Glucosensing is the ability of specialized cells to detect changes in the levels of glucose. This ability relates to food intake control and counter-regulatory responses to changes in levels of plasma metabolites in brain areas like hypothalamus and hindbrain. In pancreatic endocrine cells and intestine it relates to hormone release whereas in liver relates to the metabolic switch between glucose utilization and production in liver. There are several glucosensing mechanisms characterized in mammals. The best known is that mediated by glucokinase (GK), as demonstrated in brain neurons, pancreatic β-cells and hepatocytes (Blouet and Schwartz, 2010; Ogunnowo-Bada et al., 2014; Efeyan et al., 2015). In this mechanism (Marty et al., 2007; Polakof et al., 2011d), glucose is taken up by glucose facilitative carrier type 2 (GLUT2), phosphorylated to glucose 6-phosphate by GK, and then metabolized through glycolysis increasing intracellular ATP/ADP ratio (Figure 1). The increased ratio induces closure of ATP-dependent inward rectified potassium channel (KATP+) inducing the depolarization of membrane and the entry of calcium into the cell through L-type voltage-dependent calcium channel. This entry of calcium finally results in changes in neuronal activity (brain), modulation of hormone release (endocrine cells) or changes in metabolism (liver). There is also evidence in mammals for GK-independent glucosensing mechanisms as also displayed in Figure 1 (Fioramonti et al., 2004; Marty et al., 2007; González et al., 2009; Thorens, 2012; Donovan and Watts, 2014). The expression of liver X receptor (LXR) (Mitro et al., 2007) responds to increased glucose levels eliciting a decrease in gluconeogenic capacity (Anthonisen et al., 2010; Archer et al., 2014). The sweet taste receptors (formed by type 1 taste receptor subunits (T1Rs) 2 and 3, and α-gustducin) respond to changes in glucose levels activating an intracellular signaling cascade (Ren et al., 2009; Kyriazis et al., 2014; Murovets et al., 2015; Herrera Moro Chao et al., 2016). Enhanced glucose levels induce increased expression of sodium/glucose co-transporter 1 (SGLT-1) (Díez-Sampedro et al., 2003; González et al., 2009; Thorens, 2012). The mitochondrial production of reactive oxygen species (ROS) leads to increased expression of uncoupling protein 2 (UCP2) in response to increased glucose levels (Beall et al., 2010; Diano and Horvath, 2012). These different systems might relate since, for instance, T1R3 and α-gustducin are necessary for SGLT-1 response to increased carbohydrate levels in the diet (Wauson et al., 2013).

In fish, evidence obtained in recent years support the presence of a GK-dependent glucosensing mechanism in central and peripheral areas of rainbow trout (Polakof et al., 2011d; Soengas, 2014). Indeed, in rainbow trout changes in the levels of glucose induced dietary (Polakof et al., 2008b,c), intraperitoneal (IP) (Polakof et al., 2007a, 2008a; Conde-Sieira et al., 2010a,b, 2012b; Otero-Rodiño et al., 2015), in vitro (Polakof et al., 2007b; Aguilar et al., 2011; Conde-Sieira et al., 2011, 2012a), or intracerebroventricular (ICV) (Polakof and Soengas, 2008) treatments resulted in changes in glucosensing mechanisms in hypothalamus and hindbrain. These include changes in GK mRNA abundance and activity, glucose and glycogen levels, GLUT2 mRNA abundance, glycolytic and glycogenic potentials, and in the activity of KATP+. Besides the studies carried out in rainbow trout, a recent study provided evidence of glucose sensing properties in several hypothalamic nuclei in medaka (Hasebe et al., 2016). In peripheral tissues of rainbow trout, the presence and functioning of GK-dependent glucosensing mechanisms is supported by findings in liver (Soengas et al., 2006; Conde-Sieira et al., 2012b), Brockmann bodies (BB, main accumulation of endocrine pancreatic cells) (Polakof et al., 2007a,b, 2008b,c), and intestine (Polakof et al., 2010a; Polakof and Soengas, 2013). Interestingly, the response of glucosensing systems to glucose is more important during the day than during the night in liver but not in hypothalamus, hindbrain, and BB whose responses to hyperglycemic treatment were similar at night and day (Conde-Sieira et al., 2012a).

