The comparative endocrinology of feeding in fish: Insights and challenges

General and Comparative Endocrinology 176 (2012) 327–335

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The comparative endocrinology of feeding in fish: Insights and challenges Leah J. Hoskins, Hélène Volkoff ⇑ Department of Biology, Memorial University of Newfoundland, St. John’s, NL, Canada A1B 3X9 Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL, Canada A1B 3X9

a r t i c l e

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Article history: Available online 27 December 2011 Keywords: Fish Feeding Hormones Gene expression Comparative endocrinology Treatments

a b s t r a c t Studying the endocrine regulation of food intake in fish can be challenging due to the diversity in appetite-regulating hormones and the diversity within the fish group itself. Studies show that although the structure of the hormones is relatively conserved among vertebrates, their functions might vary between fish and mammals as well as among fish species. In addition, feeding behavior and the action of appetite regulators can be largely modulated by the feeding and reproductive status of the fish as well as the environment in which they evolve. This review gives a brief perspective of the endocrine regulation of feeding in fish, some of the methods used, and challenges encountered when using a comparative approach. Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction Feeding is ultimately the result of a balance between hunger, appetite and satiety. Hunger is the physiological need for food and constitutes a strong motivation to feeding behavior, which consists of searching for and/or ingesting food. Satiety is the physiological and psychological sense of ‘‘fullness’’ that occurs following eating and/or drinking. Appetite is the desire to eat food, which is usually associated with sensory (sight, smell, taste) perception of food. In fish, feeding behavior is often an indicator of appetite as it is associated with an increase in locomotor/swimming activity and in searching for food (with or without actual ingestion) when feed is introduced in tanks (a feeding response) and decreases as fish become satiated. Feeding stimulants, which do not necessarily have a dietary value but modify the scent of feed, are sometimes used in captive fish to improve feed palatability and enhance the feeding response by decreasing the latency time and also increasing food ingestion. For example, addition of betaine, a compound found in microorganisms, plants and animals, enhances the feeding response of winter flounder [25], striped bass [70] and Gibel carp [106]. In fish, the actual feeding process can be described as a series of nine movement patterns (particulate intake, gulping, rinsing, spitting, selective retention of food, transport, crushing, grinding, and deglutition) which sequence and frequency are adjusted to the type, size, and texture of food [20]. Feeding is a complex behavior, which is affected by external factors (e.g. environment, season, time of day, availability of food, stress) and internal factors (circulating levels of nutrients such as glucose, ⇑ Corresponding author. Fax: +1 709 864 3018. E-mail address: [email protected] (H. Volkoff). 0016-6480/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ygcen.2011.12.025

or hormones such as insulin and leptin). The body monitors longterm energy stores as well as energy utilization to regulate food intake. In fish, as in other vertebrates, feeding behavior and food intake are regulated by hormones produced by both the brain and peripheral organs [30,97,101], which are referred to as appetiteor feeding-regulating hormones. These include appetite stimulators (or orexigenic factors, such as orexins, neuropeptide Y (NPY) and ghrelin) and inhibitors (or anorexigenic factors, such as cocaine- and amphetamine-regulated transcript (CART), cholecystokinin (CCK), leptin and amylin) (see Table 1 in [101] for a more comprehensive list). Fish are a diverse phylogenetic group and relatively few fish species have been studied to date, with regards to feeding regulation. Furthermore, the diversity of species studied as well as the variation in techniques used makes it very difficult to compare these studies and to formulate general conclusions. The structure and function of appetite-regulating hormones in fish, although similar to that of other vertebrates, present some major differences and might be dependent on the fish species considered. In addition, within one given species, the mechanisms of action of these hormones and their regulation might vary with the feeding and reproductive state of the animals, and between different tissues and organs. The endocrine control of feeding might also be affected by environmental parameters as well as the time of the day/year when experiments are conducted. In addition, interactions between hormones are common, which makes it more difficult to characterize the actions of individual hormones. Furthermore, studies on the appetite regulation of fish not only use different fish species but also use an array of experimental techniques ranging from behavioral observations following hormonal treatments to genomic tools, leading to different analyses/interpretations of data

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Table 1 Different parameters and their sources of variation in the study of the endocrine regulation of feeding in fish (refer to text for references). Parameter

