Neuropeptide Y (NPY) is one of the strongest orexigenic signals in mammals, and the NPY/agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) are the principal inducer of feeding (9, 10). The relative importance of NPY in feeding regulation seems to vary among teleosts. In goldfish (Carassius auratus) (11, 12), carp (Cyprinus carpio) (13), channel catfish (Ictalurus punctatus) (14), zebrafish (15), rainbow trout (Oncorhynchus mykiss) (16), and Nile (17) and red (18) tilapias (Oreochromis sp.), NPY injections increase feeding. Food deprivation increases brain npy expression in several species, including goldfish (19), chinook and Coho salmon (Oncorhynchus tshawytscha; Oncorhynchus kisutch) (20), zebrafish (15, 21), winter skate (Leucoraja ocellata) (22), tiger puffer (Takifugu rubripes) (23), and winter (24) and Brazilian (25) flounder (Pseudopleuronectes americanus; Paralichthys brasiliensis), suggesting an orexigenic role. In some species, such as Atlantic cod (Gadus morhua) (26), tiger puffer (23), snakeskin gourami (Trichogaster pectoralis) (27), Brazilian flounder (25), channel catfish (28), and cobia (Rachycentron canadum) (29), npy brain expression levels are high around feeding time and decrease post-feeding, further suggesting a role of Npy as a short-term appetite stimulator in fish. Npy treatments have also been shown to stimulate fish growth/growth hormone (GH) secretion both in vitro [goldfish (30)] and in vivo [tilapia (Oreochromis mossambicus) (17, 31); orange-spotted grouper (Epinephelus coioides) (32)].

However, in Atlantic cod, fasting does not affect npy brain expression (26), in cunner (Tautogolabrus adspersus), short-term fasting decreases npy brain expression (33), and in both Atlantic salmon (Salmo salar) (34) and larval Atlantic halibut (Hippoglossus hippoglossus) (35), npy expression increases after feeding, suggesting that Npy might have a minor role as a feeding stimulator in these species. GH transgenesis, which results in increased feeding rates, does not affect brain npy levels in Coho salmon (36) and carp (37) but decreases npy levels in zebrafish (38).

In goldfish (39), Senegalese sole (Solea senegalensis) larvae (40), rainbow trout (41), and both Atlantic cod larvae (42) and adults (43), npy brain expression is modulated by diet, which is consistent with the role of NPY containing neurons in sensing the metabolic status (e.g., glucose levels) as reported for mammals (10) and fish [e.g., tilapia (44)]. However, in cobia (29), npy expression does not appear to correlate with diet-induced changes in food intake.

The peptide cocaine-amphetamine-related transcript (CART) was originally isolated from rat brain as a transcript regulated by acute administration of cocaine or amphetamine (45, 46). In goldfish, cart brain expression also increases following treatment with amphetamine (47). CART is a potent anorexigenic peptide in mammals (48–50) and birds (51), and CART injections inhibit food intake in goldfish (52).

Several cart genes have been identified in some fish species [e.g., two in goldfish (53), four in zebrafish (54), six in medaka (Oryzias latipes) (55), and seven in Senegalese sole (56)] whereas only one cart has been reported for others [e.g., Atlantic salmon (57), Atlantic cod (26), Atlantic halibut (35), and channel catfish (28)]. Post-feeding increases in cart brain expression have been reported for several fish species such as catfish (28), Atlantic salmon (34) and goldfish (53) suggesting that Cart acts as a short-term satiety factor in fish. Fasting has been shown to decrease cart brain expression in several fish species, and these changes are sometimes gene-specific. In goldfish, although the expression of both cart genes decreases after fasting, cart1 appears more affected than cart2 (53). In both zebrafish (58) and medaka (55), only one cart is affected by fasting, and in Senegalese sole, three out of seven cart genes are affected (56). However, fasting does not affect cart expression in other species such as winter flounder (24) or Atlantic halibut larvae (35), perhaps since only one gene has been identified in these species to date. Cart is also involved in sensing metabolic status, as hypothalamic cart mRNA levels change in response to changes in the levels of glucose in rainbow trout (41) or fatty acids in rainbow trout (59) and Senegalese sole (60).

