Hypothalamic Nutrient Sensing in Fish: Glucose, Fatty Acids, Amino Acids

© 2024. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2024) 227, jeb247410. doi:10.1242/jeb.247410
REVIEW
Hypothalamic integration of nutrient sensing in fish
José L. Soengas*, Sara Comesana,
̃ Marta Conde-Sieira and Ayelé n M. Blanco
The hypothalamus plays a crucial role in regulating feeding behavior in
fish. In this Review, we aim to summarise current knowledge on specific
mechanisms for sensing glucose, fatty acids and amino acids in fish,
and to consider how this information is integrated in the hypothalamus to
modulate feed intake. In fish, specific neuronal populations in the
nucleus lateralis tuberalis (NLTv) of the hypothalamus are equipped with
nutrient sensors and hormone receptors, allowing them to respond to
changes in metabolite levels and hormonal signals. These neurons
produce orexigenic (Npy and Agrp) and anorexigenic (Pomc and Cart)
neuropeptides, which stimulate and suppress appetite, respectively.
The modulation of feeding behavior involves adjusting the expression of
these neuropeptides based on physiological conditions, ultimately
influencing feeding through reciprocal inhibition of anorexigenic and
orexigenic neurons and signalling to higher-order neurons. The
activation of nutrient sensors in fish leads to an enhanced
anorexigenic effect, with downregulation of agrp and npy, and
upregulation of cart and pomc. Connections between hypothalamic
neurons and other populations in various brain regions contribute to the
intricate regulation of feeding behaviour in fish. Understanding how feed
intake is regulated in fish through these processes is relevant to
understanding fish evolution and is also important in the context of
aquaculture.
KEY WORDS: Feed intake, Fish, Hypothalamus, Nutrient sensing
Introduction
Much of our current understanding of the regulation of feeding
behaviour is based on work in mammals, particularly lab models
like mice and rats, with scarce information available in wild species.
In mammals, food intake is regulated within the central nervous
system (CNS) according to the levels of circulating nutrients, such
as glucose, fatty acids and amino acids. These nutrients reflect the
composition of the consumed food, and they act as a signal of the
energy status of the organism. To detect changes in the levels of
these circulating nutrients, a combination of enzymes, channels,
carriers, transporters and other molecules in the brain act as sensors,
enabling the detection and metabolism of nutrients. This
information is integrated in the hypothalamus to elicit changes in
food intake through changes in specific neuropeptides. Nutrients
interact with circulating hormones, all acting on the hypothalamus
(see Box 1). However, the focus of this Review is on the nutrient
part of the regulation, rather than on hormonal effects.
In fish, research carried out in recent years has provided evidence
for the existence of comparable mechanisms to those known in
Centro de Investigació n Marina,
̃ Laboratorio de Fisioloxı́a Animal, Departamento de
Bioloxı́a Funcional e Ciencias da Saú de, Facultade de Bioloxı́a, Universidade de
Vigo, 36310 Vigo, Spain.
*Author for correspondence ( [email protected])
J.L.S., 0000-0002-6847-3993; S.C., 0000-0002-3020-8377; M.C., 0000-00029763-6202; A.M.B., 0000-0002-7683-4154
mammals. In this Review, we aim to describe these processes in
fish, focusing not only on specific mechanisms for sensing glucose,
fatty acids and amino acids, but also discussing their impact on
metabolism and the regulation of feed intake. It is our hope that this
synthesis will allow us to identify key knowledge gaps that can be
addressed by future research. It is important to mention that fishes
form a heterogeneous group, and that, so far, knowledge on the
mechanisms underlying their nutrient sensing has been obtained
from a relatively small number of fish species. Therefore, it is not
currently possible to suggest clear trends within teleost fish
regarding these mechanisms.
Glucosensing
Mechanisms
In fish, there are multiple hypothalamic mechanisms for detecting
glucose levels, and most of them, as characterized in mammals, are
dependent on the entry of glucose into the cells and its subsequent
metabolism. The best-known glucosensing mechanism is based on
glucokinase (GCK) activity and GLUT2 (SLC2a2)-mediated
transport (Fig. 1; Marty et al., 2007; De Backer et al., 2016).
Once glucose is transported into a neuron through the low-affinity
GLUT2 transporter, GCK facilitates its phosphorylation to glucose6-phosphate. This initiates glycolysis, increasing intracellular ATP
levels and leading to the closure of ATP-sensitive potassium
(K+ ATP) channels. This closure induces membrane depolarization,
allowing calcium influx through L-type voltage-dependent calcium
channels, and ultimately enhancing neuronal activity. In fish,
researchers have used a variety of techniques to alter glucose levels
experienced by rainbow trout (Oncorhynchus mykiss) hypothalamic
cells, both in vitro and in vivo (Polakof and Soengas, 2008; Polakof
et al., 2007a, 2007b, 2008a,b,c; Conde-Sieira et al., 2010a,b, 2011,
2012; Aguilar et al., 2011; Otero-Rodiño et al., 2015a). All such
interventions lead to modifications in different components
involved in the Gck–Glut2-dependent glucosensing mechanism
within the hypothalamus. The expression of the components of this
system are increased when circulating levels of glucose rise and
decreased when blood glucose levels fall. In addition to rainbow
trout, there is evidence for central glucosensing capacity in other
fish species, such as medaka (Oryzias latipes, Hasebe et al., 2016)
or grass carp (Ctenopharyngodon idella, Chen et al., 2022).
As noted above, there are multiple glucosensing mechanisms,
and not all rely on Gck–Glut2. In mammals, an alternative
mechanism relies on the transport of glucose into the neuron by
the sodium-coupled glucose cotransporter 1 (SGLT-1), dependent
on the entry of Na+ (Fig. 1; O’Malley et al., 2006). Because glucose
is electrically neutral, the entry of Na+ through SGLT-1 is sufficient
to induce depolarization and increase neuronal activity. This
response can occur either through direct changes of the membrane
potential or indirectly through coupling with a G-protein (DíezSampedro et al., 2003). In addition to stimulating neuronal activity,
elevated glucose levels lead to increased levels of Sglt1 mRNA in
various mammalian tissues, meaning that this transporter effectively
serves as a glucosensor (O’Malley et al., 2006; González et al., 2009).
1
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ABSTRACT
Journal of Experimental Biology (2024) 227, jeb247410. doi:10.1242/jeb.247410
List of abbreviations
Acc
Acly
ACS
ALA
Ampk
BCAA
Bcat
Bckdh
Bckdk
Bsx
Cart
Cck
CNS
Cpt-1
Creb
ER
FA
FA-CoA
Fas
Fat/cd36
Fatp4
Fbpase
Foxo1
Gck
Gcn2
Gdh
Ghrl
Glp-1
Gls
Glut2
Gpase
Gpr
Gsase
ICV
IP
IP3
K+ ATP
Lat1
LCFA
Ldh
Lpl
Lxr
Mcd
MCFA
mTOR
NAT
NLTd
NLTl
NLTv
NPO
Npy
Pkc
Plc
Pomc
Pparα
Pyy
ROS
S6
SCFA
Sesn2
Sglt-1
Snat2
Srebp1c
T1r1–Tlr3
Ucp2
Vdcc
Vm
acetyl-CoA carboxylase
ATP citrate lyase
acyl-CoA synthase
α-linolenate
AMP-activated protein kinase
branched-chain amino acid.
branched-chain aminotransferase
branched-chain alpha-keto acid dehydrogenase complex
branched-chain ketoacid dehydrogenase kinase
brain homeobox transcription factor
cocaine- and amphetamine-regulated transcript
cholecystokinin
central nervous system
carnitine palmitoyltransferase 1
cAMP response-element binding protein
endoplasmic reticulum
fatty acid
fatty acid-coenzyme A
fatty acid synthase
fatty acid transporter CD36
fatty acid transporter 4
fructose 1,6-bisphosphatase
forkhead box O1
glucokinase
general control nonderepressible 2
glutamate dehydrogenase
ghrelin
glucagon-like peptide 1
glutamine synthase
facilitated glucose carrier type 2
glycogen phosphorylase
G-protein-coupled receptor
glycogen synthase
intracerebroventricular
intraperitoneal
inositol triphosphatase
inward rectifier ATP-dependent K+ channel
L-type amino acid transporter 1
long-chain fatty acid
lactate dehydrogenase
lipoprotein lipase
liver X receptor
malonyl CoA dehydrogenase
medium-chain fatty acid
mechanistic target of rapamycin
anterior tuber nucleus
lateral tuber nucleus pars dorsalis
lateral tuber nucleus pars lateralis
lateral tuber nucleus pars ventralis
preoptic nuclei
neuropeptide Y
protein kinase C
phospholipase C
pro-opiomelanocortin
peroxisome proliferator-activated receptor type α
peptide tyrosine-tyrosine
reactive oxygen species
ribosomal protein S6
short-chain fatty acid
sestrin 2
sodium/glucose linked transporter 1
sodium-dependent neutral amino acid transporter 2
sterol regulatory element-binding protein type 1c
taste receptor type 1 member 1–3
uncoupling protein 2
L-type voltage-dependent calcium channel
membrane potential
Glossary
Anorexigenic
A substance that reduces appetite, resulting in reduced food
consumption.
