Orexins and their receptors from fish to mammals: A comparative approach

General and Comparative Endocrinology 171 (2011) 124–130

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Review

Orexins and their receptors from fish to mammals: A comparative approach Kari K.Y. Wong 1, Stephanie Y.L. Ng 1, Leo T.O. Lee, Hans K.H. Ng, Billy K.C. Chow ⇑ School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China

a r t i c l e

i n f o

Article history: Received 30 November 2010 Revised 28 December 2010 Accepted 1 January 2011 Available online 7 January 2011 Keywords: Orexin Orexin receptor Evolution

a b s t r a c t Although recently discovered, orexins have been rapidly established as important neuropeptides in regulating physiological processes including food intake, sleep/wake cycles and reproduction through binding to two class B G protein-coupled receptors (OX1R and OX2R). To date, a handful of sequences for orexins and their receptors ranging from fish to mammalian species have been identified, allowing a glimpse into their evolution. Structurally, the genetic and molecular organization of the peptides and receptors amongst vertebrates are highly similar, underlining the strong evolutionary pressure that has been exerted to preserve structure and ultimately function. Furthermore, the absence of invertebrate orexin-like sequences suggests early vertebrates as the origin from which orexins evolved. With respect to the receptors, OX2R is probably evolutionary more ancient whilst OX1R is specific to mammalian species and evolved only during this later lineage. In common to all vertebrates studied, the hypothalamus remains to be the key brain region in which orexinergic neurons and fibers are localized in, establishing orexin to be an important player in regulating physiological processes especially those related to food intake and energy metabolism. To allow better understanding of the evolution of orexins and their receptors, this review will provide a comparative approach to their structures and functions in vertebrates. Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction

2. Orexins

Orexins/hypocretins were first discovered in the rat lateral hypothalamic area (LHA) in 1998 and coined to be regulators of appetite based on their ability to stimulate food intake after central administration and locality in this known ‘‘feeding center’’ [11,58]. Due to their identified role in appetite control, the neuropeptides were named orexin-A (OXA) and orexin-B (OXB), on the basis of the Greek word orexis, for appetite. They were also named hypocretins because they share some sequence identity with secretin, a brain-gut peptide, and were found in the hypothalamus. Both neuropeptides are derived from a single precursor polypeptide [11,58] and bind to two G protein-coupled receptors (GPCRs), namely the orexin 1 (OX1R) and orexin 2 (OX2R) receptors with different affinities: OX1R interacts selectively to OXA, whilst OX2R binds to both OXA and OXB. Aside from controlling appetite, the widespread distribution of orexin in rat brain fibers suggested the possibility of multiple functions. Further studies based on the orexin receptor knockout rat [76] and fish [78] models and orexin-related estrous cycle [29,52] reveal the involvement of orexins in controlling sleep/wake cycle and reproductive system of vertebrates. This review aims to provide a brief analysis of the structure and function of vertebrate orexins from a comparative perspective.

2.1. Gene and peptide structure

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E-mail address: [email protected] (B.K.C. Chow). These authors contributed equally to this publication.

0016-6480/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ygcen.2011.01.001

To date, orexin sequences ranging from mammals (human, mouse, rat, pig, dog) [14,23,57], amphibians (Xenopus laevis) [62], birds (chicken, zebrafinch) [48] to teleosts (goldfish, zebrafish, cod, stickleback, medaka, pufferfish) [1,26,77] have been identified through either molecular cloning or bioinformatic studies. The two forms of orexins are derived from a common precursor encoded by the hcrt gene that, by chromosome synteny analysis, is revealed to have conserved loci throughout vertebrate evolution (Fig. 1a). The organization of the orexin gene itself is also well conserved maintaining a two-exon structure, with the larger exon 2 encoding for the mature peptides: OXA and OXB (Fig. 1b). In the prepro-orexin polypeptide, both mature peptides are followed by a putative consensus motif (Gly-basic-basic) which allows for cleavage and C-terminal amidation (Fig. 2). Beyond the orexin sequences, the Cterminal region appears to be highly variable and is likely nonfunctional. Across mammalian species, OXA is a 33-amino acid peptide with two intra-disulfide bridges (Cys6-Cys12 and Cys7Cys14) that are fully conserved amongst tetrapods. On the contrary, OXB is a shorter 28-amino acid peptide lacking disulfide bridges and has minor substitutions. During post-translational modification, both orexins are C-terminally amidated, whilst N-terminal modification by pyroglutamic acid occurs exclusively in OXAs [57]. In contrast, non-mammalian orexins show more

