinrichs et urotensin I in the regulation of feeding in fish al., 1993). Urocortin, a novel member of the CRF remains undefined. However, fish urotensin I has peptide family, shares 45% sequence homology been shown to be more potent than CRF in with CRF and has been shown to be more potent suppressing appetite and food intake in rats than CRF in suppressing both fasting-induced (Spina et al., 1996; Jones et al., 1998). and nocturnal feeding (Vaughan et al., 1995; Spina et al., 1996). 4.4. Cocaine- and amphetamine-regulated The isolation of CRF from several fish species transcript and molecular cloning of CRF cDNA from white sucker (Okawara et al., 1988), and recently the CART is a novel neuropeptide that has been cloning of CRF from sockeye salmon and goldfish shown to have a role in the control of feeding (Ando et al., 1999; Bernier et al., 1999), illustrate behavior in rats (Kuhar and Dall Vechia, 1999). that CRF sequences between mammals and fish CART was initially isolated using polymerase are highly conserved, suggesting a conserved chain reaction differential display as mRNA pro- physiological role across evolution (Lovejoy and duced primarily in the rat hypothalamus and Balment, 1999). The NPO and NLT have been transcriptionally regulated by acute administra- shown to be the principle sites of CRF peptide tion of psychomotor stimulants such as cocaine and mRNA in the brain of teleosts (Morley et al., and amphetamine (Douglass et al., 1995). CART 1991; Okawara et al., 1992; Ando et al., 1999). is expressed in hypothalamic areas implicated in Indeed, CRF has been shown to act as a food the control of feeding behavior (Douglass et al., intake regulator in goldfish (De Pedro et al., 1997, 1995; Kristensen et al., 1998). Two CART tran- 1993, 1998a). The i.c.v. injection of CRF exerts an scripts of different length are generated by differ- inhibitory effect on food intake at 2 h postinjec- ential splicing, resulting in a mature peptide of tion in goldfish, while i.p. injection of CRF has no either 102 (long form) or 89 (short form) amino effect, supporting that CRF acts centrally (De acid residues (Douglass and Daoud, 1996). The Pedro et al., 1993). The anorectic effect of CRF in mature peptide contains several potential cleavage goldfish can be reversed by i.c.v. injection of the sites and CART may be post-translationally pro- a antagonist -helical CRF9–41 (De Pedro et al., cessed into several biologically active fragments. 1997). This suggests that the anorectic action of In both rats and mice, i.c.v. injection of recombi- CRF is mediated through specific receptors. The nant CART fragments has been shown to inhibit anorectic action of CRF appears to be indepen- both normal and starvation-induced feeding dent of activation of the pituitary–adrenal system (Lambert et al., 1998). The naturally occurring 424 X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434

CART55–102 appears to be the most potent frag- that tachykinins may function as endogenous ment, with a conserved secondary structure con- anorexigenic peptides. sisting of three disulfide bridges, but other CART Several forms of tachykinin have been isolated fragments including CART55–76 and CART62–76 from the nervous and GI tissues of fish (Jensen have also been shown to cause a dose-dependent and Conlon, 1992, and references cited therein). feeding inhibition (Lambert et al., 1998). To fur- The presence of relatively high concentrations of ther support the evidence that CART plays a tachykinin-like IR and tachykinin binding sites in major role in influencing appetite, it has been fish hypothalamus have been demonstrated shown that administration of rabbit anti- (Moons et al., 1992; Weld et al., 1994; Prasada g CART55–102 results in higher food intake in rats. Rao et al., 1996b). In goldfish, cDNA for -PPT Moreover, CART has been found to modulate the has been characterized (Lin and Peter, 1997), actions of two key regulators of food intake, which encodes SP, NKA and carassin, a 21- leptin and neuropeptide Y (Kristensen et al., amino-acid N-terminal-extended form of NKA 1998). (Conlon et al., 1991). The g-PPT mRNA is widely

Human CART62–76 and CART55–102 have been expressed throughout the brain of goldfish, with found to reduce food intake of both food-re- higher expression levels in olfactory bulbs and stricted goldfish and in fish subjected to NPY-in- hypothalamus (Lin and Peter, 1997; Peyon et al., duced feeding (Volkoff et al., 2000). As seen in 2000). In our recent studies, the potential involve- rodents, CART55–102 appears to be more potent ment of in regulation of food than CART62–76, as higher doses of the short intake was studied by examination of postprandial fragment are necessary to elicit a significant re- g-PPT gene expression in goldfish brain (Peyon et sponse. This data suggests that CART peptides al., 2000). In olfactory bulbs, g-PPT mRNA levels play a role in the regulation of feeding in goldfish. in fed fish were significantly increased at 120 min following a meal compared with levels at meal 4.5. Tachykinins time and compared with unfed fish. The hypotha- lamic region of the fed fish exhibited a significant The tachykinins are a family of peptides sharing increase in g-PPT mRNA levels at 30 and 120 min the common C-terminal sequence Phe-X-Gly-Leu- compared with levels at meal time and compared