Blood–brain barrier
A semipermeable border of endothelial cells that regulates the transfer of
solutes and chemicals between the circulatory system and the central
nervous system.
Brockmann body
An endocrine organ in some teleost fish composed of a collection of
pancreatic tissues.
Hypothalamus–pituitary–inter-renal axis
A set of direct influences and feedback interactions among three
components present in teleost fish: the hypothalamus (a part of the brain
located below the thalamus), the pituitary gland (a pea-shaped structure
located below the hypothalamus) and the inter-renal tissue (in the middle
of the head kidney). These organs and their interactions constitute the
HPI axis.
Metabotropic receptor
A type of membrane receptor that initiates several metabolic steps to
modulate cell activity.
Orexigenic
A substance that increases appetite and stimulates feeding.
Reactive oxygen species
Highly reactive chemicals that can be produced from oxygen, water or
hydrogen peroxide.
β-oxidation
A catabolic process by which fatty acids are broken down to generate
acetyl-CoA.
In fish, Sglt-1 is present in various tissues, including the
hypothalamus (rainbow trout: Sugiura et al., 2003; Soengas and
Polakof, 2013; Conde-Sieira et al., 2013; Craig et al., 2013; gilthead
sea bream, Sparus aurata: Sala-Rabanal et al., 2004), although its
involvement in glucosensing is not clear.
Another GCK-independent glucosensing mechanism involves
the stimulation of the sweet taste receptor, which is a heterodimer of
type 1 taste receptor subunits (T1Rs) formed by T1R2, T1R3 and αgustducin. Binding of glucose to this receptor induces the activation
of an intracellular signalling cascade leading to membrane
depolarization (Fig. 1; Ren et al., 2009; Herrera Moro Chao et al.,
2016). T1R2/3 is a metabotropic (see Glossary) G-protein-coupled
(GPR) receptor that can modulate neuronal activity in the presence
of glucose in the brain (Welcome et al., 2015) in a manner similar to
that of T1R2/3 located in taste buds (Kinnamon, 2012). In rainbow
trout hypothalamus, the mRNA abundance of α-gustducin, t1r2 and
t1r3 decreases under conditions of hyperglycemia, suggesting that
the sweet taste receptor may play a role in glucosensing in this brain
area (Otero-Rodiño et al., 2015a). Furthermore, levels of mRNA of
t1r2 in the brain of rainbow trout increase in fish nutritionally
programmed to cope with elevated levels of dietary carbohydrate
(Balasubramanian et al., 2016).
An alternative glucosensor system based on the nuclear liver X
receptor (LXR) has been described in mammals. Here, the
activation of LXR increases in response to increased glucose,
resulting in a decrease in gluconeogenesis (Anthonisen et al., 2010)
and changes in the mRNA abundance of certain transcription factors
(Higuchi et al., 2012; Kim and Ahn, 2004; Festuccia et al., 2014).
Glucosensing in mammals can also be mediated by enhanced
mitochondrial production of reactive oxygen species (ROS; see
Glossary) by electron leakage, which can occur through the
mitochondrial uncoupling protein UCP2a (Blouet and Schwartz,
2010; Blanco de Morentin et al., 2011), such that an increase in
2
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REVIEW
Box 1. Feeding control by hypothalamic neuropeptides
The mammalian hypothalamus integrates signals originating from both
the brain and peripheral organs, resulting in alterations in food intake.
Two distinct neuronal populations within the arcuate nucleus are
primarily responsible for signal integration: orexigenic (appetitestimulating) neurons, producing neuropeptide Y (NPY) and agoutirelated peptide (AgRP), and anorexigenic (appetite-suppressing)
neurons, producing pro-opiomelanocortin (POMC) and cocaine- and
amphetamine-regulated transcript (CART). These neuronal populations
are equipped with nutrient sensors and receptors for hormones
regulating appetite. This enables them to respond to fluctuations in the
levels of circulating metabolites – including fatty acids, glucose and
amino acids – as well as hormonal signals. The subsequent response
involves modulating the expression levels of Npy, Agrp, Pomc and Cart
based on specific physiological conditions (Schwartz et al., 2000; Levin
et al., 2004; Mobbs et al., 2005; Mountjoy et al., 2007; Fioramonti et al.,
2007; Sohn, 2015). Ultimately, feeding behaviour is influenced by the
reciprocal inhibition of orexigenic and anorexigenic neurons, and their
signalling to higher-order neurons in diverse hypothalamic and extrahypothalamic regions (Blouet and Schwartz, 2010; Morton et al., 2014).
In fish, Agrp/Npy and Pomc/Cart neurons are present in the nucleus
lateralis tuberalis (NLTv; Soengas et al., 2018). The mRNA levels of
these neuropeptides in fish are responsive to the feeding status (Bodas
et al., 2023), indicating their pivotal role in the regulation of feed intake
(Volkoff, 2016; Delgado et al., 2017). In fish, the activation of nutrient
sensors results in an enhanced anorexigenic potential, achieved through
the downregulation of agrp and npy expression and the upregulation of
cart and pomc expression (Conde-Sieira and Soengas, 2017; Delgado
et al., 2017; Soengas et al., 2018). The finding that pomc-knockout (KO)
zebrafish (Danio rerio) display increased feed intake compared with the
wild type also supports the involvement of Pomc as an anorexigenic
neuropeptide in fish (Yang et al., 2023). Additionally, like the situation in
mammals, Npy/Agrp and Pomc/Cart neurons establish connections with
other neuronal populations in both hypothalamic and extra-hypothalamic
areas in fish (Bodas et al., 2023), although the precise understanding of
their neuropeptide production remains elusive (Soengas et al., 2018).
UCP2a activity indicates a lower level of glucose (Kong et al., 2010;
Beall et al., 2012; Thorens, 2012). In fish, there is some evidence
that both the Lxr- and mitochondria-dependent mechanisms of
glucosensing are functional in rainbow trout hypothalamus (OteroRodiño et al., 2015a, 2016).
In recent years, experimental evidence from mammals has
pointed to an important role for astrocytes and tanycytes in the
glucosensing function of the hypothalamus (Pellerin and
Magistretti, 1994; López-Gambero et al., 2019). In fish, there is
little information on this mechanism, but lactate treatment can
modulate central glucose metabolism in rainbow trout, which would
suggest the possible presence of an astrocyte–neuron lactate shuttle
that would facilitate glucosensing (Polakof and Soengas, 2008;
Otero-Rodiño et al., 2015b).
In summary, in fish, there is sufficient information available on
the Glut2–Gck mechanism of glucosensing to suggest that it plays a
comparable role in fish to that known in mammals. However, more
fish species need to be assessed to in order to determine the relative
importance of this mechanism in species with different dietary
habits (e.g. carnivore, omnivore or herbivore) or habitats. In
contrast, in fish, the information regarding alternative mechanisms
of glucosensing is very scarce, demanding further research.
Impact of glucosensing on feeding and metabolism
Changes in glucose levels induce changes in feed intake and in
appetite-related neuropeptides in fish (Polakof et al., 2011; Soengas,
2014). In general, the activation of glucosensing systems induced by
Journal of Experimental Biology (2024) 227, jeb247410. doi:10.1242/jeb.247410
the presence of high levels of carbohydrate in the diet or by
increasing levels of glucose in vivo or in vitro results in decreased
feed intake, in parallel with an increased abundance of mRNA
encoding the anorexigenic (see Glossary) neuropeptides Pomc and
Cart, and decreased levels of mRNA encoding the orexigenic (see
Glossary) neuropeptides Npy and Agrp (Table 1). Moreover, in
regions of the brain where neuropeptides are generated, studies
utilizing histochemistry reveal the existence of proteins associated
with glucose sensing, as demonstratred for Gck (Polakof et al.,
2009), as well as Sglt-1, Lxr or T1r3 (Otero-Rodiño et al., 2019a,b).