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Fig. 1. (a) Chromosomal locations of orexins, hcrt gene in various vertebrate species. Genes adjacent to hcrt in different genomes are shown. The genes are named according to their annotation in the human genome. hcrt genes are boldfaced boxed. (b) The orexin gene structure. Boxes denote exons whilst introns are depicted by lines, which are drawn to scale with the exception of Xenopus. The following is denoted: orexin-A (diagonal lines); orexin-b (checkered squares); coding region (grey shading) and untranslated region, UTR (no shading).

Fig. 2. The amino acid sequence alignment of prepro-orexin from various species. Conserved amino acids are shaded. Non-conserved amino acids are denoted by lower case. Mature peptide sequences of OXA and OXB are boxed. Teleost-specific spacer sequences are underlined. Gaps introduced to maximize sequence homology are shown as ‘‘-’’.

variation particularly in the N-terminal regions and this includes amino acid substitutions resulting in the absence of N-terminal pyroglutamate modification. Despite these differences, tetrapod OXAs are generally more conserved than OXBs, whilst the opposite holds true for teleost orexins. In particular, teleost OXAs are strikingly longer in length (e.g. 47-amino acids in goldfish and zebrafish, 50-amino acids in cod) due to an additional spacer sequence inserted between positions 24 and 25 but these peptides still share up to 52.4% identity with mammals. These inserted sequences

show no significant homology and are suggested to be non-detrimental to OXA’s activity [1,27]. Of the four conserved cysteine residues (Cys6-Cys12 and Cys7-Cys14) that are found throughout tetrapods, teleost OXAs lack Cys12 and instead have a cysteine positioned at residue 21. This is novel compared to non-teleost forms, resulting in the loss of disulfide bond formation between Cys6-Cys12, whilst possibly allowing for alternative disulfide bridge arrangements [77]. Consistent with other vertebrate OXBs, teleost forms are also 28-amino acid residues in length with the

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exception of cod (29-amino acids). Overall vertebrate orexins’ genetic and molecular structures are relatively well conserved amongst different species and this highlights the strong evolutionary pressure preserving structure and ultimately physiological functions. 2.2. A controversial evolutionary origin At the time of discovery, it was found that both orexins’ C-terminal regions shared sequence similarities with secretin’s N-terminus. Due to this resemblance, potential structural and/or evolutionary relationships between secretin and orexin have since been proposed and orexins were hypothesized to be genetic circular permutation products of secretin precursors [1,11]. To date, only vertebrate orexins have been reported whilst invertebrates seem to have no orexin-like sequences [61]. Classically, secretin superfamily hormones are able to cross-interact with receptors within the same superfamily [32,50,74]. However, binding and signaling studies in heterologous expression systems indicate that secretin does not interact nor stimulate orexin receptors (both OX1R and OX2R) in mammals [20], while functional properties of these receptors in non-mammalian species are understudied. As a result of the incongruence between structure and function based on mammalian studies, the evolutionary origin of orexins has remained enigmatic. With the recent cloning and characterization of the amphibian and lungfish secretin and orexin as well as their receptors, it has been clarified that the orexins are in fact of different ancestral origin to secretin in vertebrates (data unpublished). 3. Orexin receptors and their evolution Orexins bind selectively to OX1R and/or OX2R which are members of the class B GPCRs. In mammals, both orexin receptors have been identified with OX1R initially isolated from a human brain expression sequence tag (EST) clone as HFGAN72 [57], and OX2R was later found by searching of the EST database using HFGAN72. In non-mammalian species however, only OX2R has been identified. Like their peptide counterparts, vertebrate orexin receptors are similarly highly conserved with OX1R and OX2R sharing up to 63.5% identity with the human forms, although they share much lower sequence identity with other receptor sub-families including the most closely related neuropeptide FF receptors (25.1% and 31.2%, respectively between human neuropeptide FF receptor 1

with OX1R and OX2R [5,31]). Taken together, this information suggests that the two orexin receptors are likely products of a more recent gene duplication event and this hypothesis is supported by chromosome synteny analysis (Fig. 3). OX2R’s gene environment is shown to be conserved with the nearest neighboring genes (FAM83B and GFRAL) located in close proximity in all tested genomes. In contrast, only the short-range environments for the OX1R gene are conserved in mammals, for example TINAGL1 and PEF1 genes are located in close proximity to mammalian OX1R but are not found in paralogous regions in non-mammalian genomes. Taking into the account the failure to identify OX1R-like genes in non-mammalian species, OX2R is likely to be evolutionary more ancient and is present in most vertebrate lineages, while OX1R evolved by gene duplication only after the divergence that gave rise to mammals.