The presence of GK-independent glucosensing mechanisms and their response to changes in glucose levels has recently been assessed in different central and peripheral areas of rainbow trout (Polakof and Soengas, 2013; Otero-Rodiño et al., 2015, 2016a,b,c). These include hypothalamus (mitochondrial activity, sweet taste receptor, and LXR), hindbrain (SGLT-1), liver (sweet taste receptor), BB (sweet taste receptor, LXR, and mitochondrial activity), and intestine (sweet taste receptor, SGLT-1, and LXR). Furthermore, a recent study (Balasubramanian et al., 2016) also demonstrated increased mRNA abundance of T1R2 and LXR in brain of rainbow trout nutritionally programmed to cope with enhanced carbohydrate levels in the diet.

Figure 2 summarizes the integrative responses of glucosensing systems in different fish tissues to an increase or decrease in glucose levels.

In mammals fatty acid sensing systems are involved in hypothalamus and hindbrain in the detection of changes in the levels of long-chain fatty acid (LCFA) thus contributing to energy homeostasis control (Migrenne et al., 2007; Gao et al., 2013; Duca and Yue, 2014; Efeyan et al., 2015). The best known mechanism is of metabolic nature (Figure 1) in a way that a rise in LCFA levels results in increased levels of malonyl-CoA, which inhibits carnitine palmitoyl transferase-1 (CPT-1) then resulting in the inability of mitochondria to import fatty acid-CoA for oxidation (López et al., 2005, 2007). There is also evidence for the presence of alternative mechanisms in mammals (Figure 1). These include the increased binding capacity of fatty acid translocase (FAT/CD36) in response to elevated LCFA levels resulting in changes in the expression of several transcription factors (Le Foll et al., 2009). The activation of specific isoforms of protein kinase C in response to increase levels of LCFA results in the inhibition of KATP+ activity (Benoit et al., 2009; Blouet and Schwartz, 2010). The activity of KATP+ inhibited by increased capacity of mitochondria to produce ROS in response to increased LCFA levels (Blouet and Schwartz, 2010). Finally, the activity of lipoprotein lipase increases in response to enhanced availability of triglycerides resulting in increased levels of LCFA stimulating G-protein-coupled receptors 40 and 120 (Picard et al., 2013; Ekberg et al., 2016). These systems apparently respond to specific LCFA, such as the monounsaturated fatty acid oleate (C18:1 n-9) (López et al., 2007; Blouet and Schwartz, 2010; Duca and Yue, 2014). The ability of other classes of LCFA differing in the length of their acyl chain and/or in their degree of unsaturation to elicit the activation of these systems has been scarcely assessed to date. The available studies in mammals indicate that neither saturated fatty acids like palmitate (C16:0) nor the presence of two (such as in linoleate, C18:2 n-6) or three (such as in docosahexanoate, C22:6 n-3) double bonds activate fatty acid sensing systems (Gomez-Pinilla and Ying, 2010; Ross et al., 2010; Schwinkendorf et al., 2011; Greco et al., 2014).

Lipids are major nutrients in fish where they metabolically support many different processes (Sheridan, 1994; Tocher, 2003; Polakof et al., 2010b). Therefore, not surprisingly, many studies evaluated the effects of different dietary lipids in fish metabolism (Morash et al., 2009; Torstensen et al., 2009; Sánchez-Gurmaches et al., 2010; Figueiredo-Silva et al., 2012a,b,c; Martinez-Rubio et al., 2013). However, only recent studies provide evidence for the presence of fatty acid sensing systems in central areas of rainbow trout (Librán-Pérez et al., 2012, 2013a, 2014a,b, 2015a,b) and Senegalese sole (Conde-Sieira et al., 2015a) as well as in peripheral areas of rainbow trout (Librán-Pérez et al., 2012, 2013a,b,c, 2015c).