Source of variation

Comment

Sex Reproductive stage

Gender can affect feeding and the expression of appetite related peptides Fish at different reproductive stages (e.g. spawning vs. non-spawning) might display differences in feeding behavior and in the expression of appetite regulators The degree of feeding of a fish (satiety, starvation or restricted feeding) influences its feeding behavior as well as the expression of appetite regulators The type/composition of the diet and the body composition of the fish might influence feeding Disease states usually decrease feeding behavior and might affect the expression of appetite regulators Food intake might vary among individual fish (related to genetics, age, stress?). This is particularly true for species where dominant individuals are present The feeding behavior of a fish might vary depending on it is a ‘‘reared’’, ‘‘domesticated’’ fish (e.g. aquaculture fish, goldfish) or a wild fish that has been acclimated for only a few week to captivity (e.g. skate, flounder) (e.g. decrease food intake due to confinement stress or increase food intake due to the absence of natural predators) Fish – in particular captured wild fish – have natural feeding rhythms (e.g. diurnal or nocturnal, discrete vs. continuous) that might be disrupted when fish are entrained to feed at given times of the day/night in the laboratory

Animals

Feeding status Nutrition status Health state Individual variations Fish origin

Time of feeding Holding conditions Temperature Other environmental parameters Density Time of experiment Methods used for food intake quantification Length of experiment

Season/time of the year Time of the day

Treatments

Dose Length of treatment Time post-treatment Route of administration

Peptide injected Studies on hormonal variations Protein vs. mRNA expression levels Method of protein expression analyses Method of gene expression analyses Tissue examined Genes examined

Warmer temperatures usually increase food intake Photoperiod, salinity, oxygen levels, pH, turbidity... might influence feeding High stock densities might increase competition for food and increase stress levels in fish thus affecting feeding. Conversely, low densities might also induce stress in species that school Food intake have been assessed using several methods: counting pellets ingested (by observations of feeding behavior or via X-ray), measuring wet or dry weight of remaining food. Food availability during treatment also varies (continuously available via self feeders or limited daily food administration) The time period during food intake is measured varies among studies (form minutes to days). Similarly, the time at which gene expression/levels are measured (after hormone treatment or experimental conditions such as fasting) ranges from minutes to weeks. There are virtually no time course studies A number of fish species have seasonal variations in feeding behavior as well as hormone levels/expression Fish entrained to a given feeding regimen might display food anticipatory behavior and daily cycles in the expression of appetite regulators. The response of a fish with regards to feeding and changes in hormone levels might be dependent on time of day when a peptide is administered or a tissue is extracted Dose-response curves are not always available. The lack of effect on feeding and hormone levels/expression following treatment could be due to low ineffective doses or to high doses that desensitize the hormone receptors Treatments can be single acute, short-term or long-term (via pump implantation) or repeated injections (it is noteworthy that repeated handling has a stress effect) The effect on feeding and hormone expression can be present a few minutes, hours or days following treatment Hormones can be administered orally, in the water, via central – intracranial, intracerebroventricular – or peripheral – intraperitoneal or systemic – injections. For each route, variations in techniques occur (e.g. stereotaxic vs. free-hand method for central injections) Commercially available mammalian hormones vs. recombinant species-specific hormones might have varied degrees of effectiveness Most studies examine gene expression levels while some report changes in protein levels Methods include serum/plasma levels or extracellular levels, western blots and immunohistochemistry Methods include in situ hybridization, qPCR, microarrays, reporter genes Brain, gut, and different regions within brain (e.g. forebrain vs. hypothalamus) and gut (e.g. stomach vs. posterior gut vs. pyloric caeca) Different gene variants of the peptides and their receptors

and conflicting conclusions/hypotheses regarding the role of specific hormones, not only between species but sometimes within the same species. 2. Assessment of the role of appetite-regulating hormones in fish A direct approach to examine the role of a peptide in the regulation of feeding in fish is to submit fish to hormone treatments in vivo and to assess food intake. The administration of the hormones can be carried out via several routes including injections, oral administration, implanted pellets or via osmotic mini-pumps (see [101] for a more detailed description). The number of studies using this direct approach remains limited mainly due to the difficulties in setting up the technique in a wide variety of species. Whereas some species such as salmon and goldfish appear to

respond well to treatments, others are more challenging either because of their large size (e.g. skate) which would require large doses of peptide, or because they are prone to stress and stress-induced anorexia (e.g. cod). In addition, the diversity of administration routes (e.g. orally or via injections in the brain or periphery), the nature of the peptide used (i.e. mammalian vs. species-specific compounds), and the duration of treatment (short-term vs. longterm or repeated treatments) render the results very difficult to compare and generalizations impossible to make. For example, in goldfish, CCK decreases food intake not only one hour after a single peripheral or central injection [91] but also via continuous infusion for 2 weeks (Fig 1). However, whereas increased food intake is observed in tilapia 10 h after peripheral injections of NPY [16] and after 30 days of being fed with NPY-containing pellets [43], in goldfish, food intake is unaffected by either single peripheral injections ([53]; Volkoff and Hoskins, unpublished data) or chronic peripheral