4. Distribution of orexins in the vertebrate brain While orexinergic neurons are localized in the hypothalamus in all examined vertebrates, the location of orexinergic fibers is more diversified amongst species. In mammals, orexin neurons are restricted to the hypothalamus, precisely in the perifornical and dorsomedial hypothalamic nuclei, dorsal and lateral hypothalamus [40,44,46,51]. In contrast, orexin brain neuron fibers are projected to a range of brain regions including the median eminence, arcuate nucleus, pituitary, olfactory bulb, cerebral cortex, thalamus subfornical organ, area postrema, hippocampus, amygdala, indusium griseum, brainstem and spinal cord [7,9,10,44,51,63]. Similarly in the chicken, in situ hybridization and immunohistochemistry studies have also revealed the hypothalamus (paraventricular hypothalamic nucleus (PVN) and lateral hypothalamus) to be the exclusive brain locality in which orexin neurons are found [48]. From the PVN, orexin fibers are extended into the caudal preoptic area (POA) where their density is the highest [65]. Likewise, reptilian orexin neurons are also confined to the hypothalamus within the PVN in the turtle Pseudemys and lizard Anolis, and dorsolateral nuclei in the lizard Gekko [12,15], while orexinergic fibers are abundantly found in the septal region, preoptic area and hypothalamus. In contrast to mammalian, avian and reptilian species, amphibian orexins were found outside the hypothalamus and widely distributed in a number of brain regions, especially in the suprachiasmatic nucleus and to a lesser extent in the POA and tuberal region [17,34,64,66]. The common distribution of orexins in

Fig. 3. Chromosomal locations of (a) OX1R and (b) OX2R in various vertebrate species. Genes adjacent to OX1R and OX2R are shown. The genes are named according to their annotation in human genome. OX1R and OX2R genes are boldfaced boxed.

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the frog brain has led to postulation that orexin functions both as a neuroendocrine factor and as a neurotransmitter in amphibians [62]. In fish, the distribution of orexinergic neurons is more varied amongst different species. For example, orexin neurons are localized in the preoptic area and suprachiasmatic nucleus in the lungfish and zebrafish; nucleus posterioris periventricularis (NPPv) in the medaka; and NPPv and nucleus lateralis tuberis (NLT) in the goldfish. In contrast, fish orexin fibers extensively innervate the brain including regions such as the aminergic nuclei, raphe, locus ceruleus (LC), the mesopontine-like area, dopaminergic clusters, and histaminergic neurons [2,22,26,30,41,78]. 5. Physiological roles of vertebrate orexins 5.1. Food intake The regulation of feeding behavior is one of the key roles played by the hypothalamus. In mammals, orexin neurons are found abundantly in the LHA and dorsomedial hypothalamic nucleus, otherwise known as the classical ‘‘feeding center’’. In addition, orexin fibers also innervate important nuclei including the PVN, arcuate nucleus and LC whose neurons express key feeding-related components (e.g. leptin receptors, neuropeptide-Y) and are associated with feeding. During fasting, prepro-orexin mRNA expression is up-regulated, implying orexin to be associated in the feedback mechanism regulating food intake [58], which is further supported by the observed dose-dependent increase in food intake after intracerebroventricular (ICV) injection of OXA or OXB [58]. Of the two orexins, OXA’s effects are more potent, functioning via OX1R as demonstrated by intraperitoneal (IP) injection of OX1R antagonist which was able to inhibit the OXA-triggered food intake, feeding behavior and weight gain [19,55]. Furthermore, orexin is suggested to be necessary for neuropeptide-Y and ghrelin to exert their full effects on feeding behavior as it has been demonstrated that ICVinjections of orexin anti-serums attenuate neuropeptide-Y and ghrelin-induced feeding [45,73]. In addition, orexin-deficient mice show lowered ghrelin-induced food intake compared to their wildtype littermates [73]. ICV-ghrelin was able to induce neuronal activity and gene expression of neuropeptide-Y and orexin [43,73]. Clearly, orexins, neuropeptide-Y and ghrelin play independent roles in regulating feeding. Similarly in birds, orexin neurons and fibers are present in the PVN and LHA. Despite this, it is intriguing to find that both mammalian orexins cannot induce feeding in the chicken and pigeon [8,16,28]. Therefore, it is possible that orexins are either not involved or play a minor role in controlling feeding behavior in birds. Moreover, this may be the result of avian orexins being structurally different to other tetrapod forms and therefore further experimentation using endogenous avian orexin peptides is needed to confirm orexins’ roles in feeding in birds. In amphibians, no orexinrelated feeding experiment has been reported. However, the presence of abundant orexin fibers in the amphibian LHA [34,66], suggests its involvement in the regulation of feeding. In fish, a range of experimental data is available to support the role of orexin in controlling feeding behavior. For example, icvinjection of human orexins induces feeding in goldfish, whereas ip-injection of glucose or anti-orexin serum reduces food consumption [41,75]. Like in mammals, OXA also induces a more potent stimulatory effect in feeding than OXB in goldfish and fasting increases prepro-orexin brain expression and physical activities in zebrafish [47]. Furthermore, orexins are suggested to work interdependently with other peptides involved in food intake control. This was demonstrated by the colocalization of neuropeptide-Y and OXA neurons in the NPPv and the close contact of their respective nerve endings [30]. In addition, a mutual relationship of orexins with ghrelin regarding food intake has also been shown;