Orexins (OXs) A and B (or hypocretin 1 and 2) are neuropeptide products of a single gene precursor, prepro-orexin (pOX), through proteolytic cleavage. Two orexin receptors have been identified, OXR1 and OXR2. OX-A binds to both receptors with similar potencies whereas OX-B binds preferentially to OXR2 receptors (61). In mammals, orexins have been implicated in the regulation of many physiological functions, including feeding, sleep–wake cycles, reproduction, and cardiovascular function (62–65). Orexins and/or orexin receptors have been identified in several fish species, including goldfish (66), cavefish (Astyanax fasciatus mexicanus) (67), zebrafish (68), barfin flounder (Verasper moseri) (69), orange-spotted grouper (70), Atlantic cod (71), winter flounder (72), and dourado (Salminus brasiliensis) (73). Orexins have been shown to increase feeding and locomotor behavior in both mammals (74) and fish (75–81). Consistent with its role as an orexigenic peptide, ox brain mRNA expression increases following fasting [e.g., cavefish (67), goldfish (77, 82), zebrafish (68), winter flounder (72), Atlantic cod (71), and dourado (73)] and around feeding time [e.g., cavefish (67), orange-spotted grouper (70), and goldfish (83)].

Galanin (GAL) is a 29–30 amino acid peptide first identified in mammals (84) and shown to have actions in brain and peripheral tissues to increase appetite and regulate metabolism (85, 86). Gal has been isolated in several fish species [reviewed in Ref. (87)] and appears to act as an orexigenic peptide. Injections of GAL stimulate food intake in goldfish (88) and tench (Tinca tinca) (89). Although long-term food deprivation does not affect brain gal mRNA expression in goldfish, the expression levels of gal decrease after the scheduled feeding time in fed fish, suggesting that Gal is a short-term regulator of appetite (90). Related to its role in metabolism, high gal mRNA expression has been linked to increased locomotion in zebrafish (91).

Melanin-concentrating hormone (Mch) was first isolated from the salmon pituitary as a skin-paling factor (92, 93) and later isolated and identified as an orexigenic factor in mammals (94). In fish, the role of Mch in food intake regulation is still unclear. In goldfish, central injections of MCH inhibit appetite, and fasting induce a decrease in brain Mch-immunoreactive (ir) cells (95–97), suggesting an anorexigenic role. However, in other teleost species, such as winter flounder (98), barfin flounder (99), zebrafish (100), and Atlantic cod (101), fasting-induced increases mch mRNA levels and -ir cells, pointing to an orexigenic role.

The corticotropin-releasing hormone (CRH) family includes CRH [or corticotropin-releasing factor (CRF)], urocortin (Ucn), urocortin 2, and urocortin 3. Members of the CRF family of neuropeptides have been shown to decrease feed intake in mammals (102). In goldfish, Crf and urotensin I (UI, the homolog of UCN in mammals) stimulate the hypothalamic–pituitary–interrenal axis (the fish homolog to the hypothalamic–pituitary–adrenal axis) to induce secretion of glucocorticoids (e.g., cortisol) and act as anorexigenic factors (6, 103). Central injections of CRF (104–106) or UI inhibit food intake in goldfish. Similar effects have been shown in rainbow trout (106). In Ya fish (Schizothorax prenanti), fasting decreases crf brain expression levels (107), consistent with the anorexigenic role of Crf-related peptides in fish.

The vertebrate melanocortin system is phylogenetically well conserved, and it has been identified in fish, amphibians, and mammals (108–110). It consists of (1) melanocortin peptides, which includes melanocyte-stimulating hormones (α-, β-, and γ-MSH) and adrenocorticotropic hormone, all derived from the gene pro-opiomelancortin (Pomc), (2) five G protein-coupled melanocortin receptors (MCRs), and (3) endogenous melanocortin antagonists, agouti and AgRP (111). In vertebrates, components of the melanocortin system are involved in a diverse range of physiological functions, including regulation of food intake, appetite, and anticipatory behavior (112).