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infusions of NPY (Fig 1). In addition, whereas acute single brain injections of 5 ng/g NPY elicit an orexigenic effect in goldfish [66], when administered by chronic brain infusion at either 5 ng/g per day (data not shown) or 10 ng/g per day (Fig. 1), NPY has no effect on food intake. It is possible that the chronic infusion caused the ‘‘diffusion’’ of the peptide within the brain and that these doses were too low to elicit any effect. Conversely, it is also possible that doses were too high and that NPY receptors were down regulated or became desensitized to chronically sustained levels of NPY. Indeed, in goldfish, high doses of orexin [23,96] or NPY [66] have been shown to desensitize receptors. For both peptides, food intake displays a bell-shaped dose–response curve with an initial increase followed by a decrease and return to control levels at higher doses [66,96].

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Histological/molecular techniques are also often used as means to indirectly assess the role of hormones in regulating feeding. Examining the tissue distribution of the protein itself or its mRNA provides clues on the physiological role of the peptide examined: if a hormone or its mRNA is expressed in regions of the brain or the gut known to regulate feeding, it could then be inferred that that hormone might have a role in the regulation of feeding. Similarly, one can examine changes in protein/mRNA levels for that hormone following stimuli that are known to affect the expression levels of appetite-regulating hormones. A number of techniques have been used to localize and quantify appetite-regulating hormones in fish. Techniques include reverse transcription polymerase chain reaction (RT-PCR), quantitative PCR (qPCR), microarrays and in situ hybridization for mRNA, and western blot and immunohistochemistry for protein. Although PCR techniques are often more sensitive in detecting the presence of mRNA, histological techniques have the advantage of allowing to describe the organization of hormone-containing cells, neurons and fiber systems. Although the quantification of hormone concentrations within tissues and blood would be an invaluable asset, given the species-specific nature of the hormones involved and the technical difficulties in developing hormone assays, specific assays exist only for very few fish appetite-regulating hormones. Examples include ghrelin in striped bass [75], salmon [34] and goldfish [93] and leptin in rainbow trout [44]. In summary, given the wide range of methodologies used, caution should be used when comparing studies.

3. Fish diversity and diversity of appetite regulating hormones

Fig. 1. (A) Effects of long-term intraperitoneal (IP) infusion of NPY and CCK on food intake in goldfish. Fish were administered NPY (n = 8) and CCK (n = 7) at a dose of 50 ng/g body weight or saline (n = 6) via osmotic minipumps for 2 weeks. (B) Effects of long-term intracerebroventricular (ICV) infusion of NPY and CCK on food intake in goldfish. Fish were administered NPY (n = 6) or CCK (n = 8) at a dose of 10 ng/g body weight or saline (n = 5) by osmotic minipump for 10 days. Food intake was quantified daily for 1 h, and food intake (measured in milligrams of food consumed per gram of body weight per hour) was averaged and analyzed separately for the first (day 1–7 for IP treatment and day 1–5 for ICV treatment) and second (day 8–14 for IP treatment and day 6–10 for ICV treatment) halves of the treatment periods. Data are expressed as mean ± SEM. Treatment groups within each time interval were compared using one-way ANOVAs followed by Student-Newman–Keuls multiple comparisons tests. Different superscript letters indicate groups that are significantly different (p < 0.05). (C) Goldfish model of intraperitoneal (left) and intracerebroventricular (right) minipump implantations for long-term peptide infusion. The arrow indicates the site of pump implantation. Scale bars indicate 2 cm.