Met-NH2 (Maggio, 1988). Mammalian nervous with unfed fish. These results indicated an acute tissues contains the tachykinins, (SP), postprandial increase in g-PPT gene expression in (NKA), (NPK) and olfactory bulbs and the hypothalamus of goldfish neuropeptide g, all derived from the prepro- brain, suggesting an involvement of tachykinins in tachykinin (PPT)-A gene (Carter and Krause, central regulation of food intake. 1990). Alternative RNA splicing of the PPT-A gene primary transcript results in the generation 4.6. Serotonin of four mRNAs called a-, b-, g- and d-PPT mRNA (Carter and Krause, 1990; Khan and Serotonin (5-HT) has been implicated in the Collins, 1994). The SP sequence is encoded by all central control of feeding behavior and body four PPT mRNAs; NKA is encoded only by b- weight in mammals. Stimulants of synthesis and and g-PPT mRNAs, and NPK and Npg are N-ter- release of hypothalamic 5-HT reduce food intake minally extended derivatives of NKA. In mam- and weight gain, and increase energy expenditure mals, the tachykinin peptides have been found in (Leibowitz and Alexander, 1998). The regulatory hypothalamic sites previously implicated in the action of 5-HT in feeding is mediated by 5-HT control of reproduction and sexual and appetitive receptors located in various medial hypothalamic behaviors (Kalra et al., 1991b). It has been shown nuclei (Leibowitz and Alexander, 1998). In addi- that NPK can acutely and consistently suppress tion, the 5-HT(2A/2C) receptor pathway has been feeding behavior, while the effect of i.p. adminis- shown to antagonize NPY-induced feeding within tration is more effective than central treatment in the hypothalamic PVN (Currie and Coscina, decreasing food intake (Sahu et al., 1988b; 1997). Recently, a central anorectic action of 5- Achapu et al., 1992). In addition, central and HT in teleosts has been demonstrated (De Pedro peripheral administration of SP acutely suppresses et al., 1998b). The i.c.v. injection of 5-HT signifi- feeding behavior in rat (Dib, 1999). These suggest cantly reduced food intake of goldfish at 2 h X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434 425 postinjection, whereas i.p. injection of 5-HT did fish and mammals, are also regulators of GH not affect food intake. In addition, pre-treatment secretion (Himick and Peter, 1995b). In goldfish, a with the CRF antagonist -CRF9–41 partially treatment with CCK-8s or BBS concomitantly blocked the inhibitory effects of 5-HT on food suppressed feeding and increased serum GH levels intake in goldfish, suggesting that CRF may, in at 30 min following treatment (Himick and Peter, part, mediate the feeding inhibition elicited by 1994a,b). CCK and BBS have been shown to 5-HT in goldfish (De Pedro et al., 1998b). 5-HT stimulate GH secretion via direct actions on the has been previously shown to have an inhibitory pituitary (Himick et al., 1993; Himick and Peter, effect on pituitary growth hormone release in 1995a). Thus, CCK and/or BBS may integrate the goldfish (Somoza and Peter, 1991). The possible regulation of satiation following a meal and the relationship between regulation of growth hor- short-term postprandial increase in GH secretion. mone (GH) and feeding by 5-HT remains to be NPY stimulates GH secretion in vitro and in defined. vivo in goldfish (Peng et al., 1993). Our recent studies showed that the increase in NPY gene expression before a scheduled feeding was associ- 5. Growth hormone and feeding ated with increased serum GH levels (Narnaware et al., 2000). In addition, an increase in NPY gene Growth in fish is regulated by the brain neu- expression following food deprivation was also roendocrine-GH-insulin-like growth factor axis associated with increased serum GH levels, which (Peter and Marchant, 1995). Growth of fish can subsequently decreased after refeeding. These re- be stimulated by manipulation of selected neu- sults suggest that NPY may be an important roendocrine regulators of GH; however, growth neuropeptide to integrate stimulation of feeding cannot occur without adequate food intake. In- and GH secretion. On the other hand, GH may deed, GH has been shown to play an important be involved in the pathways mediating NPY-in- role in regulating food intake in fish (for a review, duced feeding in fish. However, the mechanisms see Peter, 1995). Chronic administration of GH underlying the effects of GH on feeding remain results in an increase in food intake and subse- unclear, and an increase in serum GH