The treatment of rainbow trout with oleate induced responses compatible with fatty acid sensing in hypothalamus (Librán-Pérez et al., 2012, 2013a, 2014a), BB (Librán-Pérez et al., 2012, 2013a, 2015c), and liver (Librán-Pérez et al., 2013b,c, 2015c). These responses include decreased lipogenic and fatty acid oxidation capacities, reduced activity of KATP+, and changes in the expression of transcription factors resultant of FAT/CD36 modulation. This response is comparable in general with that reported in mammals. Furthermore, in rainbow trout, similar responses occurred after treatment with the medium-chain fatty acid (MCFA) octanoate, and this is in contrast to mammals (Hu et al., 2011). This different behavior between fish and mammals might relate to the findings that body lipids in teleosts contain considerable amounts of MCFA (Davis et al., 1999; Trushenski, 2009) and/or MCFA oxidation in fish, at least in rainbow trout, is equally preferred compared with that of LCFA (Figueiredo-Silva et al., 2012a), in contrast with mammals (Ooyama et al., 2009). The response of fatty acid sensing systems in rainbow trout hypothalamus to increased levels of oleate or octanoate is also supported by the response of these tissues to specific inhibitors in vitro (Librán-Pérez et al., 2013a). Another peculiarity of fatty acid sensing systems in fish is their apparent capacity to respond to changes in the levels of polyunsaturated fatty acid (PUFA) of the n-6 and particularly n-3 series. These PUFA are very relevant for fish since their diets are particularly rich in long chain PUFA (Sargent et al., 2002) and PUFA are therefore abundant in their tissues (Mourente and Tocher, 1992; Tocher, 2003). Furthermore, the brain of marine fish is particularly rich in n-3 PUFA, mainly in α-linolenate (C18:3 n-3), eicosapentanoate (C20:5 n-3), and docosahexanoate (C22:6 n-3) (Tocher et al., 1992; Betancor et al., 2014). Conde-Sieira et al. (2015a) demonstrated that not only oleate but also α-linolenate activated fatty acid sensing systems present in the hypothalamus of Senegalese sole. This is completely different to that described in mammals (see above) and may relate to the importance of n-3 PUFA in fish. However, the capacity of PUFA to activate fatty acid sensing systems appears to be specific of certain PUFA since eicosapentanoate did not induce any significant change in fatty acid sensing systems (Conde-Sieira et al., 2015a).

Although levels of a particular fatty acid cannot be decreased, lipolysis inhibitors have been used to decrease circulating levels of all fatty acids, and this resulted in decreased activity of fatty acid sensing systems in mammals (Oh et al., 2012, 2014). A similar experimental approach in rainbow trout also resulted in the inhibition of fatty acid sensing systems in hypothalamus, BB, and liver, and these changes apparently relate to the activation of hypothalamus-pituitary-interrenal (HPI) axis (Librán-Pérez et al., 2014b, 2015d).

Figure 3 summarizes the integrative responses to changes in levels of specific fatty acids of fatty acid sensing systems in different fish tissues.

In summary, the evidence obtained in recent years support the presence in fish central and peripheral areas of several of the sensing mechanisms for glucose and fatty acid already characterized in mammalian models. However, these mechanisms are not exactly the same since besides responding to glucose or LCFA they also respond to other molecules such as MCFA or PUFA. Clearly, the assessment of amino acid sensing mechanism is lacking in fish, and this is of crucial importance considering that most fish species are carnivorous. Finally, there is also no information available regarding cellular mechanisms integrating information of main nutrient sensing systems into shared regulatory pathways.