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ICV-ghrelin at a dose sufficient to stimulate food intake is able to simulate expression of OXA mRNA in the goldfish diencephalon and the opposite is also found to be true [39]. Both neuropeptide-Y- and ghrelin-induced food intake were completely inhibited by application of an orexin receptor antagonist [39]. 5.2. Sleep/wake cycle In mammals, the importance of orexins in sleep/wake cycle has been shown in narcoleptic canines [33] and OX2R knockout mouse models [76] with a disrupted sleep/wake cycle. Orexins are suggested to maintain the balance between the sleep and wake stages. Orexin neurons are active during the wake stage but in low activity during the sleep stage. During the wake stage, orexin neurons send stimulating signals to depolarize the ‘‘arousal center’’ [59,79]. This has been demonstrated by in vitro and in vivo experiments. For in vitro experiments, OXA application to the rat brain slices induces dose-dependent depolarization of serotonergic and cholinergic neurons [6,70]. In in vivo experiments, ICV-orexins can induce hyper-locomotion and stereotypy [42]. During the sleep stage, the ventrolateral preoptic nucleus (VLPO) is suggested to send inhibitory signals to both orexin neurons and the ‘‘arousal center’’ [59,79]. In birds, ICV injection of mammalian OXA induces potent and dose-dependent arousal-promoting effects. OXA injection evoked a dose-dependent decrease in duration of sleep-like postures. It also increased alertness of the chicken [28]. In the pigeon, these changes are accompanied by a substantial increase in head and neck exploratory movements as well as in wing-flapping behavior [8]. In amphibians, although no sleep-related experiment has been reported, orexin fibers are found in areas similar to the mammalian ‘‘arousal center’’. Amphibian orexin fibers innervate the raphe nuclei, cholinergic nuclei in the isthmic and upper rhombencephalon of amphibians and also histaminergic cells similar to those in the mammalian tuberomammillary nucleus (TM) [34,66]. Furthermore, amphibian orexin fibers also innervate cholinergic and non-cholinergic region of the pedunculopontine tegmental nucleus which has been described to be important in regulation atonia during REM sleep in mammals [18,34,36,71,72]. From the immunostaining pattern of orexins in amphibians, it is suggested that orexins also play a role in the sleep–wake cycle, acting as arousal agents. In fish, sleep-related experiments using orexin and OX2R knockout fish have been conducted. The effects of orexins differ in larva and adult fish. Overexpression of orexin in zebrafish larva leads to reduced arousal threshold and hypersensitivity to arousing stimuli [53]. ICV-OXA in normal adult zebrafish reduced activities and promoted sleep. However, OX2R knockout adult fish showed sleep fragmentation and decreased sleep at night [78]. Based on experiments performed on larva and adult fish, it is still difficult to conclude whether orexin acts as an arousal agent or sleep inducer. This is further complicated by the expression pattern of orexin in fish brain which has been shown present in both ‘‘arousal’’ and ‘‘sleeping’’ centers. Orexinergic fibers were found in a single cluster of histaminergic neurons in ventrocaudal hypothalamus, raphe nucleus, isthmic and upper rhombencephalic tegmentum resembling the mammalian ‘‘arousal center’’ [26,27,35]. Orexinergic fibers and OX2R were found in melatonin-releasing pineal gland, and orexins were shown to stimulate pineal gland explants to release melatonin [3,78,81]. As melatonin is the main sleep-promoting agent in fish, it is proposed that fish orexins have dual effects on the sleep–wake cycle similar to those in mammals; however the regulatory mechanisms remain unclear. In mammals and fish, there are at least two separate centers for controlling sleep and wake, and future usage of orexin/receptor cell-specific knockouts should pro-