levels is not quent improved food conversion efficiency in sev- necessarily associated with an increase in food eral teleosts. Injection of GH into rainbow trout intake, as increased physiological levels of GH has also been shown to increase appetite (Johnson and decreased growth rates and hypophagia can and Bjornsson, 1994). In goldfish, a short-term occur together in goldfish (Peter et al., 1976). relationship between circulating serum GH levels In mammals, growth hormone-releasing hor- and feeding has been demonstrated (Himick and mone (GHRH) and SRIF are major regulatory Peter, 1995b). When fed a 2% wet bw ration, peptides of GH secretion. Both GHRH and SRIF goldfish exhibit an acute elevation in serum GH at are also involved in the central regulation of 30 min after feeding. This initial rise in serum GH feeding, and integration of central and peripheral is followed by a sharp decrease and then, over the functions related to nutrition, metabolism and next 3 h, a more gradual decrease to serum GH growth in mammals (Feifel and Vaccarino, 1994). levels significantly lower than in unfed control fish In rats, i.c.v. injection of GHRH in picomoles (Himick and Peter, 1995b). increased feeding, while high dosages (nanomole) In fish, it has been well established that the of GHRH suppressed feeding (Vaccarino et al., control of pituitary GH secretion is mutifactorial, 1985; Vaccarino and Buckehnam, 1987). Picomole with a balance of stimulatory and inhibitory neu- doses of GHRH are ineffective in stimulating GH rohormones acting directly on the pituitary soma- release from the pituitary, and peripheral injec- totrophs on a seasonal basis (Peng and Peter, tions of GHRH have no effect or decrease food 1997). In addition, interactions among neurohor- intake. Similarly, systemic administration of mones could contribute to the regulation of GH SRIF-14 decreased feeding in rats (Feifel and secretion. Somatostatin (SRIF) is the major in- Vaccarino, 1990). Central administration of hibitor, while a number of neuropeptides and SRIF-14 in picomole doses increased food intake amides stimulate GH release (Peng and Peter, in rats, whereas significant suppression was pro- 1997). Notably, several neuropeptides and amides, duced with the nanomole dose tested (Feifel and which have been shown to regulate food intake in Vaccarino, 1990). 426 X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434

GHRH has been isolated and characterized 1998). In goldfish brain, three PSS cDNAs have from common carp hypothalamus (Vaughan et been determined, which encode PSS-I (SRIF-14), al., 1992). GHRH cDNA has been cloned from PSS-II (SRIF-28) and a third SRIF precursor several fish species (Peng and Peter, 1997). Inter- PSS-III, potentially processed into [Pro2]SRIF-14 estingly, fish GHRHs are encoded by the same (Lin et al., 1999a). SRIF-14 is a potent inhibitor gene as the pituitary adenylate-cyclase activating of both basal and stimulated GH release in fish polypeptide, while in mammals these two peptides (Peng and Peter, 1997). [Pro2]SRIF-14 also are encoded by separate . Recently, a demonstrated an inhibitory effect on GH release GHRH receptor has been cloned and character- in goldfish and rainbow trout, with similar po- ized in goldfish (Chan et al., 1998). GHRH recep- tency to SRIF-14 (Nishii et al., 1995; Lin et al., tor mRNA is expressed in the pituitary and 1999a). Recently, type one SRIF receptors have throughout the brain. Stimulation of GH release been cloned from goldfish brain (Lin et al., by synthetic human or carp GHRH has also been 1999b). SRIF receptor mRNAs and three PSS observed in several fish species (Peng and Peter, mRNAs are widely expressed in goldfish brain, 1997). However, the effects of GHRH on feeding providing an anatomic basis for a wide range of have not been examined in fish. On the other physiological functions of SRIF, similar to mam- hand, SRIF peptides have been isolated and char- mals. Effects of SRIF on feeding have not been acterized in several fish species (Lin et al., 1998). investigated in fish. In rainbow trout, plasma The presence of multiple forms of SRIF has been SRIF-14 concentrations exhibited a significant di- demonstrated in fish by isolation of SRIF pep- urnal rhythm, with a major increase associated tides or molecular cloning of cDNAs encoding for with the postprandial period, implicating a possi- preprosomatostatin-I (PSS-I), probably processed ble involvement of SRIF-14 in feeding (Holloway into SRIF-14, and PSS-II, potentially processed et al., 1994). into larger forms of SRIF (SRIF-25 or SRIF-28). In fish, gonadotropin-releasing hormone, thyro- In addition, several SRIF-14 variants have been tropin-releasing hormone and dopamine are identified in fish and other vertebrates (Lin et al., among other GH stimulators (Peng and Peter, 1997). The involvement of these factors in regula- tion of food intake in fish remains to be investigated.