While we tend to compare fish with what we know in mammals, it is becoming more and more obvious that major differences in the structure and function of appetite-related hormones exist between fish and mammals and between fish species. Fishes are an extremely diverse vertebrate group that include agnathans (jawless fishes), chondrichthyans (cartilaginous fishes), sarcopterygians (lobe-finned fishes), and actinopterygians (ray-finned fishes, which are 97% composed of teleosts) [67]. Fishes thus present a wide variation in morphology, behavior, and physiological adaptations [67,95]. Based on fish species studied to date, it appears that the structure of appetite regulators is somewhat conserved among vertebrates with regards to gene structure, amino acid composition, or 3D protein configuration. For example, NPY [88] and CART [65] cDNAs and proteins are relatively well conserved between mammals and fish. Fish leptin proteins, however, have a low degree of similarity in amino acid composition to mammalian leptins and to other fish leptins (for example, salmon leptin-1 has 22% similarity with human leptin and 16% with Fugu or medaka [78]), but the tertiary structures of all vertebrate leptins are very similar [19]. Fishes, as other vertebrates, have undergone two rounds of tetraploidization (whole genome duplication, 2R theory) but actinopterygians (ray-finned fish), which represent over 95% of the species of fish, have undergone an extra round of duplication, an event called 3R [49,61,87]. This increased copy number of genes renders the characterization of genes encoding appetite related peptides in fish even more complex. First, multiple isoforms/variants are probably present for most appetite related peptides in fish, but only a handful have been identified. These forms might be very similar in structure and difficult to isolate with classical cloning techniques. In recent years, the availability of genomics tools, i.e. the sequencing of the genome of a few fish species (e.g. zebrafish and Fugu) has provided new means of ‘‘fishing out’’ these isoforms but the availability of genome databases is, to date, still limited to a very small number of species. Secondly, different isoforms might have different tissue distributions and divergent functions. For example, in goldfish, two CART forms are present, CART I and II. Both mRNAs

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are present in the brain, but form I is predominant in the olfactory bulbs and hypothalamus, whereas form II is predominant in the optic tectum. Hypothalamic CART I, but not CART II, mRNA expression is affected by fasting and displays periprandial variations, suggesting that only one of the CART forms is implicated in the regulation of feeding [99]. Similarly, six CART cDNAs have been identified in medaka. Whereas five of these forms are primarily expressed in the brain, one form occurs in the skin, and only one brain form responds to starvation, suggesting different functions among the homologous genes [64]. Similarly, two leptin forms have been identified in medaka [47], zebrafish [29] and salmon [44]. In each species, the two leptins are differentially expressed and in zebrafish, food deprivation induces a decrease in liver mRNA expression of only one of the two forms [29].

4. Fish diversity and diversity in tissues producing appetiteregulating hormones The two major tissues/organs producing appetite-regulating hormones are the brain and the gastrointestinal tract (GIT) (other tissues include pancreas, liver and gonads). As in other vertebrates, the fish brain has three divisions: the hindbrain (which consists of the cerebellum ventrally and the medulla dorsally), midbrain (which includes the optic tectum), and forebrain. The forebrain can be further divided into the telencephalon (which comprises the olfactory bulbs and the cerebral hemispheres) and the diencephalon (which includes the thalamus, hypothalamus and preoptic area) [11,12]. Although the general morphology of the fish brain is relatively constant, there is considerable variation in brain morphology and in the relative size of regions across species, which is often related to life history, ecology and behavior. For example, it has been suggested that in cichlid fish, algal scrapers have small optic lobes and large telencephala whereas planktivores have enlarged optic lobes [90]. In fish, the main neuroendocrine regions producing/containing appetite-regulating hormones are the telencephalon, preoptic area and hypothalamus [17]. It appears that the relative distribution of the peptides/mRNAs varies with the hormone considered and the species examined. For example, orexin immunoreactive (OX-ir) cells are found in the anterior hypothalamus and along the third ventricle within the preoptic area (POA) in zebrafish [4] and medaka [2] whereas in the Australian lungfish, OX-ir cells are also found in the POA, the infundibular hypothalamus and within the telencephalon [51]. Fishes display a diversity of digestive tract anatomies and physiologies [5,7,103]. The GIT of fishes can generally be subdivided into four topographical regions: the headgut (mouth and pharynx), foregut (esophagus and stomach), midgut, and hindgut [103]. In general, the length and mass of the GIT is greater in herbivores relative to carnivores, but generalizations are difficult as these parameters also depend on factors other than feeding strategies such as fish size, feeding status (starved vs. fed) and environmental factors such as temperature [69,103]. Furthermore, there is a wide variety in the morphology of the GIT among fish species. For example, some fish species, such as in the families cyprinidae (carp and goldfish) and labridae (wrasses and cunners), lack a defined stomach and corresponding ‘‘gastric’’ enzymes are secreted by the anterior intestine. In lampreys, chondrichtheans and dipnoids (lungfish), which have a short GIT, the surface area is increased by folding and twisting the intestine along its longitudinal axis, to form ‘‘spiral valves’’. In a number of, but not all, teleost fishes, blind-ended ducts (pyloric caeca) found in the anterior intestine, increase the surface area for digestion and absorption [103]. The GIT of fish not only displays morphological changes between species, but also displays plasticity as changes may occur within individual fish, in