In mammals, the detection of changes in glucose levels by glucosensing mechanisms results in regulatory responses, including food intake, allowing the animal to control blood glucose levels (Marty et al., 2007). Accordingly, reduced glycaemia increases food intake whereas enhanced glycaemia decreases food intake (Morton et al., 2014; Ogunnowo-Bada et al., 2014; Rogers et al., 2016).

Similar changes in food intake in response to altered glucose levels occur in fish (Polakof et al., 2011d, 2012a). Decreased food intake occurred in rainbow trout fed with a diet enriched in carbohydrates (Kaushik et al., 1989; Suárez et al., 2002; Krogdahl et al., 2004; Polakof et al., 2008b,c; Figueiredo-Silva et al., 2013). A similar response was observed after ICV or IP hyperglycaemic treatments in the same species (Ruibal et al., 2002; Polakof et al., 2007a, 2008a; Conde-Sieira et al., 2010a,b, 2012b). In contrast, increased food intake occurred in rainbow trout fed a diet with a reduced amount of carbohydrates (Sánchez-Muros et al., 1998; Capilla et al., 2003; Polakof et al., 2008b,c) or after IP or ICV hypoglycaemic treatments (Polakof et al., 2007a, 2008a; Conde-Sieira et al., 2010a,b). Comparable responses of food intake to changes in glucose levels also occurred in other fish species including goldfish (Narnaware and Peter, 2002), tilapia (Saravanan et al., 2012; Figueiredo-Silva et al., 2013), Siberian sturgeon (Gong et al., 2014) or sea bass (Castro et al., 2015).

In brain areas producing AgRP/NPY and POMC/CART histochemical studies in rainbow trout support the presence of GK (Polakof et al., 2009) suggesting a functional relationship between glucosensors and neuropeptides. However, few studies in fish described changes in the mRNA abundance of those neuropeptides in response to changes in glucose levels. The mRNA abundance of hypothalamic NPY decreased in hyperglycaemic-treated rainbow trout (Conde-Sieira et al., 2010b, 2012b; Aguilar et al., 2011; Otero-Rodiño et al., 2016a). A similar decline occurred in fish fed with a carbohydrate-enriched diet, such as in rainbow trout (Figueiredo-Silva et al., 2012c) and goldfish (Narnaware and Peter, 2002) whereas in the whole brain of gilthead sea bream no changes occurred (Babaei et al., 2017). CART mRNA levels in hypothalamus increased in response to elevated glucose levels in catfish (Subhedar et al., 2011) and rainbow trout (Conde-Sieira et al., 2010b, 2012b; Otero-Rodiño et al., 2015) or after rainbow trout were fed with a carbohydrate-enriched diet (Figueiredo-Silva et al., 2012c). Hypothalamic POMC mRNA levels increased in hyperglycaemic rainbow trout (Conde-Sieira et al., 2010b; Otero-Rodiño et al., 2015). Finally, AgRP mRNA abundance did not display changes in hypothalamus of rainbow trout after hyperglycaemic treatment (Otero-Rodiño et al., 2015, 2016a). Therefore, the mRNA abundance in glucosensing central areas (hypothalamus and hindbrain) of the four neuropeptides involved in the food intake regulation is affected by changes in glycaemia, and this is compatible with the changes observed in food intake (Polakof et al., 2008a,b).

In fish fed with a lipid-enriched diet, a decrease in food intake usually takes place. This occurred for instance in rainbow trout (Peragón et al., 2000; Rasmussen et al., 2000; Gélineau et al., 2001; Forsman and Ruohonen, 2009; Figueiredo-Silva et al., 2012c; Saravanan et al., 2013), chinook salmon (Silverstein et al., 1999), polka-dot grouper (Williams et al., 2006), Senegalese sole (Bonacic et al., 2016) or grass carp (Li et al., 2016). Moreover, enhanced lipid storage is also usually associated with a reduced food intake (Shearer et al., 1997; Silverstein et al., 1999; Johansen et al., 2002, 2003). Therefore, lipid metabolism is clearly influencing food intake control in fish. Considering the relative high importance of fatty acids within the lipid pool, both in fish diets and in tissue composition, is not surprising that the available studies in fish focussed on fatty acids.