These findings imply a functional connection between glucosensors
and neuropeptides in these brain areas.
As well as having a role in regulating appetite, glucosensing
mechanisms are also involved in regulating other aspects of energy
homeostasis: for example, glucosensing influences hormone secretion
and energy expenditure, which modulate the activity of peripheral
organs such as the liver and pancreas (Timper and Brüning, 2017;
López-Gambero et al., 2019). In fish, intracerebroventricular (ICV)
glucose administration affects hepatic metabolism (Polakof and
Soengas, 2008). Therefore, the presence of glucose in the fish brain
is a signal of energy abundance, which induces a reduction in the
activity of the hepatic pathways involved in glucose production and
release.
In mammals, hypothalamic detection of high glucose levels
induces pancreatic counter-regulatory responses to restore normal
blood glucose levels. These responses are mainly mediated by
parasympathetic and sympathetic efferent nerves that innervate
pancreatic α- and β-cells, inducing the release of the hormones
insulin and glucagon (Blouet and Schwartz, 2010; Ogunnowo-Bada
et al., 2014; Roh et al., 2016). In rainbow trout, changes in glucose
concentration in the brain result in increased Gck activity and
expression in Brockmann bodies (see Glossary), which are
homologous to the mammalian endocrine pancreas (Polakof and
Soengas, 2008). Accordingly, in fasted fish, plasma insulin levels
decrease and plasma glucagon levels increase (Navarro and Gutiérrez,
1995), whereas the expression of insulin is higher in zebrafish (Danio
rerio) exposed to elevated glucose levels (Jurczyk et al., 2011).
Although there is a reasonable amount of information available
regarding the impact of hypothalamic glucosensing on feed intake in
fish, the impact of central glucosensing on peripheral metabolism is
basically unknown and requires further research, especially
considering the impact of metabolic changes on fish growth.
Fatty acid sensing
Mechanisms
The most-accepted mechanism through which fatty acids (particularly
long-chain fatty acids; LCFAs) are sensed in mammalian
hypothalamic cells is metabolic in nature. Increased plasma levels of
LCFAs lead to an increase in the levels of malonyl-CoA, which in turn
inhibits carnitine palmitoyltransferase 1 (CPT-1; also known as
carnitine acyltransferase 1; Fig. 2). This enzyme is in the outer
mitochondrial membrane, and it is responsible for catalyzing the
transport of LCFAs into mitochondria. Inhibition of CPT-1 prevents
the mitochondria from importing fatty acid-CoA for β-oxidation (see
Glossary; López et al., 2005, 2007; Gao et al., 2013). This mechanism
is also likely to be functional in fish. For example, hypothalamic cells
of several fish species show increased levels of malonyl-CoA and/or
decreased Cpt-1 in response to the LCFA oleate (C18:1 n-9),
both in vitro and in vivo [rainbow trout: Librán-Pérez et al., 2012,
2013b, 2014a; Velasco et al., 2017b; Senegalese sole (Solea
senegalensis): Conde-Sieira et al., 2015; Chinese perch (Siniperca
chuatsi): Luo et al., 2020].
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1
Glucose
Glucose
Glucose
1
T1r2
Glucose
Sgl
Glut2
t-1
Gck
Gsase
Glycogen
Glucose-6P
3
T1r3
Gpase
Glucose
Na+
2
Vm
Fructose-6P
FBPase
−
Plc/IP3
pathway
Glycolysis
4
Lxr
+
PPAR
SREBP1c
Ldh
Pyruvate
Lactate
ER
Nucleus
Ca2+
Ca2+
Ca2+
Ucp2
1
ADP
ATP
K+ATP channel
5 Pyruvate
ROS
Acetyl-CoA
NADH,
FADH2
Respiratory
chain
Ca2+
Krebs
cycle
Vdcc
ATP
K+
Mitochondria
Ca2+
Vm
Unlike the situation in mammals, where fatty acid-sensing
mechanisms only respond to some LCFAs, the fish hypothalamus
seems to detect monounsaturated fatty acids, medium-chain fatty acids
(MCFAs) and polyunsaturated fatty acids (PUFAs). For example,
increased malonyl-CoA and/or decreased Cpt-1 levels in the fish
hypothalamus occur not only in response to oleate, but also to the
MCFA octanoate in rainbow trout (Librán-Pérez et al., 2012, 2013b,
2014a) and the PUFA α-linolenate (ALA) in Senegalese sole (CondeSieira et al., 2015). The ability of fish (especially marine species) to
respond to changes in PUFA levels might relate to the high amount of
n-3 PUFAs in fish diets (Sargent et al., 2002) and consequently in their
tissues (Mourente and Tocher, 1992; Tocher, 2003).
Alternative mechanisms of fatty acid sensing are also present in
the fish hypothalamus. One such mechanism involves the fatty acid
translocase (also known as cluster of differentiation 36; Fat/cd36;
Fig. 2). This protein increases its capacity to bind to fatty acids in
response to increased fatty acid levels, resulting in the modulation of
mRNA abundance of several transcription factors, such as srebp1c
and ppara (Le Foll et al., 2009). In fish, administration of oleate
(which is not sensed by mammals) and/or octanoate upregulates the
expression of hypothalamic mRNAs encoding Cd36, Srebp1c and
Pparα in rainbow trout (Librán-Pérez et al., 2012, 2014a) and
Chinese perch (Luo et al., 2020). A similar response also occurs
upon feeding rainbow trout with a lipid-enriched diet (Librán-Pérez
et al., 2015a). Similarly, an oleate-induced increase in abundance of
cd36 mRNA and an oleate- and ALA-induced increase in ppara
mRNA occur in the head of Senegalese sole post-larvae when the
same nutrients are administered orally (Velasco et al., 2017a).
Expression of cd36 is also upregulated in the brain of grass carp fed
a high-fat diet (Tian et al., 2017) and in the hypothalamus of
Chinese perch after ICV treatment with oleate, linolenate or αlinolelante (Luo et al., 2020). Intraperitoneal administration of
oleate and ALA downregulate ppara and srebp1c in the Senegalese
sole hypothalamus (Conde-Sieira et al., 2015). Finally, Fat/cd36
gene knockout suppresses the spontaneous linoleate preference in
zebrafish (Liu et al., 2017).
Another response of mammalian hypothalamic neurons to
increased levels of LCFAs is the inhibition of K+ ATP channels
(Fig. 2). This inhibition can be caused either by the activation of
specific isoforms of protein kinase C (PKC) (Benoit et al., 2009) or by
4
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Fig. 1. Schematic summary of processes involved in glucosensing in the fish hypothalamus. A rise in circulating glucose levels is sensed through
different mechanisms. (1) Increased transport of glucose by Glut2 leads to phosphorylation by Gck, initiating glycolysis, increasing intracellular ATP levels
and leading to the closure of K+ ATP channels, which induces membrane depolarization, allowing calcium influx via Vdcc. (2) Transport of glucose into the
neuron via Sglt-1 is dependent on the simultaneous entry of Na+, inducing depolarization. (3) Binding of glucose to T1r2–T1r3 induces activation of
intracellular signalling, leading to membrane depolarization. (4) Activation of Lxr in response to increased glucose levels decreases gluconeogenesis and
results in changes in transcription factors. (5) Increased levels of glucose enhance mitochondrial production of ROS by stimulating electron leakage. For
definition of all symbols, see list of abbreviations.