particular in species that undergo seasonal changes in feeding. For example, in winter flounder, which undergo an annual fast over the winter, the mucosal folding is reduced in all sections of the intestine during the fast [60]. Similarly, in salmon, fasting decreases mass and enzyme capacities by 20–50% within 2 days, and 40–75% after 40 days in all sections of the GIT (stomach, pyloric caeca, and throughout the intestine) [46] and in the characid fish species Hyphessobrycon luetkenii, short-term fasting decreases gut size and shifts intestinal epithelia from simple columnar to pseudostratified [28]. Appetite-regulating hormones have been shown to be present in several regions of the GIT from the stomach to the hindgut. Most of these gut hormones are released in response to food or feeding, can induce satiety, and also have effects on gut motility and secretion [35]. However, their morphological distribution might vary depending on the hormone and/or the species considered. For example, in juvenile Atlantic herring, expression analysis by in situ hybridization shows that positive CCK endocrine-like cells are mainly located in the pyloric caeca and to a lesser extent in the rectum, with a few positive cells in the stomach and the midgut [39]. In Atlantic cod larvae, CCK-immunoreactive (IR) cells are mostly found in the anterior midgut, are present in lower numbers in the posterior midgut and hindgut of some individual larvae, and are absent in the foregut [33].

5. The effects of feeding status on feeding In most fish, as in mammals [27], food deprivation usually increases the mRNA expression of orexigenic factors and decreases that of anorexigenic factors. However, contradictory results have been reported. These differences could be true species-specific differences in response to fasting – as fishes might have different sets/ patterns of appetite-related peptides and might respond differently to nutritional challenges – or might be due to expression analysis in different parts of the brain (e.g. whole brain vs. hypothalamus or telencephalon) or the gut (anterior vs. posterior), or to different experimental conditions (e.g. different length of fasting). For example, whereas fasting decreases CCK mRNA levels in the anterior intestine of winter flounder [54] and yellowtail [63] suggesting that CCK is a satiety factor, it increases CCK mRNA levels in skate [55]. This latter discrepancy might be due to the more acidic pH that occurs in the intestine of fasting elasmobranchs which would in turn stimulate the synthesis and secretion of CCK – compared to teleosts [55]. When examining the effects of fasting on the gut, one should also keep in mind that fasting can induce reversible changes in gut morphology in some species, usually seen as a decrease in intestinal length and thickness, which might affect the distribution or expression levels of gastrointestinal hormones. Results also depend on the tissue examined. For example, fasting increases NPY mRNA expression after 3 days in goldfish hypothalamus [66], after 2 and 4 weeks in winter flounder hypothalamus [54], and after 2–3 weeks in Chinook and coho salmon [83] hypothalami and after 2 weeks in Brazilian flounder whole brain [13]. However, a one-week fasting does not affect NPY mRNA expression in either cod forebrain [41] or tilapia whole brain [77]. In the latter example, it is possible that using large portions of the brain for expression studies might have ‘‘diluted’’ the signal and masked any significant local changes in NPY expression. Different regions of the brain might also respond differently to fasting. For example, although both hypothalamus and telencephalon are brain regions that have been implicated in the regulation of feeding in fish, in skate, a 2-week fasting period increases NPY mRNA expression in the telencephalon but not in the hypothalamus [55]. The length of food deprivation might also influence the results. For example, in goldfish, a fast of 10 days, but not 3 days,