In recent studies in rainbow trout a decrease in food intake was observed after IP (Librán-Pérez et al., 2012) or ICV (Librán-Pérez et al., 2014a; Velasco et al., 2016a,b) administration of oleate or octanoate, with the effect being more important for octanoate. The effect of octanoate is specific of fish (at least rainbow trout) since in mammals treatment with this fatty acid did not affect food intake (López et al., 2007; Hu et al., 2011). Moreover, when rainbow trout fed diets containing different lipid composition, the lower food intake occurred in fish with the highest levels of fatty acid in plasma (Luo et al., 2014). This finding supports that central fatty acid sensing mechanisms mediated the lipid-induced decrease in food intake. Further support come from results obtained in rainbow trout where the decrease in food intake induced by treatment with a fatty acid synthase (FAS) inhibitor is counteracted by the simultaneous presence of an acetyl-CoA carboxylase inhibitor (Librán-Pérez et al., 2012), i.e., a response similar to that of mammals (Loftus et al., 2000; Gao and Lane, 2003; Hu et al., 2011). In Senegalese sole IP treatment with oleate, α-linolenate, or eicosapentanoate also resulted in a decrease in food intake (Conde-Sieira et al., 2015a). Furthermore, when levels of circulating fatty acid decreased through pharmacological treatment a clear increase in food intake occurred in rainbow trout (Librán-Pérez et al., 2014b).

In mammals, the activation of fatty acid sensing systems results in food intake inhibition through changes in the expression of anorexigenic and orexigenic neuropeptides (López et al., 2005; Oh et al., 2016). Accordingly, the increase in LCFA levels results in a decrease in the mRNA abundance of AgRP and NPY as well as in an increase in mRNA abundance of CART and POMC. Therefore, not surprisingly, several studies have described changes in mRNA abundance of neuropeptides in fish fed lipid-enriched diets. Feeding fish with these diets resulted in increased mRNA abundance of POMC in rainbow trout (Librán-Pérez et al., 2015b), and increased mRNA abundance of CART in rainbow trout (Figueiredo-Silva et al., 2012c; Librán-Pérez et al., 2015b) and Atlantic salmon (Hevrøy et al., 2012). Feeding diets enriched in lipids also induced a decrease in NPY mRNA abundance in grass carp (Li et al., 2010) but not in rainbow trout (Figueiredo-Silva et al., 2012c; Librán-Pérez et al., 2015b) or orange-spotted grouper (Tang et al., 2013). Finally, AgRP mRNA abundance did not change in Atlantic salmon (Hevrøy et al., 2012) but decreased in rainbow trout (Librán-Pérez et al., 2015b) fed with lipid-enriched diets.

Other available studies described the impact of treatments with specific fatty acids on mRNA abundance of orexigenic and anorexigenic neuropeptides. In rainbow trout oleate either through IP (Librán-Pérez et al., 2012), in vitro (Librán-Pérez et al., 2013c) or ICV (Librán-Pérez et al., 2014a; Velasco et al., 2016a,b) treatments resulted in hypothalamus in a decrease in mRNA abundance of NPY and an increase in mRNA abundance of CART and POMC. Changes observed in NPY mRNA levels after oleate treatment are comparable to those of mammals (Blouet and Schwartz, 2010). The changes displayed by neuropeptides point to an enhancement of the anorexigenic potential, which is in agreement with the effects in food intake after treatment with the same fatty acid. The treatment of rainbow trout with octanoate also resulted in decreased NPY mRNA abundance after ICV treatment (Librán-Pérez et al., 2014a), and increased mRNA abundance of CART and POMC after ICV and in vitro treatments (Librán-Pérez et al., 2013c, 2014a). These changes also suggest an enhancement of the anorexigenic potential in hypothalamus in response to octanoate treatment supporting the reduced food intake observed after treating the same species with octanoate (Librán-Pérez et al., 2012, 2014a). This effect of octanoate is exclusive to fish, at least rainbow trout, since in mammals octanoate does not induce any change in mRNA abundance of neuropeptides (Hu et al., 2011). In Senegalese sole, the treatment with oleate also induced a decrease in the mRNA abundance of AgRP while that of CART increased, i.e., a balance favoring an anorexigenic response (Conde-Sieira et al., 2015a). In the same species, the IP treatment with the PUFAs α-linolenate or eicosapentanoate (Conde-Sieira et al., 2015a) decreased mRNA abundance of AgRP (α-linolenate) and increased mRNA abundance of CART (α-linolenate and eicosapentanoate) thus favoring enhanced anorexigenic potential, in a way similar to the effects elicited by oleate. This was the first time in any vertebrate species in which any PUFA induced changes in hypothalamic mRNA abundance of neuropeptides involved in food intake control. Interestingly, parameters involved in fatty acid sensing changed only in the case of α-linolenate (Conde-Sieira et al., 2015a) suggesting a complex relationship between changes in fatty acid sensing and neuropeptide mRNA abundance.