REVIEW
Journal of Experimental Biology (2024) 227, jeb247410. doi:10.1242/jeb.247410
Table 1. Changes in feed intake and mRNA abundance of hypothalamic neuropeptides in different fish species exposed to different diets or
experimental treatment with nutrients in vivo or in vitro
Species
Glucose/carbohydrates
Increased glucose
Catfish (Clarias gariepinus)
Rainbow trout (Oncorhynchus
mykiss)
HC diet
LC diet
Fatty acids/fats
Increased octanoate,
linolenate or ALA
Increased oleate,
octanoate or ALA
Increased fatty acids
HF diet
Decreased fatty
acids
Amino acids/proteins
Increased leucine
High leucine diet
Increased valine
Increased
methionine or
lysine
HP diet
Atlantic salmon (Salmo salar)
European eel (Anguilla anguilla)
Goldfish (Carassius auratus)
Gilthead sea bream (Sparus auratus)
Grass carp (Ctenopharyngodon
idella)
Nile tilapia (Oreochromis niloticus)
Japanese flounder (Paralichthys
olivaceus)
Japanese seabass (Lateolabrax
maculatus)
Rainbow trout
Neuropeptide
mRNA
↑ cart
↓ npy
≈ agrp
↑ cart, pomc
≈ npy, cart
↓npy, agrp
Rainbow trout
Senegalese sole
(Solea senegalensis)
Atlantic salmon
Chinook salmon
(Oncorhynchus tshawytscha)
Polka-dot grouper
(Cromileptes altivelis)
Rainbow trout
Senegalese sole
Rainbow trout
Catfish hybrid (Pelteobagrus
vachelli×Leiocassis longirostris)
Chinese perch
Rainbow trout
Tiger puffer (Takifugu rubripes)
Atlantic salmon
Golden pompano (Trachinotus
ovatus)
Grouper (Epinephelus coioides)
Chinese perch
Rainbow trout
Chinese perch
↓
↓
↓
Figueiredo-Silva et al., 2013
Liu et al., 2019**
↓ agrp
Han et al., 2022
↓ npy
↓
↓
↑
↓ npy, agrp
↑ cart, pomc
↓ npy, agrp
↑ cart, pomc
↓ npy, agrp
↑ cart, pomc
↓ npy, cart, pomc
↓ npy, agrp
↑ cart, pomc
↑ npy, agrp
↓ cart, pomc
≈ npy, agrp, cart,
pomc
↑ npy
Rainbow trout
Reference
Subhedar et al., 2011
Ruibal et al., 2002; Polakof et al., 2007a, 2008a;
Conde-Sieira et al., 2010a,b, 2012; Aguilar et al., 2011;
Figuereido-Silva et al., 2012a,b; Otero-Rodiño et al.,
2015a, 2016
Krogdahl et al., 2004
Suárez et al., 2002
Narnaware and Peter, 2002
Babaei et al., 2017; Basto-Silva et al., 2021
Chen et al., 2022
↓
↓
↓
↓
Siberian sturgeon (Acipenser baerii)
Rainbow trout
Chinese perch (Siniperca chuatsi)
Feed
intake
Kaushik et al., 1989; Suárez et al., 2002; Polakof et al.,
2008b,c; Figuereido-Silva et al., 2012a,b
Gong et al., 2014
Sánchez-Muros et al., 1998; Capilla et al., 2003;
Polakof et al., 2008b,c
Luo et al., 2020; Feng et al., 2022
Librán-Pérez et al., 2012, 2014a; Velasco et al., 2016a,b,
2017a
Conde-Sieira et al., 2015
↓
↓
Hevrøy et al., 2012
Silverstein et al., 1999
↓
Williams et al., 2006
↓
Peragón et al., 2000; Rasmussen et al., 2000; Gélineau
et al., 2001; Forsman and Ruohonen, 2009; Saravanan
et al., 2013; Librán-Pérez et al., 2015a
Bonacic et al., 2016
Librán-Pérez et al., 2014b
↓
↓
Zhao et al., 2020
↓
↓
Chen et al., 2021
Comesaña et al., 2018a,b
↓
↓
↓
Wei et al., 2022
Comesaña et al., 2021a; Lai et al., 2023
Tan et al., 2016
↓
↑
↑
↑
Niu et al., 2021
Chen et al., 2021
Comesaña et al., 2018a,b
Zou et al., 2022
↓
Skiba-Cassy et al., 2013; Basto-Silva et al., 2022
agrp, agouti-related peptide; cart, cocaine and amphetamine-related transcript; FI, feed intake; HC, high carbohydrate; HF, high fat; HP, high protein; LC, low
carbohydrate; LF, low fat; npy, neuropeptide Y; pomc, pro-opio melanocortin; ↑, increase; ↓, decrease; ≈, no change.
the enhanced production of ROS, owing to electron leakage from
mitochondria (Schönfeld and Wojtczak, 2008). In the fish
hypothalamus, changes in the mRNA abundance of components of
the K+ ATP channel and/or mitochondrial uncoupling (through UCP2a)
occur in response to various fatty acids in rainbow trout (Librán-Pérez
et al., 2012, 2013b, 2014a; Velasco et al., 2016a,b, 2017b) or
Senegalese sole (Conde-Sieira et al., 2015; Velasco et al., 2017c), thus
supporting the role of this channel.
Lipoprotein lipase (LPL) has also been identified as a lipid sensor
in the mammalian hypothalamus. The activity of LPL increases in
5
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FAs
Ffar1
Gpr84
FAs
FAs
2
Fat/
cd36
Acetyl-CoA
Fatp4
Acc-P
Mcd
Malonyl-CoA
5
Gpr119
6
?
1
Fas
FA
Plc/IP3
pathway
FA
Lpl
Acs
FA-CoA
(primarily LCFA-CoA)
3
Gene expression
orexigenic/anorexigenic
neuropeptides
1
Pkc
Cp
FA-CoA
Ucp2
ADP
ATP
K+ATP channel
ER
Ca2+
t-1
Nucleus
E-oxidation
Acetyl-CoA
(if excessive)
ROS
Respiratory
chain
4
NADH,
FADH2
Krebs
cycle
Ca2+
Ca2+
Ca2+
ATP
K+
Mitochondria
Vdcc
Ca2+
Vm
Fig. 2. Schematic summary of processes involved in fatty acid sensing in the fish hypothalamus. A rise in circulating levels of LCFA, MCFA or PUFA is
sensed through different mechanisms. (1) Increased levels of malonyl-CoA, inhibiting Cpt-1. (2) Increased capacity of Fat/cd36 to bind to fatty acids, resulting in
the modulation of Srebp1c and Pparα. (3) Inhibition of K+ ATP channels by the activation of specific isoforms of Pkc. (4) Inhibition of K+ ATP channels by enhanced
production of ROS owing to electron leakage by mitochondria. (5) Increased Lpl activity. (6) Activation of Ffar1, Gpr84 and Gpr119, triggering the activation of
Plc/IP3 signalling and ultimately leading to an increase in intracellular Ca2+ levels. For definition of all symbols, see list of abbreviations.
knowledge on Gpr-mediated fatty acid sensing in the fish brain is still
very scarce and more research on this topic is required.
Impact of fatty acid sensing on feeding and metabolism
Lipids have an important impact on feed-intake regulation in fish:
fish fed lipid-enriched diets display different feed-intake levels
(usually decreased) compared with those fed a normal diet.
Moreover, enhanced lipid storage is also usually associated with
reduced feed intake (Shearer et al., 1997; Silverstein et al., 1999;
Johansen et al., 2002, 2003). Among the lipid pool, fatty acids are the
most important lipids in terms of energy use; thus, it is not surprising
that the differences in feeding observed with lipid-enriched diets are
predominantly caused by fatty acids (Table 1). For example, in
rainbow trout, the lowest feed intake is seen in fish fed with lipidenriched diets that result in higher plasma levels of fatty acids (Luo
et al., 2014) and PUFAs (Roy et al., 2020). Moreover, a clear
increase in feed intake is observed in rainbow trout displaying a
pharmacologically mediated fall in circulating fatty acid levels
(Librán-Pérez et al., 2014b). In addition, intraperitoneal (LibránPérez et al., 2012) or ICV (Librán-Pérez et al., 2014a; Velasco et al.,
2016a,b) administration of oleate or octanoate results in a significant
6
Journal of Experimental Biology
response to a rise in LCFA levels (Picard et al., 2014). It is not clear
whether this lipid sensor is active in fish: in rainbow trout
hypothalamus, the abundance of lpl mRNA decreases in response
to ICV administration of oleate (Velasco et al., 2016a,b) or in vitro
incubation with this fatty acid (Velasco et al., 2017b).
Finally, it is well established that hypothalamic neurons in
mammals express GPRs – particularly GPR40 and GPR120 [also
named free fatty acid receptor 1 (FFAR1) and 4 (FFAR4),
respectively] – that can detect and respond to LCFAs (Dragano
et al., 2017). Activation of these receptors is enhanced as LCFA
levels increase, triggering the activation of the phospholipase C
(PLC)/inositol 1,4,5-triphosphate (IP3) intracellular signalling
pathway, and ultimately leading to an increase in intracellular Ca2+
levels (Usui et al., 2019). The presence of GPR84, which binds to
MCFAs, has also been reported in the mammalian brain (Ichimura
et al., 2009). In contrast to mammals, Ffar4 is absent in fish;
consequently, Ffar1 is the only putative receptor for LCFAs in fish
(Fig. 2). Recent studies have provided evidence for the presence of
fatty acid-sensing mechanisms involving Ffar1 in rainbow trout
hypothalamus (Velasco et al., 2020), as well as for mechanisms
involving Gpr84 and Gpr119 (Fig. 2; Velasco et al., 2021). However,
decrease in feed intake in rainbow trout, with the effect being greater
for octanoate.