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vide the needed information to further characterize the function of this ligand-receptor axis in regulating sleep/wake cycle in vertebrates. 5.3. Reproduction In mammals, orexinergic fibers are found to project from the lateral hypothalamus to the septal-preoptic and arcuate nucleusmedian eminence regions. These areas are directly involved in the control of the hypothalamo-gonadotropic axis through the synthesis and release of the gonadotropin-releasing hormone (GnRH). OXA stimulates GnRH expression and release in GnRH neurons [24,37,54,60]. In addition to various brain regions, orexins and their receptors are found expressed in the gonads of rat and sheep [69,80], and their expression is related to the sex and estrous cycle whereby young cycling females have higher expression than males or middle-aged females without cycle. The expression of orexin receptors is augmented in the ovary in proestrous, during which ICV-OXA in female rats results in luteinizing hormone (LH) and prolactin surges that are essential for ovulation [25,52,56]. It has also been suggested that orexins can regulate the male reproductive system as testicular testosterone secretion could be stimulated by intratesticular injection of OXA [4]. In birds, OX2R is expressed in the pituitary and the testis, and prepro-orexin has been detected in the gonads of both sexes, thus suggesting a neuroendocrine role of orexin in bird reproductive function [48,49,65]. In amphibians, particularly in urodetes, orexin fibers were found in the paraventricular organ (PVO), which suggests its involvement in sexual behavior since PVO-lesioned males display a characteristic impairment in courtship behavior [13,66]. In fish, the expression pattern of orexins supports a role of orexin in reproductive functions. Orexinergic fibers were found to reach the median eminence in lungfish, OXA was detected in the pituitary of medaka and Japanese sea perch, whilst OXB was detected in the pituitary LH cells of Nile tilapia [2,35,67,68]. However, the effect which orexins exert on the fish reproductive system may be different to from that of mammals, ICV-GnRH was found to suppress food intake and decrease orexin mRNA expression in goldfish in a dose-dependent manner. Alternatively, ICV-OXA inhibited spawning behavior and lowered GnRH expression [21]. From the data obtained, orexins seem to act as inhibitory agents in reproduction. 6. Conclusion Orexins and their receptors have been well conserved throughout evolution. Orexins are believed to have arisen early in the vertebrate lineage and subject to strong evolutionary pressure maintaining high sequence identity amongst species. With respect to the orexin receptors, OX2R likely evolved first whereas OX1R has a more recent lineage and is a product of gene duplication after the divergence leading to mammals. With little exception, the strong preservation of genetic and molecular structures particularly for the orexin peptides reflects the importance of their physiological roles in vertebrates. Functionally, orexins show stimulatory effects on feeding and sleep/wake, implying that orexins are important factors in controlling feeding and sleep/wake cycle since early vertebrate evolution. In birds, the wake-promoting effect of orexins has also been demonstrated; however, no effects on feeding behavior have been reported. Furthermore, orexin’s importance in regulating feeding behavior and the reproductive system has been demonstrated by OX1R antagonist administration in the rat, attenuating OXA induced food intake and reducing the release of gonadotropin [38]. In fish however, orexins are reported to have inhibitory effect on spawning [21]. Based on these data, it

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