The melanocortins are posttranslational products of the POMC prohormone, which also gives rise to the opiate peptide β-endorphin. Posttranslational processing of the POMC prohormone is tissue-specific, which results in the production of different POMC peptides by different cell types and, therefore, multiple physiological functions. Pomc is a single copy gene in mammals and birds, but in most teleosts, there are two to three different pomc transcripts [e.g., zebrafish (113), carp (114), barfin flounder (115), gilthead sea bream (Sparus aurata) (116), and sockeye salmon (Oncorhynchus nerka) (117)], proposed to result from the whole or partial genome duplication (118). In salmonids, Atlantic salmon and rainbow trout, three copies of pomc gene and one splice variant have been described, i.e., pomc (-a1, -a2, -a2s, and -b) (119, 120). However, the functions of the fish pomc subtypes remain largely unexplored. In rainbow trout, fasting induces increased expression levels of both hypothalamic pomca1 and pomcb (121), whereas in olive flounder (Paralichthys olivaceus), pomc2 but not pomc1 and pomc3 mRNA levels increase with fasting (122), suggesting a form-specific response of pomc in some species.

The repertoire of MCRs (MC1R to MC5R) found at the target cells has undergone significant diversification and specialization. Therefore, MCRs differ in their affinity for the different melanocortins, agouti, and AgRP. Of importance to energy homeostasis are MC3R and MC4R that are expressed throughout the central nervous system (CNS). Fish Mcr and ligands are expressed in a highly conserved pattern relative to mammals (123, 124). This conservation is also seen in the melanocortin neural circuits involved in hypothalamic control of energy homeostasis, underlining that the melanocortin functions originated early in evolution (125). The presence of Mc4r in teleosts has been reported in several species [e.g., goldfish (126), zebrafish (127), spotted scat (Scatophagus argus) (128), snakeskin gourami (129), fugu (109), common carp (130), and Ya fish (131)]. In Atlantic salmon, several paralogs of Mcr have been described, mc1r (-p1 and -p2), mc2r, mc4r (-a-p1, -a-p2, -b-p1, and b-p2), mc5r, mrap2 (-p1 and -p2) (Lars Ebbesson, Uni Environment, Bergen, Norway, personal communication). Mc3r seems to have been lost early in teleost evolution and is not present in salmonids, as observed for pufferfishes, tiger puffer and tetraodon (Tetraodon nigroviridis) (132). The only known mc3r in teleosts is the zebrafish mc3r; however, mc3r has also been identified in the spiny dogfish (Squalus acanthias) (133). In snakeskin gourami, the mc4r mRNA expression varies during daily feeding and fasting period, and its correlation with npy expression indicates a role in feed intake control (27, 129). However, in barfin flounder and sea bass (Dicentrarchus labrax), progressive fasting did not modify the hypothalamic mc4r mRNA expression (134, 135). Intracerebroventricular injections of MCR agonist decrease food intake in juvenile rainbow trout (136) and in goldfish (126, 137) in a dose-dependent manner, whereas the injection of MCR antagonists increases food intake in rainbow trout and in goldfish (137). The importance of Mc4r in the regulation of fish growth is also emphasized by naturally occurring mutations of the Mc4r in swordtails (Xiphophorus nigrensis and Xiphophorus multilineatus), which dramatically affects growth (138, 139).

An interesting fact is the existence of two endogenous antagonists in the melanocortin system, agouti and AgRP. These proteins are paracrine-signaling molecules and act as subtype-selective endogenous antagonists. AgRP exerts its major physiological function in the hypothalamus, where it acts as a potent orexigenic factor (140) due to its ability to antagonize the MC3R and MC4R (141). agrp genes have been identified in several fish species (57, 124, 126, 130, 131, 142–144). Hypothalamic agrp expression in goldfish (137), sea bass (agrp1, not agrp2) (144), and zebrafish (124) dramatically increased during fasting. In addition, GH-transgenic common carp has higher feed intake and higher hypothalamic agrp1 mRNA expression levels than non-transgenic fish (37). agrp mRNA abundance in the hypothalamus of rainbow trout (59) and Senegalese sole (60) also responds to changes in the levels of specific fatty acids. Altogether, it is suggested that the role of AgRP in energy homeostasis and its relation to the melanocortin system is conserved across vertebrates (51, 145).