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decreases the hypothalamic mRNA expression of CART I [1]. The small number of fasting studies, the limited number of species examined and the wide range of experimental procedures used makes it difficult to establish species-specific responses to fasting. 6. The influence of gender and reproductive status on feeding In fish, there is a close relationship between feeding, gender and reproductive parameters. Sex-specific differences in feeding behavior have previously been reported in fish. For example, during the spawning season, territorial male cunners feed less often and have different diets than females [31]. Gender-specific differences in levels of appetite regulating hormones have also been noted in a few species. For example, in tilapia, gastric ghrelin mRNA levels are higher in females compared to males [71], and in salmon, the number of ghrelin cells per unit area in the stomach is higher in females than in males [79]. Reproductive stage can also affect feeding and the expression of appetite-regulating hormones. For example, declines in feeding behavior are often seen during periods of reproductive behaviors: European eels [94], Atlantic salmon [62] and Atlantic cod [24,85] eat very little during spawning and spawning migration, and male domino damselfish reduce time spent feeding during courtship and nest guarding [56]. Appetite-related hormones have been shown to affect reproductive events in fish. For example, NPY induces the release of gonadotropins and gonadotropin-releasing hormone (GnRH) in several fish species (see [109] and references therein) and NPY brain mRNA expression is twice as high in adult Brazilian flounder, than in juvenile fish [14], suggesting that NPY may play a key role in sexual maturation and reproductive events in fish. Similarly, orexins appear to regulate reproductive behavior as centrally-injected orexin inhibits spawning behavior and decreases GnRH mRNA expression levels in the brain in goldfish [36]. Conversely, reproductive hormones can affect feeding and the expression of appetite-related hormones. For example, in goldfish, central injections with GnRH induce a decrease in food intake [36,58], which is, in part, due to down-regulation of brain mRNA expression of orexin, an appetite stimulating-hormone [36]. Seabass treated for 31 days with implants containing gonadal steroids (testosterone and estrogens) display a significant decrease in food intake [50]. In catfish, changes in the reproductive stages are correlated with changes in both NPY [59] and CART [6] immunoreactivity in the forebrain, including the telencephalon, a brain region implicated in the control of feeding in catfish [86]. In male tilapia, castration, which leads to low levels of gonadal steroids, reduces NPY-immunoreactive fiber density in the forebrain [80], a brain region implicated in the control of feeding and metabolism in this species [50] and these changes are reversed by testosterone replacement. 7. The influence of environment/season/time of the day on feeding The effects of external cues in the environment (e.g. temperature and photoperiod) must be considered when studying hormones that regulate feeding. For example, with regards to temperature, it has been reported that food intake generally increases with rising temperatures [8,32,40,89], but the endocrine mechanisms regulating this temperature-induced change in feeding are not known. In Atlantic cod, brain mRNA expression levels of CART, but not NPY, are higher in fish held at 2 °C than in fish held at either 11 or 15 °C, suggesting that CART is involved in temperature-induced appetite changes in this species [40]. Photoperiod can affect feeding activity [37,68,89,92] as well as the expression of appetite-regulating hormones. For example, in ornate wrasse,

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constant light conditions induce greater locomotor and feeding activities and higher orexin receptor mRNA hypothalamic expression levels when compared to fish exposed to a natural photoperiod [22]. In fish, natural daily feeding rhythms vary among species, and range from diurnal (e.g. Atlantic salmon, [73]) to nocturnal (e.g. catfish, [9]). It has been suggested that alteration of normal daily feeding rhythms can induce poor performance and eventually diseases and death [52]. The endocrine mechanisms regulating these rhythms are poorly known. In vertebrates, the rhythmic expression of circadian-regulatory genes (such as Bmal, clock and period) regulates the rhythmic secretion of hormones such as melatonin and the expression of downstream target genes, possibly including those involved in energy balance [110]. Little is known about the daily fluctuations of circadian-related proteins or appetite-regulating peptides in fish. Rhythms in the expression of circadian-related proteins have been demonstrated in several tissues in fish: in zebrafish eye, the mRNA expression of Bmal1, Per1 and Clock1 each display daily rhythms [108] and cyclical mRNA expression patterns have also been reported for Clock in zebrafish brain [102] and for Per1 in golden rabbitfish brain [72]. In Atlantic cod hypothalamus, Clock mRNA is expressed cyclically over the day with highest expression observed in the late afternoon, whereas Per2 mRNA expression remains relatively constant over the day (Fig 2A). As for daily fluctuations in levels of appetite-regulating hormones, most studies to date only analyze short-term periprandial variations in expression [15,105], but a few recent studies point to the existence of daily rhythms in these hormones in fish. In zebrafish, the number of synaptic structures in orexin cells projecting to the pineal gland displays a circadian rhythmicity and peaks during subjective day in both fish held at 14 h light/10 h dark cycles and fish held in constant darkness, suggesting a circadian control independent of light entrainment [3]. In grouper, hypothalamic orexin mRNA levels are greater in the light phase than in the dark phase [107]. In Atlantic cod, hypothalamic orexin, but not NPY, mRNA levels display a cyclic pattern over the day in which levels increase around mealtime and remain high for the rest of the day before decreasing during the nightly rest period, which is consistent with the roles of orexin in both appetite stimulation and wakefulness (Fig. 2B). Circannual rhythms in fish are closely correlated with seasonal variations in environmental factors (e.g. water temperature and day length). Some species such as winter flounder [10,82] and Arctic charr [38] display pronounced seasonal variations in food intake and growth which make them valuable models for studying mechanisms of appetite regulation. Both species decrease their feeding and locomotor activities in the winter. In winter flounder, the hypothalamic mRNA expressions of the orexigenic hormones NPY and orexin are higher whereas the gut mRNA expression of the satiety hormone CCK is lower in winter than in summer [54], which is consistent with the fact that animals eat little and are submitted to ‘‘natural fasting’’ during the winter. Similarly, in Arctic charr, for which food intake and growth are high during summer and very low during winter, the stomach mRNA expression of the orexigenic hormone ghrelin is high in winter and low in summer [26]. Feeding can also be influenced by interactions between fish. In laboratory or aquaculture settings, inappropriate stock densities can lead to stress, which in turn might lead to decreased feeding behavior. The optimum holding conditions for feeding depend on the species considered. For example, in juvenile burbot, a demersal bottom-feeding species, feeding activity is higher when stock density is high (9 kg/m2) and when shelters are not provided to the fish [104] whereas in Atlantic cod [48] and sea bass [81], both pelagic species, food intake is lower at high (40 kg/m3 for cod, 100 kg/m3 for seabass) than at low densities. Social interactions between fish also affect feeding and the expression of feeding-regulating