A decrease in abundance of npy/agrp mRNA and/or an increase
in pomc/cart mRNA in response to feeding a lipid-enriched diet is
observed in the hypothalamus of several fish species (Table 1). A
similar increase also occurs in response to increased levels of
specific fatty acids, such as oleate, octanoate or ALA (Table 1). The
octanoate-mediated modulation of neuropeptide expression appears
to be exclusive to fish; this fatty acid does not induce any change in
mRNA abundance of neuropeptides in mammals (Hu et al., 2011).
Apart from its effects on feeding, the hypothalamic detection of
fatty acids impacts several peripheral metabolic processes involved
in energy homeostasis, such as hepatic glucose production and
lipogenesis (Obici et al., 2002; Morgan et al., 2004; Migrenne et al.,
2011). In fish, several studies have demonstrated that ICV treatment
with fatty acids also alters parameters related to glucose and lipid
metabolism in peripheral tissues (including the liver and the
Brockman bodies), as in mammals (Migrenne et al., 2011; CondeSieira and Soengas, 2017). Thus, ICV-administered oleate and
octanoate lead to increased levels of glucose and glycogen and
decreased levels of fatty acid and total lipid, as well as decreased
activities of Gck, fructose 1,6-bisphosphatase (Fbpase), fatty acid
synthase (Fas) and Cpt-1 in the liver of rainbow trout. These changes
counter-regulate the elevated fatty acid levels as detected in the brain
(Librán-Pérez et al., 2015c). The functional connection between
central fatty acid sensing and production/release of fuels from the
liver is likely to be mediated through the vagus and splanchnic
nerves, which innervate the liver and the gastrointestinal tract
(Burnstock, 1959; Seth and Axelsson, 2010). At least in rainbow
trout, the hypothalamus–inter-renal–pituitary axis (see Glossary) has
also been implicated in the counter-regulatory response of the liver to
a fall in circulating fatty acid levels (Librán-Pérez et al., 2015c), in a
manner comparable to that described in mammals (Oh et al., 2012,
2014). Regarding the Brockman bodies, ICV administration of
oleate and octanoate in rainbow trout results in the modulation of
parameters related to lipid metabolism in this tissue (Librán-Pérez
et al., 2015b).
In summary, lipid-enriched diets typically result in decreased feed
intake in fish, likely owing to increased levels of fatty acids in the
blood. Changes in feed intake are associated with changes in
hypothalamic npy/agrp and pomc/cart expression, particularly in
response to lipid-enriched diets or fatty acid administration. Moreover,
hypothalamic detection of fatty acids influences peripheral metabolic
processes, including glucose and lipid metabolism. However, further
research on this subject is required to provide mechanistic detail in a
wider range of fish species.
Amino acid sensing
Mechanisms
In mammals, branched-chain amino acids (BCAAs), namely
leucine, isoleucine and valine, emerge as particularly relevant in
terms of nutrient sensing. This significance stems from the fact that
postprandial plasma levels of most amino acids, except for BCAAs,
remain stable (Heeley and Blouet, 2016). Notably, among the three
BCAAs, only leucine appears to be detected in the hypothalamus
(Morrison and Laeger, 2015; Heeley and Blouet, 2016).
Furthermore, mammalian hypothalamic neurons involved in the
regulation of food intake respond specifically to changes in leucine
levels (Heeley et al., 2018). In teleost fish, the available data suggest
that amino acid sensing is like that observed in mammals, albeit with
some notable differences; for example, valine is orexigenic in fish,
but not in mammals (Fig. 3). In fish, amino acid-sensing
Journal of Experimental Biology (2024) 227, jeb247410. doi:10.1242/jeb.247410
mechanisms are predominantly activated by leucine, as observed
in rainbow trout (Comesaña et al., 2018a,b, 2021b) and Atlantic
salmon (Comesaña et al., 2021a). Valine has a limited effect on
hypothalamic amino acid-sensing mechanisms in rainbow trout, but
it exerts stronger effects in other brain areas, such as the
telencephalon (Comesaña et al., 2018a,b, 2022). The mechanisms
of amino acid sensing that have been characterized in the
hypothalamus of these fish species are based on: (1) metabolism
of BCAA, (2) metabolism of glutamine, (3) taste receptors, (4)
amino acid carriers, (5) mTOR signalling pathway and (6) Gcn2
kinase. Each of these mechanisms were first characterised in
mammals (although the specific mechanisms may differ in fish) and
are discussed in more detail below.
Metabolism of BCAA
The metabolic breakdown of the three BCAAs involves the
enzymes branched-chain aminotransferase (BCAT) and branchedchain α-keto acid dehydrogenase complex (BCKDH) (AdevaAndany et al., 2017). In mammals, food intake is reduced following
increases in BCKDH activity or central administration of the
transamination product of leucine by BCAT (Blouet et al., 2009),
whereas deletion of BCAT reverses the effect (Purpera et al., 2012).
In the hypothalamus of rainbow trout, this amino acid-sensing
mechanism is activated by leucine through Bckdh (Comesaña et al.,
2018a,b, 2021b).
Metabolism of glutamine
Amino acid levels can also be sensed through metabolism of
glutamine, as BCAA metabolism and the glutamine–glutamate cycle
are linked. BCAAs are precursors of glutamine, because the BCAT
enzyme produces glutamate which, in turn, is converted to glutamine
by the enzyme glutamine synthetase (GLS) (Adeva-Andany et al.,
2017). In mammals, leucine stimulates the activity of the enzyme
glutamate dehydrogenase (GDH) which produces α-ketoglutarate
(a substrate for the Krebs cycle) from glutamate (Jewell and Guan,
2013). Thus, increased levels of leucine result in enhanced
metabolism of glutamine and glutamate, and ATP production. In
rainbow trout, leucine fails to stimulate Gdh activity in the
hypothalamus (Comesaña et al., 2018a), but this mechanism is
activated through increased Gls (Fig. 3; Comesaña et al., 2018a,b,
2021b). In addition, exposure to leucine decreases glutamate levels
in zebrafish brain, supporting the link between leucine and the
degradation of glutamate by Gdh (da Silva Lemos et al., 2022).
Taste receptors
In mammals, three receptors belonging to the taste receptor type 1
family (T1Rr1, T1R2 and T1R3) detect sweet and umami tastes. These
receptors are also present in the mammalian hypothalamus, where they
contribute to amino acid sensing. The receptors heterodimerise in the
presence of glucose (T1R2–T1R3) and amino acids (T1R1–T1R3),
triggering a cascade of second messengers that depolarizes the
membrane (Fig. 3; Behrens and Meyerhof, 2016). In fish, unlike in
mammals, amino acids can be detected by both heterodimers (Morais,
2017), and an increase in leucine levels increases the levels of t1r2 and
t1r3 mRNA in the hypothalamus of rainbow trout (Comesaña et al.,
2018a,b).
Amino acid carriers
Amino acid carriers provide an additional mechanism for sensing
the levels of amino acids. Among all amino acid carriers, two are
particularly noteworthy in this regard, and both fall within the solute
carrier (SLC) superfamily; they are L-type amino acid transporter 1
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Leu
T1r1
T1r2
Leu
Leu
T1r3
Snat
Lat1
2
3
4
Gln
2
1
Leu
Gls
Leu
Bcat
Sesn2
Gcn2
6
5
Glu
KIC
Bckdh
mTOR
Elf2D
Plc/IP3
pathway
Bckdk
ER
Ca2+
Acetyl-CoA
Selective gene
expression
Ca2+
Ca2+
Nucleus
ADP
ATP
K+ATP channel
Respiratory
chain
NADH,
FADH2
Krebs
cycle
Ca2+
ATP
K+
Mitochondria
Vdcc
Ca2+
Vm
(LAT1) and sodium-dependent neutral amino acid transporter 2
(SNAT2; Fig. 3). LAT1 and SNAT2 are present in the blood–brain
barrier (see Glossary). They are key regulators of leucine
intracellular concentration and are required for the activation of
mTOR signalling (Hundal and Taylor, 2009; Dodd and Tee, 2012;
Taylor, 2014). In fish hypothalamus, leucine upregulates snat2
expression in rainbow trout (Comesaña et al., 2018a,b) and both lat1
and snat2 in Atlantic salmon (Comesaña et al., 2021a), suggesting
that these two amino acid carriers might act as independent amino
acid-sensing mechanisms.
mTOR signalling
The mTOR signalling pathway in mammals is well known to be
activated by nutrients, especially by leucine (Dodd and Tee, 2012;
Yue et al., 2022), although the mechanism of action is unclear.