The GI-tract is the largest endocrine organ in vertebrates and produces around 30 different neuropeptides and hormones. These peptides act on several tissues, including the GI-tract itself, exocrine glands, and the CNS (173, 174). Most of the GI peptides are sensitive to the gut nutrient content, and some of them are important in the control of appetite and meal size (174, 175). GI peptides may act on the CNS via an endocrine action by traveling in the blood, which requires that they pass the blood–brain barrier, and/or by stimulating afferent vagal nerve fibers (174, 176, 177). Studies on rainbow trout show that appetite returns when 80–90% of the stomach content has been emptied (178), indicating that gut filling, feed digestion, and transit rates may affect appetite control with both hunger and satiety signals. Indeed, most of the gut-derived appetite-regulating factors are also involved in digestion, thus coordinating these two processes (179).

In mammalian species, there is a range of other peripheral tissues that produce and release factors (peptides/cytokines) that affect appetite, such as the thyroid and pancreatic hormones.

The anadromous (sea-migrating) life-strategy of Arctic charr (Salvelinus alpinus) is characterized by substantial seasonal changes in food intake, growth, and adiposity. In the wild, most of the annual growth and energy accumulation occurs because of an intense appetite burst during the short seawater residence in summer, whereas overwintering in freshwater is characterized by anorexia and depletion of energy reserves (322–325). The seasonal cycle in food intake and growth in this species seems to be a strictly genetically programmed process as captive offspring of Arctic charr exhibit pronounced seasonal changes in food intake and growth when held at constant temperature and given food in excess (326, 327). Because of the physiologically regulated seasonal feeding cycles, Arctic charr represent an interesting model for investigation of adaptive mechanisms underlying long-term regulation of appetite and energy homeostasis (328).

It has been suggested that the seasonal feeding cycle is regulated by a lipostatic mechanism (297, 328–330). Leptin, the principal regulator of the lipostatic mechanism in mammals (331), does not appear to be involved in signaling the large variations of adiposity in the Arctic charr (297). However, hepatic leptin production increases at the end of the winter fasting period (297), when fat mobilization and increased plasma glucose occurs (325). It is possible that leptin has a role in depressing metabolism during long-term seasonal fasting, when fat stores are depleted by the suppression of liver lipolytic pathways (292, 297). It is also possible that leptin is more important as a glucostat than an adipostat in Arctic charr, as suggested in zebrafish (302).

The role of Ghrl in controlling the seasonal variation in appetite of charr has also been explored. Stomach ghrl mRNA expression seems to be negatively correlated with feed intake and growth (332), supporting that Ghrl acts as an anorexigenic factor, as suggested in one study on rainbow trout (191). The expression levels of a range of putative central appetite-controlling genes in Arctic charr such as pomc, cart, mc4r, agrp, and npy were not correlated to its annual feeding cycle (333). Further studies are needed to understand how anadromous Arctic charr can maintain an anorexic state when overwintering despite the massive loss of fat reserves.

Mouthbrooder fish hold their eggs in their mouth until their young are free-swimming. Several fish are classified as mouthbrooders, some being paternal (male holds eggs) and others maternal (most common). Eggs can be fertilized in the environment or in the female’s mouth (in the case of maternal brooding). Teleost mouthbrooder fish include cichlids (e.g., mbuna Astatotilapia burtoni) and tilapias such as Oreochromis mossambicus and Oreochromis niloticus, sea catfish (e.g., Ariopsis felis), cardinalfish (e.g., Pterapogon kauderni), and gouramis (e.g., dwarf gourami Colisa lalia). While guarding eggs, most mouthbrooders do not eat or feed less, often resulting in a weight decrease (334–338).