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compared to subordinate fish [74], suggesting that higher orexin levels might induce the increased locomotor activity seen in the dominant individuals. 8. Interactions between hormones Interactions between appetite-related hormones have been demonstrated in several fishes. For example, central injections of leptin in goldfish decrease brain NPY expression [98] and increase brain CART expression [99], and intracranial administration of leptin in catfish increases brain CART immunoreactivity [86]. In the goldfish brain, orexin- and NPY-containing neurons lie in close proximity to each other [45] and brain NPY mRNA expression increases following central injection of orexin [100]. In grouper, intraperitoneal injections of orexin increase hypothalamic NPY mRNA expression levels [107], suggesting an interaction between these two systems. Similarly, the possibility of direct interactions between the NPY and CART systems is suggested by neuronal connections in walking catfish brain [84]. However, in goldfish, chronic infusion of NPY via central or peripheral routes of administration has no effect on hypothalamic mRNA expression levels of orexin and CART, as compared to saline-infused controls (Fig. 3A and B). Goldfish co-treated with amylin at 1 ng/g and CCK at

Fig. 2. Daily hypothalamic Clock and Per2 (A) and OX and NPY (B) mRNA expression profiles in Atlantic cod. Mixed sex fish (average body weight of 170 g) were maintained in four flow-through 1000 L tanks under a photoperiod of 16L:8D (lights on at 06:00). Fish were fed daily at 10:00. Fish were acclimated to this photoperiod and feeding schedule for two weeks prior to the start of the experiment. On sampling day, whole brains were excised from fish in both fed and fasted tanks at 07:00 and 09:00 (n = 8 at each sampling time for both fed and fasted groups). At 10:00, fed tanks were offered their usual daily ration of food. Fish were then sampled from both fed and fasted tanks (n = 8 per group) 10 min after feeding, as well as in subsequent sampling intervals at 11:00, 13:00, 17:00, 22:00 and 03:00 (the next day; n = 8 at each sampling time per group). At each sampling time, individuals were randomly collected from duplicate tanks (four fish per tank) to eliminate tank bias. Sampling at night was conducted with the aid of red flashlights. mRNA expression levels of each gene are expressed as a percentage normalized to the 10:00 group (n = 5–6 at each sampling time). Data are presented as mean ± SEM. Shaded areas on the X axis indicate dark hours. Vertical arrows indicate feeding time (10:00). Cosinor analysis was used to determine if mRNA expression patterns follow a statistically significant daily rhythm and one-way ANOVA with Tukey’s multiple comparison post-hoc analysis was used to determine differences in mRNA expression levels over time (p < 0.05). Cod showed significant variations in hypothalamic mRNA expressions over the day in both fed and fasted fish for Clock (fed fish: F(7, 35) = 2.82, p = 0.02, fasted fish: F(7, 29) = 6.34, p = 0.00014) and OX (fed fish: F(7, 36) = 3.32, p = 0.0079; fasted fish: F(7, 40) = 2.59, p = 0.027) and for fasted fish for NPY (F(7, 32) = 2.61, p = 0.030) but not in fed fish for NPY (F(7, 30) = 2.009, p = 0.087) and in either fed or fasted fish for Per2 (fed fish: F(7, 35) = 0.35, p = 0.93; fasted fish: F(7, 32) = 1.06, p = 0.41). There was a significant interaction effect between feeding status and time (i.e. expression response to time did not depend on feeding status, and vice versa) for Clock (F(7, 64) = 3.16, p = 0.0062) but not for Per2 (F(7, 67) = 0.46, p = 0.86), OX (F(7, 76) = 1.55, p = 0.16) and NPY (F(7, 62) = 2.05, p = 0.063).