Several studies have evaluated the role of mTOR signalling in amino
acid sensing in the fish brain. For example, in rainbow trout
hypothalamus, this mechanism is activated by leucine. In rainbow
trout, ICV and IP treatment with leucine upregulates abundance of
mtor mRNA and the phosphorylation status of the protein mTOR, i.e.
the percentage of the protein in the phosphorylated (active) form
(Comesaña et al., 2018a,b). Additionally, valine is also detected by
this mechanism in the hypothalamus of rainbow trout (Comesaña
et al., 2022), whereas in cultured brain cells of Chinese perch, leucine
(but not valine or isoleucine) activates the downstream mTOR
protein S6 (Chen et al., 2021). However, it has been suggested that
the presence of insulin is also necessary for the activation of mTOR
by leucine (Ahmad et al., 2021). In fact, in vitro incubation of
rainbow trout hypothalamus with different concentrations of leucine
in the absence of insulin does not affect mTOR or its downstream
proteins but does increase levels of mRNA encoding the mTOR
inhibitor Sesn2 (Comesaña et al., 2021b). The mTOR signalling
pathway is also considered as an integrative pathway, linking
nutrient-sensing information with the expression of neuropeptides
involved in the regulation of feed intake (Soengas, 2021), as
discussed below.
Gcn2 kinase
The amino acid-sensing mechanism that depends on GCN2 kinase
(Fig. 3) is mostly activated under conditions of amino acid
deficiency. When levels of circulating amino acids decline, tRNAs
are no longer ‘charged’ (i.e. linked to an amino acid); uncharged
tRNAs interact with and activate GCN2 kinase, which
phosphorylates eukaryotic initiation factor 2α (eIF2α), thereby
8
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Fig. 3. Schematic summary of processes involved in amino acid sensing in the fish hypothalamus. A rise in circulating levels of leucine is sensed
through different mechanisms. (1) Metabolic breakdown of leucine via Bcat and Bckdh leads to the production of acetyl-CoA and succinyl-CoA and
subsequently ATP. (2) Production of glutamine. (3) Increased expression of T1r2 and T1r3. (4) Enhanced production of Lat1 and Snat2 carriers.
(5) Activation of mTOR. (6) Activation of eIF2α. For definition of all symbols, see list of abbreviations.
inhibiting it, and resulting in the selective control of translation
(Battu et al., 2017). In fish, this mechanism has been studied in
peripheral tissues with different amino acid deficiencies (SkibaCassy et al., 2016; Wang et al., 2016; Miao et al., 2021; Dou et al.,
2023). The abundance of phosphorylated EIf2α protein increases
with lysine deprivation in cultured brain cells of Chinese perch (Zou
et al., 2022). However, this mechanism of amino acid sensing is
apparently also responsive to leucine abundance because abundance
of eIf2a mRNA increases in the hypothalamus of rainbow trout
cultured with leucine in vitro (Comesaña et al., 2021b).
Impact on feeding and metabolism
Like diets that are high in carbohydrate or lipid, diets with elevated
protein levels or higher levels of leucine also lead to a reduction in
feed intake in fish (Table 1). This effect involves concomitant
changes in npy, agrp and pomc gene expression. Neither valine nor
isoleucine affect food intake in mammals, where leucine is the only
BCAA involved in food intake regulation (Lueders et al., 2022). In
fish, similar results are observed with isoleucine: ICV treatment of
Chinese perch with isoleucine has no effect on food intake (Chen
et al., 2021). However, in contrast to mammals, ICV administration
of valine in fish produces an orexigenic response but without
changes in neuropeptides (Table 1). Interestingly, ICV treatment
with lysine or methionine in Chinese perch also elicits increased
feed intake (Zou et al., 2022)
Apart from detecting the presence of nutrients to allow the
regulation of feed intake, the fish hypothalamus also uses this
information to regulate peripheral metabolism, thus maintaining
energy homeostasis (Soengas et al., 2018). In mammals, amino acid
levels and glucose metabolism are closely related – the hypothalamic
detection of leucine also modulates hepatic metabolism, with the
effect of reducing glucose production (Su et al., 2012; Arrieta-Cruz
and Gutiérrez-Juárez, 2016). This effect has not yet been
demonstrated in fish, but some studies have shown that central
detection of amino acids in fish has peripheral effects. Thus, in
Chinese perch, levels of preproghrelin in the intestine and leptin in
the liver change after ICV injection of leucine, valine or isoleucine
(Chen et al., 2021). In addition, in the same species, ICV injection of
valine acts as a nutritional signal in the brain to modulate peripheral
metabolism, attenuating protein degradation (Wang et al., 2020).
Integration of nutrient-sensing systems
Once nutrient-sensing systems are activated/inhibited, the relevant
information is integrated in the hypothalamus through changes in
the levels of agrp/npy and pomc/cart mRNA, which all encode
neuropeptides involved in the regulation of feed intake (Fig. 4). This
occurs through changes in signalling pathways, causing the
activation/inhibition of transcription factors that ultimately
regulate feed intake. The relevant mechanisms of integration are
well understood in mammals (for reviews, see Blouet and Schwartz,
2010; Morton et al., 2014). Below, we discuss the current state of
knowledge around the hypothalamic integration of nutrient-sensing
information in fish.
Signalling pathways
The AMP-activated protein kinase pathway
In mammals, one of the hypothalamic signalling pathways that is
sensitive to changes in nutrient-sensing systems is the AMP-activated
protein kinase (AMPK) pathway. The levels of hypothalamic AMPK
and the phosphorylation status of the protein decrease as the levels of
glucose, fatty acids or amino acids increase (Cai et al., 2007; Beall
et al., 2012; Fromentin et al., 2012; Oh et al., 2016). Ampk is present
Journal of Experimental Biology (2024) 227, jeb247410. doi:10.1242/jeb.247410
in fish brain (Soengas, 2021), but few studies have addressed changes
under conditions relating to the control of feed intake. The results of
those that have are mostly in agreement with the mammalian model
(Fig. 4). For example, feed deprivation results in increased levels and
phosphorylation status of the protein Ampkα in the hypothalamus of
rainbow trout (Conde-Sieira et al., 2019) (although note that this is
not seen in the brain of channel catfish, Ictalurus punctatus;
Abernathy et al., 2019). Furthermore, when rainbow trout are fed a
lipid-enriched diet (Librán-Pérez et al., 2015a), the phosphorylation
of Ampkα in the hypothalamus decreases. Similar changes are seen
in fish with hyperglycaemia or those fed a diet high in carbohydrates
(Nipu et al., 2022; Kamalam et al., 2012; Xu et al., 2017). In rainbow
trout, the phosphorylation of Ampkα is decreased in response to
higher levels of nutrients such as oleate (Velasco et al., 2016a, 2017b;
Blanco et al., 2020), octanoate (Velasco et al., 2017b), glucose
(Otero-Rodiño et al., 2017) or β-hydroxybutyrate (Comesaña et al.,
2019). In contrast to the mammalian model, the phosphorylation of
Ampkα is not increased in rainbow trout hypothalamus when the
levels of leucine are increased (Comesaña et al., 2018a,b, 2020,
2021).
The involvement of Ampk in the integration of nutrient sensing is
further supported by the fact that the phosphorylation of Ampkα
decreases in rainbow trout hypothalamus following treatments that
suppress appetite (i.e. treatments that mimic the activation of nutrientsensing pathways; Velasco et al., 2016b, 2017a, 2019, 2020, 2021;
Blanco et al., 2020). In contrast, it should be noted that Siberian
sturgeon treated with the anorexigenic hormone adiponectin show
enhanced levels of Ampkα2 (Tang et al., 2022). There are several
different isoforms of Ampkα, and it seems that Ampkα2 is involved in
regulation of feed intake, whereas Ampkα1 appears to modulate
peripheral metabolism to maintain homeostasis, as observed in
rainbow trout (Conde-Sieira et al., 2019, 2020). Finally, it is known
that there is an interaction between hormones and the integration of
nutrient-sensing pathways through Ampk, because the presence of
oleate counteracts the stimulatory effect of ghrelin on Ampk in
rainbow trout hypothalamus (Velasco et al., 2016a).