Very little is known about the endocrine mechanisms responsible for brooding-induced fasting. Fed mbuna females with large ovarian eggs (pre-spawning or spawning) have larger gonadotropin-releasing hormone (Gnrh1) neurons (339), which has also been observed in convict cichlid, Amatitlania nigrofasciatus (340) and higher mRNA expression levels of whole brain gnrh1 (major Gnrh form involved in reproduction), than mouthbrooding females carrying eggs, which is reflected by higher gonadosomatic indexes and higher circulating levels of sex steroids (341). However, no significant differences are seen in gnrh2, in contrast with fasting-induced changes reported for other fish species [e.g., winter flounder (342) and Ya fish (343)]. Similarly, no differences are seen in npy, pomc or mch whole-brain expression, between mbuna holding eggs in their mouths and pre-spawning females (341). However, orexin increases in fasting mbuna females, which is consistent with its stimulatory role on feeding and inhibitory actions on spawning (66). The increase in cck is more surprising, as Cck is a satiety factor that is normally secreted when the GI-tract is full. This increase in cck might be a response to long-term fasting to attenuate hunger and prevent feeding by counteracting increases in orexigenic peptides such as orexin.

Interestingly, when comparing fed and fasted mouthbrooding females from which eggs/fry have been removed, no differences in brain expressions of appetite regulators (npy, cck, orexin, pomc, and mch) were seen (341), possibly because of changes in physiology and metabolism. However, as no information is available about the effects of fasting on appetite regulators for pre-spawning females or immature fish, it is difficult to draw definitive conclusions on the changes that lead to brooding-induced fasting.

Like the above-mentioned Arctic charr, many other fish species, including rainbow trout and Atlantic salmon, tolerate long fasting periods. Rather than a genetically driven seasonal halt in feed intake as in charr, they adapt to long periods with low food availability in the wild. To better understand the potential role of various peptides in this process, plasma protein and/or gene expression levels of candidate appetite-regulating hormones and neuropeptides have been analyzed during variable periods of food deprivation in salmon and trout.

Most fish species spawn eggs, in which the developing embryo relies on yolk nutrients until it is sufficiently developed to capture, ingest, and digest feed. After onset of exogenous feeding, the larvae continue to grow and develop into juveniles—a transition triggered by environmental cues that induce a coordinated program to remodel the organism. The transition involves a wide range of changes in behavior, habitat, and physiology, and many fish larvae change food sources as they become adults; therefore, it has major consequences for feeding behavior and most likely in the control of appetite (356).

Several studies have aimed to understand the various aspects of the feeding biology and nutritional requirements of developing fish larvae to improve their performance in aquaculture. However, very few have focused on the mechanisms that control appetite and food intake (42, 357). This may be partly explained by biological and technical challenges when working with fish larvae, such as the accurate determination of food intake, the use of individual larva (instead of pools), or the handling of individual variability in growth and development.

There are several described cases where fish larvae continue to eat, despite having an apparently full GI-tract. For instance, Atlantic halibut larvae continue to ingest prey despite a full gut and with gut transit rates so high that the prey is eliminated (defecated) undigested and sometimes even alive (358). Apparently, the feedback systems and satiety signals originating in the GI-tract are not functional in these early stages. It has been argued that fish larvae have adapted to low concentrations and availability of prey in the wild. Consequently, satiety signals may not be required to prevent overfeeding. In aquaculture conditions, however, larvae are reared with constant and abundant food availability and continuous light, and therefore appetite-controlling mechanisms become crucial to avoid continuous ingestion of prey, short gut transit times of ingested food, reduced time for digestion, low digestive efficiency, and nutrient absorption (359). This is of particularly interest for altricial-gastric species, which lack a fully developed and functional stomach prior to metamorphosis (360–364).