In a way similar to that described above for fatty acid sensing systems and food intake responses, the decrease in rainbow trout of circulating levels of fatty acid resulted in decreased mRNA abundance of POMC and CART. This change favors enhanced orexigenic potential (Librán-Pérez et al., 2014b), i.e., the opposed response of that elicited by increased levels of fatty acids.

The mechanisms linking the function of nutrient sensing systems with changes in the expression of neuropeptides, which ultimately regulate food intake, are mostly unknown in mammals. Changes in the expression of neuropeptides might relate to modulation of forkhead box01, phosphorylated cAMP response-element binding protein, and/or brain homeobox transcription factor (Diéguez et al., 2011). The actions of these factors would result in the enhancement of CART and POMC expression and the inhibition of AgRP and NPY expression resulting in decreased food intake (López et al., 2007; Diéguez et al., 2011). However, it is not clear how these transcription factors relate to the activity of the different nutrient sensing systems. Several possibilities have been suggested in mammals (López et al., 2007; Diéguez et al., 2011; Gao et al., 2013; Morton et al., 2014) including direct action of malonyl CoA or CPT-1, indirect action through CPT-1 inhibition, modulation by AMPK, mTOR, protein kinase B (Akt), or carbohydrate-responsive element-binding protein and/or involvement of ceramides.

In fish, several recent studies carried out in rainbow trout provided evidence for several of these hypothetical mechanisms. Indeed, Librán-Pérez et al. (2015b) demonstrated that protein levels of AMPK, Akt, and mTOR increased in hypothalamus of fish fed a lipid-enriched diet. Furthermore, Gong et al. (2016a) demonstrated increased Akt protein levels in isolated hypothalamic cells incubated with leptin. Finally, Velasco et al. (2016b) also suggested the possible involvement of ceramides in the connection between activation of hypothalamic fatty acid sensing systems, neuropeptide mRNA abundance, and control of food intake. Besides these preliminary studies, there is no other evidence in fish about hypothalamic pathways related to integration of metabolic information coming from different nutrient sensor systems (glucose, fatty acids, amino acids) into a shared pathway controlling food intake via neuropeptide expression.

Food intake regulation is a complex process in which nutrient sensing systems are apparently involved in fish, in a way again comparable to that of mammals with notable differences including the capacity of several nutrients like MCFA or PUFA to modify food intake control in fish. Again, there is no information regarding the involvement of amino acid sensing systems in fish on food intake regulation, and this clearly needs assessment in the near future. Once characterized such a putative effect, the next step would be the assessment of how and why changes in those sensing systems translate into expression of anorexigenic and orexigenic neuropeptides ultimately regulating food intake. The possible mechanisms are mostly unknown, even in mamamals, and therefore it is quite probable that important differences between fish and mammals arise considering their different gastrointestinal morphology and physiology, and dietary habits.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.