The mTOR signalling pathway
As discussed above, mTOR is thought to play an important role in
integrating nutrient-sensing pathways. In fish, mTOR is involved in
regulation of feed intake. In zebrafish, feed deprivation results in a
decrease in mTOR levels (Craig and Moon, 2011), whereas mTOR
levels and/or phosphorylation status increase under the anorectic
(i.e. appetite-suppressing) conditions elicited by the presence of
nutrients, as demonstrated in rainbow trout (Velasco et al., 2017b;
Comesaña et al., 2018a,b; Blanco et al., 2020). Accordingly, ICV
treatment with the appetite-stimulating amino acid valine in rainbow
trout results in decreased levels of mTOR (Comesaña et al., 2022).
The response of mTOR to changes in nutrient levels is also
supported by changes in its downstream proteins. For example, in
Chinese perch, the levels of phosphorylated S6 increase after ICV
treatment with the anorexigenic amino acid leucine, whereas a
decrease occurs after treatment with the orexigenic amino acid
valine (Chen et al., 2021). Interestingly, these changes are abolished
in the additional presence of rapamycin, an inhibitor of mTOR
(Chen et al., 2021). It should be noted that the involvement of
mTOR in the integration of nutrient sensing might depend on the
different species assessed, as well as on the specific amino acid
involved. For example, in rainbow trout, leucine has an anorectic
effect; however, in vitro, rainbow trout hypothalamus does not show
any response to leucine in terms of the levels and phosphorylation
status of mTOR or any effects on downstream proteins (Comesaña
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Assimilation
and storage
Feeding
Hormones
Nutrients
e.g. Ghrl, Cck, Pyy,
Glp-1, Insulin, Leptin
Glucose
Amino acids
Fatty acids
Ingestion and
rejection
Hormone
receptors
Nutrient sensing
mTOR
Akt
Other signals?
Ampk
Foraging and
procurement
Nucleus of
orexigenic neuron
Creb
Bsx
Nucleus of
anorexigenic neuron
Foxo1
Npy/Agrp
Bsx
Second order neurons
(NPO, NAT, NLTI, NLTd,
other areas?)
Pomc/Cart
Hypothalamic NLTv
Feed intake
et al., 2021a,b). This suggests that the anorectic effect of leucine in
rainbow trout is independent of mTOR signalling in the
hypothalamus. In contrast, a comparable treatment with the
orexigenic amino acid valine does result in changes in mTOR and
downstream proteins (Comesaña et al., 2022).
Additional studies support a role for hypothalamic mTOR in
feed-intake regulation in fish, supporting its role as an integrator of
nutritional signals. Multiple treatments that induce anorectic
conditions in fish cause an increase in mTOR levels and/or
phosphorylation status (Penney and Volkoff, 2014; Librán-Pérez
et al., 2015a,b; Dai et al., 2018; Velasco et al., 2017a, 2018, 2019,
2021; Blanco et al., 2020). Furthermore, hypothalamic mTOR
activation modulates the abundance of pomc and npy mRNA in
Japanese sea bass (Liang et al., 2019).
The protein kinase B (Akt) signalling pathway
In the mammalian hypothalamus, Akt levels and phosphorylation
status are increased in the presence of higher levels of nutrients (Hu
et al., 2016; Park et al., 2011). Current evidence suggests that Akt is
also involved in the hypothalamic mechanisms that regulate feed
intake in fish (Fig. 4). For example, exposure to various nutrients in
vivo and in vitro activates Akt signalling through increased
phosphorylation of the Akt protein (Velasco et al., 2017b; OteroRodiño et al., 2017; Comesaña et al., 2018a; Blanco et al., 2020).
Furthermore, a comparable increase in Akt protein levels occurs in
the brains of fish fed diets enriched in specific nutrients, including
carbohydrates (Dai et al., 2014; Jin et al., 2014; Jörgens et al., 2015)
or lipids (Librán-Pérez et al., 2015a,b; Dai et al., 2018; Xu et al.,
2019). Akt activation also occurs under other conditions that elicit
anorectic responses (Gong et al., 2016; Velasco et al., 2016b, 2017a,
2020, 2021; Blanco et al., 2020). The involvement of hypothalamic
Akt in regulation of feed intake is also supported by the fact that an
opposing response (decreased phosphorylation status) is observed
under orexigenic conditions (Velasco et al., 2017a). In mammals,
the activation of Akt signalling in the hypothalamus results in
changes in fatty acid metabolism through the activation of the
transcription factor SREBP1c and its targets ATP citrate lyase
(ACLY) and FAS (Kim et al., 2007). Accordingly, in the rainbow
trout hypothalamus, enhanced phosphorylation of Akt occurs in
parallel with increased levels of acly, fas and srebp1c mRNA
(Velasco et al., 2016b), thus indirectly supporting the involvement
of Akt in signalling related to nutrient sensing.
Transcription factors
Brain homeobox transcription factor
In mammals, brain homeobox transcription factor (BSX) is one of
several transcription factors that are activated in response to the
signalling pathways discussed above. It interacts with cAMP responseelement binding protein (CREB; see below) in the mammalian
hypothalamus, leading to an increase in mRNA encoding BSX,
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Fig. 4. Schematic summary of processes involved in the integration of nutrient-sensing information in the fish hypothalamus. After processes
involved in feed procurement, ingestion and assimilation (orange boxes), nutrient-sensing systems (blue boxes) are activated in parallel with changes in
hormone levels ( pink boxes). This results in changes in signalling pathways (green boxes), including Ampk inhibition, and activation of Akt and mTOR.
Changes in these signalling pathways alters the phosphorylation status of the transcription factors Creb, Foxo1 and Bsx, leading to inhibition of feed intake
( purple box) via changes in the expression of neuropeptides in orexigenic (Npy/Agrp) and anorexigenic (Pomc/Cart) neurons of the hypothalamic NLTv.
Synaptic connections (grey circles) between orexigenic and anorexigenic neurons as well as with other second-order neurons modulate the responses.
Together, this integration results in the homeostatic control of feed intake. For definition of all symbols, see list of abbreviations.
NPY and AgRP (Fig. 4; Nogueiras et al., 2008; Varela et al., 2011;
Lee et al., 2016). BSX levels are reduced under anorectic conditions
and increase under orexigenic conditions (Nogueiras et al., 2008; Lage
et al., 2010). Only a few studies in fish have evaluated changes in Bsx
that could relate to the regulation of feed intake. Thus, we know that
feed deprivation in goldfish increases bsx mRNA levels in the
hypothalamus (Vinnicombe and Volkoff, 2022). Accordingly, in
rainbow trout, exposure to oleate (Conde-Sieira et al., 2018), leucine
(Comesaña et al., 2021a,b) or glucose (Conde-Sieira et al., 2018;
Blanco et al., 2020) (all of which reduce feed intake) results in
decreased levels of Bsx. However, ICV treatment with the orexigenic
amino acid valine also results in a decrease in levels of Bsx protein in
rainbow trout (Comesaña et al., 2022). The effects of glucose on Bsx in
the rainbow trout hypothalamus disappear after insulin treatment
(Blanco et al., 2020), suggesting that there is an interaction between
this nutrient and hormone that has an impact on integrative
hypothalamic mechanisms. Other conditions that are known to
induce an anorexigenic response in rainbow trout also decrease the
levels of Bsx protein (Velasco et al., 2019, 2020, 2021). However, in
goldfish, treatment with the anorexigenic hormone Cck does not alter
levels of bsx mRNA (Vinnicombe and Volkoff, 2022).
cAMP response-element binding protein
CREB is another transcription factor that is thought to be involved in
the connection between brain metabolism and the expression of
neuropeptides that regulate appetite in mammals. A decrease in
CREB levels in the mammalian brain induces a decrease in the
abundance of Npy and Agrp mRNA, resulting in decreased food
intake (Fig. 4; Belgardt et al., 2009; Varela et al., 2011; Blanco de
Morentín et al., 2011). In fish, the available information regarding
the possible involvement of Creb in regulation of feed intake is
scarce and is mostly restricted to rainbow trout. In this species, Creb
phosphorylation decreases in response to raised levels of oleate
(Velasco et al., 2017b; Conde-Sieira et al., 2018), octanoate (Velasco
et al., 2017b) and glucose (Conde-Sieira et al., 2018; Otero-Rodiño
et al., 2019b). In response to leucine, the phosphorylation of Creb is
decreased in rainbow trout in vivo after ICV (Comesaña et al., 2018a)
or IP (Comesaña et al., 2018b) treatment, but no changes occur in
response to leucine under in vitro conditions (Comesaña et al.,
2021a,b). Interestingly, ICV treatment of rainbow trout with valine
also fails to elicit a Creb response (Comesaña et al., 2022), as does
supplementation of feed with methionine in zebrafish (Pisera-Fuster
et al., 2021). The presence of an inhibitor of Creb blocks the response
of Creb to fatty acids in rainbow trout hypothalamus (Velasco et al.,
2017b), indirectly supporting its role in regulation of feed intake. The
changes in Creb that occur in response to changes in nutrient levels
are comparable to those observed under other anorectic conditions in
rainbow trout, such as treatment with the anorexigenic hormones
Cck or Glp-1 (Velasco et al., 2019). Moreover, in zebrafish,
increased levels of Creb also occur under the orexigenic conditions
elicited by feed deprivation (Craig and Moon, 2011).