Some studies have started to explore the ontogeny expression of several appetite regulators (71, 240, 365, 366), and their detailed spatial and differential distribution in fish larvae (159). Key factors in appetite control are present very early in fish development, such as npy at zygote stage in blunt snout bream (Megalobrama amblycephala) (367) and at blastula stages in orange-spotted grouper (170), ghrl (240) and ox (71) at cleavage stage, and gastrin (240) at blastula stage in Atlantic cod. In Atlantic halibut, only ghrl and cart mRNA expression levels were significantly modified throughout development, while ontogeny did not affect npy, pyy, and pomc-c expressions levels in the brain of the developing larvae (35). Ghrl was widely distributed in the GI-tract and present in the anterior GI-tract before the gastric glands and pepsinogen production appeared in newly Atlantic halibut hatched yolk-sac larvae (368). Notably, increased levels of ghrl in the GI-tract during metamorphosis were correlated with stomach development (360, 369). cart mRNA expression levels decreased at the initiation of halibut metamorphosis, while cart levels in whole larvae of Atlantic cod increased during the corresponding developmental phase (365). In Atlantic cod, cck, npy, and ox show a similar pattern of a moderate but consistent decrease from 3 days post-hatching (dph) until 60 dph (42, 365). The differences in cart expression between Atlantic halibut and Atlantic cod larvae are intriguing and may be a result of different factors, including the use of whole cod larvae versus halibut head and differences in developmental rate (370, 371).

Many of the neuropeptides involved in appetite control in higher vertebrates and adult teleost are present in the brain of fish larvae, suggesting a role of these genes in appetite control also in the early stages (35, 159, 168, 372–374). In the recent study of Le et al. (159), the development expression patterns of npy, cart, and ox genes were analyzed in brain regions of Atlantic cod, from start of exogenous feeding until juvenile stage. Both spatial and temporal expression patterns of orexigenic and anorexigenic factors during larval ontogeny indicated a progressive development of the brain regulatory networks that control appetite. In addition, the wide distribution and co-expression of npy, cart, and ox in hypothalamus, led the authors to propose that this is the main area for appetite control in fish larvae, comparable to mammals and adult fish (6, 374–376). However, it remains unclear to what extent these appetite-regulating genes are functional at these early developmental stages.

Few have assessed the response of these factors in terms of feed intake (35, 40) or different diets (40, 42, 377). In Atlantic cod larvae, Kortner et al. (42) showed that the expression levels of cck and npy were diet-specifically modulated and followed the same expression profile as the genes coding for digestive enzymes, suggesting a close connection between appetite control and digestion processes. Recently, two studies in Senegalese sole larvae have analyzed the effect of fatty acids ingestion in the control of food intake (378, 379). The administration of several fatty acids (leate, linoleate, α-linolenate, or eicosapentaenoate) in sole post-larvae enhanced the expression of the anorexigenic neuropeptides cart4 and pomcb and decreased the orexigenic npy, with no major discrepancies between the different fatty acids tested (378). However, the transcriptional analysis of several anorexigenic: pyya, pyyb, glp1, cckl, cart1a, cart1b, cart2a, cart4, pomc-a, pomc-b, crf; and orexigenic: gal, npy, agrp2 factors showed a dissimilar response to feeding times and dietary fatty acid composition (cod liver oil, linseed oil, soybean oil, or olive oil) that was generally not in agreement with their putative function (40). For example, the changes observed for sole npy in developmental stages 16 and 34 dph were not consistent. At 16 dph npy expression levels increased before feeding, as expected, but then continue to increase up to 3 h after feeding (40), which is counterintuitive for an orexigenic factor (1, 12). At 34 dph, npy expression was only affected by the dietary fatty acid profile. This was similar to the results obtained by Kortner et al. (42), where cod npy was diet-specifically modulated in larvae at 16 dph, but no evident changes were found at 29 dph. Furthermore, in Atlantic halibut larvae, npy levels increased 5 h after refeeding (35). The differences observed between species may suggest that the Npy is still not fully functional in appetite regulation in larvae, possibly reflecting a yet underdeveloped appetite-regulating system. Furthermore, the response of npy, pyy, pomc-c, and cart to food deprivation and refeeding in Atlantic halibut larvae did not appear to be coordinated (35), lacking a consistent expression pattern to explain their contribution to appetite control in early larvae as it was for Senegalese sole larvae (40). In addition, the differences observed between both studies in Senegalese sole larvae may be explained by the different approaches used: use of complex diets fed through the whole larval and post-larval stage (379) versus a tube-fed single meal of pure fatty acids solution (378).