6. Concluding remarks

Fig. 1 summarizes our current understanding of brain regulation of food intake in fish, and the relationship between food intake and GH. The brain orexigenic signal molecules, NPY, orexins, galanin and b-END, stimulate food intake in fish, whereas brain anorexigenic signal molecules, CCK, BBS, CRF, CART peptide and serotonin, are satiation factors in fish. Tachykinins may also be involved in the anorectic action in fish. The brain hypothalamic area is associated with regula- tion of food intake, while sites outside the hypo- thalamus could also be involved in this function. Fig. 1. A diagrammatic summary of the brain regulation of There is correlation between short-term changes food intake and relationship between food intake and growth in serum GH levels and feeding behavior, al- hormone secretion. Bombesin, BSS; cocaine- and am- though possible mechanisms integrating these phetamine-regulated transcript, CART; cholecystokinin, CCK, functions remain to be defined. Some of the stud- corticotropin-releasing factor, CRF; growth hormone, GH; b-endorphin, b-END; insulin-like growth factor, IGF; neu- ies described in this review are only initial, and ropeptide Y, NPY; serotonin, 5-HT. +, stimulation; −, more work remains to be carried out with regard inhibition. to the precise mapping of brain sites for synthesis X. Lin et al. / Comparati6e Biochemistry and Physiology, Part A 126 (2000) 415–434 427 and release of neurohormones related to their Anastasi, A., Erspamer, V., Bucchi, M., 1971. Isolation feeding regulatory activities, and their innervation and structure of bombesin and alytensin, two and the localization of their receptors in the brain. analogous active peptides from the skin of the Eu- The possible morphological and functional inter- ropean amphibians, Bombina and Alytes. Experen- action among orexigenic or anorexigenic signals, tia 27, 166–167. Ando, H., Hasegawa, M., Ando, J., Urano, A., 1999. and between orexigenic and anorexigenic signal- Expression of salmon corticotropin-releasing hor- ing systems, need to be elucidated. Immediate mone precursor gene in the preoptic nucleus in early gene (c-fos) expression, as a marker for stressed rainbow trout. Gen. Comp. Endocrinol. neuronal activation by neuropeptide, allows the 113, 87–95. mapping of extended neuronal systems that re- Anglade, I., Wang, Y., Jensen, J., Tramu, G., Kah, O., spond to the administration of brain neurohor- Conlon, J.M., 1994. Characterization of trout mones. This technique would be applicable in galanin and its distribution in trout brain and pitu- mapping of neuronal systems involved in brain itary. J. Comp. Neurol. 350, 63–74. regulation of feeding in fish. Other approaches, Antoni, F.A., 1986. Hypothalamic control of adreno- such as antisense techniques, gene targeting and corticotropin secretion: advances since the discovery transgenic fish models, would be useful for studies of 41-residue corticotropin-releasing factor. Endocr. on the physiological role of individual neuropep- Rev. 7, 351–378. tides in feeding regulation or their interaction Arends, R.J., Vermeer, H., Marents, G.J.M., Leunis- with other neuropeptides. Several aspects are sen, J.A.M., Bonga, S.E.W., Flik, G., 1998. Cloning and expression of two mR- open for future research. First, some fish neuro- NAs in the common carp (Cyprinus carpio L.). Mol. hormones that have been currently characterized, Cell. Endocrinol. 143, 23–31. a such as MCH, -MSH and glutamate and GABA, Baker, B.I., 1993. The role of melanin-concentrating could be assessed for their regulatory effects on hormone in colour change. Ann. N.Y. Acad. Sci. food intake in fish. 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