Forkhead box O1
Forkhead box O1 (FoxO1) is likely to be involved in the
hypothalamic integration of nutrient-sensing pathways to regulate
feed intake in mammals (Gross et al., 2009). In mammals, conditions
that increase the levels of FoxO1 protein cause an increase in the
expression of Agrp mRNA while decreasing the levels of Pomc
mRNA; changes that lead to a decrease in food intake (Belgardt
et al., 2009; Blanco de Morentin et al., 2011). In general, in fish,
increased levels of nutrients result in increased abundance and
phosphorylation of the protein Foxo1, as observed in rainbow trout
Journal of Experimental Biology (2024) 227, jeb247410. doi:10.1242/jeb.247410
in response to increased levels of oleate (Conde-Sieira et al., 2018;
Blanco et al., 2020), octanoate (Velasco et al., 2017b) and glucose
(Conde-Sieira et al., 2018; Blanco et al., 2020). The lack of response
of rainbow trout hypothalamus to oleate in the presence of a Foxo1
inhibitor supports the specificity of this response (Velasco et al.,
2017b). There is also evidence for an interaction between nutrient
levels and hormones in the dynamics of Foxo1 in the hypothalamic
response: in rainbow trout, the presence of insulin counteracts the
effects of oleate on the abundance of foxo1 mRNA (Blanco et al.,
2020). In contrast to its response to glucose or fatty acids,
hypothalamic Foxo1 does not appear to respond to changes in the
levels of amino acids in fish, as demonstrated in rainbow trout
(Comesaña et al., 2018a,b, 2020, 2021a,b, 2022). A range of
anorectic conditions other than those produced by increased nutrient
levels also result in increased levels of Foxo1 protein in rainbow trout
(Velasco et al., 2016b, 2017a, 2019, 2020, 2021; Blanco et al.,
2020).
Conclusions and future directions
In this Review, we present an overview of how the fish
hypothalamus integrates metabolic and endocrine information to
elicit changes in feed intake and peripheral energy metabolism. The
underlying mechanisms are similar in some respects to those known
in mammals, but are not identical (Delgado et al., 2017; Soengas
et al., 2018). The relevant metabolic effects result from the
activation/inhibition of nutrient-sensing systems.
Glucosensing mechanisms in the fish hypothalamus involve a
complex interplay of multiple systems, including the well known
Gck–Glut2 pathway, Sglt-1, sweet taste receptors, Lxr and potential
mitochondria-based mechanisms. Together, these mechanisms
enable the hypothalamus to finely regulate responses to changes
in glucose levels. Glucosensing in the hypothalamus influences
feeding behaviour, the expression of appetite-related neuropeptides
and metabolic responses in fish. Future research in this area should
focus on: (1) investigating changes in the discharge frequency of
neurons in response to circulating glucose concentrations; (2) the
precise roles of the glucosensing systems not dependent on Gck–
Glut2; (3) the importance of astrocytes and tanycytes; and
(4) investigating how chronic changes in glucose levels, induced
through diet or environmental conditions, impact overall metabolic
health and energy balance in fish.
Compared with glucose-sensing pathways, fish and mammals are
more divergent in terms of their fatty acid-sensing mechanisms. Unlike
that of mammals, the fish hypothalamus responds not only to LCFAs
but also to MCFAs, reflecting the unique metabolic adaptations in fish.
Mechanisms involving malonyl-CoA, enzymes such as Cpt-1, Fas and
Acly, as well as the fatty acid translocase (Fat/cd36), have been
identified as crucial components of fatty acid sensing in fish.
Moreover, the impact of fatty acid sensing on feeding regulation and
metabolic processes in fish is evident. Further research is needed to
delve deeper into the specific signaling pathways involved,
particularly: (1) the identification and characterization of Ffar1,
Gpr84 and Gpr119; (2) investigating the crosstalk between central
(hypothalamus) and peripheral (liver, Brockman bodies) fatty acidsensing mechanisms; and (3) exploring species-specific adaptations
and responses to diverse types of fatty acids, considering the diversity
in fish physiology and ecology.
Amino acid sensing has only recently been investigated in fish
hypothalamus. However, leucine has already emerged as a crucial
amino acid influencing regulation of feed intake in both mammals and
fish, albeit with species-specific responses. The effects of amino acids
such as valine, lysine and methionine on feed intake in fish also differ
11
Journal of Experimental Biology
REVIEW
from the responses in mammals. Understanding these differences will
shed light on the diverse metabolic adaptations across species.
Because most of our information on amino acid sensing in fish is
restricted to a few species, it is essential to enhance our understanding
of the universality or specificity of the relevant mechanisms in fish
species other than salmonids. Furthermore, the roles of amino acid
carriers, such as Lat1 and Snat2, in the fish hypothalamus need further
exploration. Considering the carnivorous nature of many fish species,
understanding their amino acid sensing will have practical applications
in optimizing dietary formulations for improved growth and health in
farmed fish.
The hypothalamic integration of neuroendocrine signalling and
nutrient sensing in the regulation of feed intake is a complex and
intricate process, of which our current understanding is limited. We
have identified some of the signalling pathways and transcription
factors involved in this integration, but changes in feed intake
stemming from alterations in neuropeptide expression are also the
result of a complex interplay between nutrient and hormonal signal
transduction. This interaction remains largely unexplored; for
example, in mammals we have only limited evidence pertaining
to the interactive effects of hormones such as leptin or ghrelin on
fatty acid sensing (López et al., 2007; Blanco de Morentin et al.,
2011; Lockie et al., 2019). In fish, studies conducted in rainbow
trout have demonstrated the existence of interactive effects between
nutrient-sensing mechanisms and hormones such as ghrelin
(Velasco et al., 2016a) and insulin (Blanco et al., 2020).
In conclusion, what we know of glucosensing, fatty acid sensing and
amino acid sensing mechanisms in the fish hypothalamus underscores
the remarkable adaptability of fish to varying nutritional conditions.
These diverse sensory pathways – involving well-established systems
such as Gck–Glut2, as well as newly assessed components, such as
fatty acid translocase and amino acid carriers – play pivotal roles in
regulating feeding behaviour and metabolic responses. The complex
integration of neuroendocrine signalling, transcription factors and
nutrient sensing in the hypothalamus highlights the need for further
research to unravel the species-specific nuances. As our understanding
deepens, addressing the long-term effects of altered sensing
mechanisms on energy homeostasis in fish becomes essential. This
holistic perspective not only enhances our knowledge of fundamental
physiological processes but also holds promise for optimizing dietary
formulations and promoting sustainable and efficient aquaculture
practices.
Competing interests
The authors declare no competing or financial interests.
Funding
The authors acknowledge the support of research grants from the Agencia Estatal
de Investigació n and European Regional Development Fund (PID2022–136288OBC31/AEI/10.13039/501100011033/FEDER,UE) and Xunta de Galicia (Axudas para
a consolidació n e estruturació n de unidades de investigació n competitivas e outras
acció ns de fomento nas universidades do SUG, ED431B 2022/01) to J.L.S. A.M.B.
was recipient of a postdoctoral fellowship (Program Ramó n y Cajal) from Ministerio
de Ciencia e Innovació n y Universidades (MICIU) (RYC2022-037124-I).
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