Altogether, these studies support the hypothesis that a feedback signaling system from the GI-tract to the CNS is still not fully established in the early larval stages. This, however, does not rule out that developing fish larvae may have their own specific system of appetite regulation adapted to their feeding ecology or that larvae possess a rudimentary, still developing, regulatory system. Fish larvae are often considered as “feeding machines” because they can ingest food at rates above their own weight daily (357, 380–382). This suggests that larvae are constantly hungry and motivated to feed, although several studies have shown that some fish larvae exhibit a circadian prandial pattern and do not feed constantly (383–385). Given the complexity of appetite-controlling mechanisms and how difficult it is to interpret results due to the lack of specific information on the roles played by some of the potential anorexigenic and orexigenic factors in fish, it remains a challenge to elucidate the appetite-control system in fish larvae with different digestive tract morphologies and feeding strategies. A better understanding will greatly increase our basic knowledge on larval physiology and help to improve larval rearing regimes and feeding protocols in hatcheries.

Several species have an aggressive and voracious feeding behavior, most of them usually being carnivorous top predators. Well-known examples include Perciformes such as bluefish (Pomatomus saltatrix), bluegill (Lepomis macrochirus), cobia, groupers, tilapia and African cichlids, salmonids (e.g., rainbow trout), pikes (e.g., Northern pike Esox lucius), some characids (e.g., dourado and piranhas), as well as elasmobranchs, i.e., sharks and rays (338).

Within the teleosts, several studies have examined the effects of fasting and feeding on the expression of a few appetite regulator genes. However, there are no data on how endocrine mechanisms might regulate the increased feed intake in these voracious fish, and no comparative study has been performed between voracious species and a “gentler” herbivore/omnivore species (e.g., cyprinids, some flatfish species).

In response to fasting, it appears that most voracious fish display a similar trend to what occurs in non-aggressive species [e.g., the omnivorous goldfish and pacu (Piaractus mesopotamicus)], i.e., increases in expression of orexigenic factors [e.g., ox in dourado (73) and piranha (225), and ghrl in piranha (386)] and decreases in expression of anorexigenic factors [e.g., cart in piranha (225)]. However, few studies have examined periprandial changes in voracious fish. Taking the example of orexin, its expression appears to increase around feeding time and decrease after feeding, similar to what is seen for other fish species, such as orange grouper (70) and tilapia (387). In dourado, ox expression is similar before, during, and after feeding, suggesting a constant state of feeding/searching behavior. In addition, ox expression levels in fasted fish increase at mealtime and dramatically at post-feeding time, suggesting that dourado have a high motivation to search for food that persists after meal time (73). In contrast, pacu, a fish from the same order (Characiformes) as dourado, shows high ox levels at pre-feeding, and these tend to decrease at mealtime and post-feeding. Moreover, if pacu is not fed at the scheduled mealtime, ox levels increase at mealtime but return to basal levels within 1 h, suggesting that the fish have “given up” on searching food (388), which is reflected by their calm behavior (Volkoff, personal observation).

Voracious fish are often aggressive during feeding. Although aggression is often related to reproduction, in these species it also occurs outside the reproductive context (389). Interestingly, early studies in cichlid fish (Tilapia heudelotii macrocephala) and in bluegill have shown that electrical stimulation of the hypothalamic region elicited both feeding and aggressive responses (390, 391). The brain monoaminergic system, especially serotonin [5-hydroxytryptamine (5-HT)], plays a key role in controlling aggressive behavior (392). 5-HT has been reported to inhibit aggressive behavior in several voracious species, e.g., trout (393) and pikeperch (Sander lucioperca) (394). Interestingly, surface Mexican tetra (Astyanax mexicanus) species are aggressive predators, in particular during feeding episodes, whereas blind cave forms of this species exhibit reduced aggressiveness and have a tendency to continuously search for food. These differences in foraging and aggressive behaviors are related to 5-HT network modifications within hypothalamic neurons (395, 396). 5-HT also has anorexigenic actions in rainbow trout (397) and in mammals (387) and has been shown to interact with appetite regulators. For example, the behavioral effects produced by orexin administration, i.e., increased locomotion and feeding, are blocked by 5-HT antagonists (398). It would therefore be valuable to compare 5-HT levels between voracious and non-voracious fish.