hormones. The presence of dominant aggressive individuals might result in physical damage or reduced access to feed in subordinate fish. In pairs of female rainbow trout, which form a dominant-subordinate relationship, subordinate fish eat much less and have higher preoptic area mRNA levels of the feeding stimulator NPY as compared to dominant fish [21]. In dominant-subordinate pairs of male zebrafish, brain orexin mRNA levels are higher in dominant

Fig. 3. Effects of long-term administration of NPY and CCK on hypothalamic mRNA expression of appetite-related neuropeptides in goldfish. NPY (n = 7–8) and CCK (n = 4–6) at a dose of 50 ng/g body weight were infused IP via osmotic minipumps for 2 weeks (A) and NPY (n = 4–6) and CCK (n = 5–7) at a dose of 10 ng/g body weight were infused ICV via osmotic minipumps for 10 days (B). Fish were administered saline in both IP (n = 6) and ICV (n = 5–6) studies as a control treatment. Brains were sampled one hour after food was received on the final day of the infusion period. Data are presented as percentages of the expression of the control (saline-infused fish) group. Data are presented as mean ± SEM. For each treatment, the expressions of each gene of interest were compared using one-way ANOVAs followed by Student–Newman–Keuls multiple comparisons tests. Different superscript letters indicate groups that are significantly different (p < 0.05).

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1 ng/g have a food intake lower than that of fish treated with either 1 ng/g CCK or 1 ng/g AMY, suggesting synergistic anorexigenic interactions between amylin and CCK [91]. However, in goldfish, chronic peripheral infusion of CCK reduces hypothalamic mRNA expression of amylin (Fig 3B), which suggests that the down-regulation of amylin might be an effort to reduce the satiating effects of continuous levels of CCK. In contrast, although chronic central infusion of CCK reduces food intake, it does not alter hypothalamic mRNA expression of amylin (Fig 3A), which suggests that the targets for food intake regulation differ when CCK is administered peripherally, as compared to centrally.

9. Concluding remarks In summary, fishes display a great diversity of feeding habits as well as feeding responses when faced with nutritional and environmental challenges. In addition, within one single species, the synthesis patterns and actions of a given hormone appear to be dependent on the feeding and reproductive status of the animal, as well as the time of the day/year in which the fish are examined. Although progress has been made, our understanding of these complex mechanisms remains incomplete. The number of taxa studied remains low, and only represents a limited proportion of the existing fish species. In addition, because studies use different species at various physiological stages and use different techniques and assessment methods, information gained is often fragmented and difficult to compile into general statements. Table 1 shows some sources of variations that might occur between feeding studies. In addition, tools are sometimes limited when examining comparative feeding endocrinology in fish. One problem that arises when dealing with non-model species, which results in their infrequent utilization, is that these animals are often more difficult to obtain and to maintain in laboratory conditions (in particular in the case of wild animals) and might require longer acclimation times as well as longer ‘‘trial and error’’ periods in order to be used as experimental animals. In addition, molecular tools are still limited. Although fish genomic tools are on the rise, with the complete or partial sequencing of genomes for several fish species (e.g. Takifugu, Tetraodon, zebrafish, medaka, Atlantic cod, little skate), they are not representative of all species, and given the differences in structure of some appetite-related peptides, they might not be helpful for researchers using non-model fish species, in particular the more ‘‘primitive’’ species such as elasmobranchs or primitive actinopterygians. Tools are also limited for proteomics studies and researchers are often forced to limit their analyses at the gene /RNA level, and assume a correlation between RNA and protein expressions, which might not always be true [57]. Today, some model fish species are being used for gene manipulation [18] which could lead to important new insights in the study of feeding. For example, transgenic medaka over-expressing melanin-concentrating hormone (MCH) have been shown to have normal growth and feeding behavior [42], whereas zebrafish over-expressing orexin display abnormal sleeping patterns [76]. It is certain that the availability of these techniques for non-model species in the future will provide unique insights into the field of comparative feeding endocrinology in fish.

Acknowledgments This work was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC), Discovery (DG) and Research Tools and Instruments (RTI) Grants to H.V. and an NSERC postgraduate fellowship to L.J.H.

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