Intra-species differences (sometimes referred to as personality/motivation) in basal locomotor and feeding activities are often observed between individuals. These differences might be due to different expression levels of appetite regulators or monoamines. For example, in tilapia, low serotonergic activity in the hypothalamus is correlated with a personality characterized by high feeding motivation (399). Similarly, in salmonid fish, subordinate individuals characteristically exhibit higher plasma cortisol levels than dominant ones (400). There are most likely different causes for voraciousness in fish, and more direct studies are needed to explain the underlying mechanisms of the appetite-controlling networks that result in these large differences in feeding behaviors.

Although most fish rely in part on vision to feed (401), this sense is not essential for some species. The best example is that of fish living in cave environments, which are characterized by constant darkness and food scarcity (338, 402). Cavefish such as the Mexican tetra are often blind and have specialized anatomical features to better locate food and maximize food intake (396, 403, 404). Such adaptations include well-developed olfactory bulbs (405), taste buds (406), and lateral line neuromasts (407–409). In addition, these fish display behavioral adaptations for detecting prey and increasing feeding efficiency: they are opportunistic feeders, show increased swimming/exploratory and feeding behaviors (410), do not sleep (411), and do not exhibit schooling behavior (403, 412, 413). This enhanced food-finding efficiency is present not only in adults but also in young larvae when the yolk has been depleted (414). Overall, surface fish placed in the dark are less efficient at finding food than cavefish (415–417).

To cope with a particularly food-limited habitat compared to most surface fish, cavefish have developed behavioral (increased appetite, with ingestion of large amounts of food during feeding events) and metabolic adaptations. The latter include reduced basal metabolic rate, increased metabolic efficiency, starvation resistance (reduced weight loss during fasting), and increased body fat composition (403, 413, 418).

Peripheral injections of known orexigenic factors in cavefish, such as OX, GHRL, and apelin, increase not only food consumption but also the whole brain mRNA expressions of orexigenic factors (e.g., GHRL injections induce an increase in ox brain expression), whereas injections of CCK reduce food intake and induce a decrease in the whole brain expression orexigenic factors (e.g., apelin) (67, 79). Peripheral injections of OX greatly increase locomotor activity and ox brain mRNA levels in cavefish. Basal ox mRNA levels in whole brain are higher in cave fish than in surface fish (Buenos Aires tetra, Hyphessobrycon anisitsi, a characid surface species closely related to Astyanax) (405), suggesting that the higher overall locomotor/feeding activity in cavefish compared to the surface forms might be mediated by an increase in ox levels (67, 79). Coding mutations in mc4r also contribute to the increased appetite and starvation resistance of cavefish compared with surface fish (419).

Cavefish are avid feeders and become very active around feeding time when appetite increases (420). Brain ox mRNA expression levels increase before and decrease after a scheduled mealtime (67), suggesting that orexin acts as a short-term hunger signal and is linked to food anticipatory activity. Conversely, the brain expression of the anorexigenic pyy increases after feeding (67), suggesting a role for Pyy as a short-term satiety factor. However, cck brain expression does not display periprandial variations in cavefish (67), which might contribute to a less rapid satiety and longer bouts of feeding.

Short-term food restriction increases ox brain mRNA transcription levels in cavefish (67), indicating a role in the long-term regulation of feeding in cavefish and perhaps triggering an increased motivation to seek food. However, as opposed to most surface fish examined to date, short-term fasting does not increase brain mRNA levels of pyy and cck, suggesting that the anorexigenic systems are inhibited during fasting, perhaps to slow down digestion/gastric emptying of food in the gut or to maintain a hunger state that would favor food-seeking behavior.