Feeding is the process by which food is obtained to provide energy. It must satisfy growth, survival, and reproductive requirements and has driven the evolution of specialized feeding behaviors and apparatus in metazoan. Regulation of feeding is a complex mechanism, which involves a combination of physical, chemical, and nutritional factors (Neary et al., 2004; Coll et al., 2007; Woods et al., 2008). Food-taking behavior is dependent on environmental signals (odors and taste), hunger signals (metabolic signals), and also endocrine satiety signals that via the blood stream or the vagal afferent terminals act on the hypothalamus, brain stem, or afferent autonomic nerves to modulate feeding response (Figure 1; Konturek et al., 2004; Stanley et al., 2005; Chaudhri et al., 2006; Woods et al., 2006, 2008). In mammals, psychological factors such as mood (emotions) and food reward have also been shown to affect eating behavior (Christensen, 1993; Berridge, 1996). In vertebrates, a group of small regulatory peptides that are produced by the brain-gut axis play a major role in the endocrine regulation of feeding and control of energy homeostasis (Figure 1; Coll et al., 2007; Chaudhri et al., 2008). These peptide hormones are divided into two groups, those that stimulate appetite (orexigenic peptides) and induce food intake and those that cause loss of appetite (anorexigenic peptides) and reduce food consumption and increase energy expenditure (Ahima and Osei, 2001; Wilding, 2002; Suzuki et al., 2010). The action of such peptides involves the activation of specific G-protein coupled receptors (GPCRs), which undergo conformational changes and promote the activation of intracellular signaling mechanisms that ultimately lead to a cellular response (Table 1; Marinissen and Gutkind, 2001; Xu et al., 2004; Fredriksson and Schioth, 2005).

The involvement of GPCRs in the regulation of vertebrate feeding and appetite is well recognized (Shioda et al., 2008). Much less is known about their homologs and cognate activating peptides in non-vertebrates. However, comparative sequence approaches and functional studies suggest that the involvement of GPCRs in metazoa feeding behavior emerged early and has been maintained during the species radiation (Brody and Cravchik, 2000; Hewes and Taghert, 2001; Fredriksson and Schioth, 2005; Teng et al., 2008). GPCRs have emerged via gene or genome duplication events followed by selection of the gene duplicates. Understanding the origin of GPCRs represents a valuable tool for the characterization of basic physiological functions that have been maintained during evolution. The present review takes a comparative approach and targets rhodopsin GPCR subfamily members in the model species, C. elegans (a nematode) and D. melanogaster (a arthropod) that are sequence and function homologs of vertebrate GPCRs implicated in feeding regulation. To enrich the data and provide insight into how divergent life style and feeding strategies may have shaped receptor evolution in invertebrates the sequence of the target GPCRs were identified in other nematodes and arthropods with available genome data.

G-protein coupled receptors are one of the largest groups of receptors present in cells. Based upon their structure and sequence similarity five distinct superfamilies have been defined in human: glutamate (G), Rhodopsin (R), Adhesion (A), Frizzled (F), and Secretin (S) and are collectively known as GRAFS (Fredriksson and Schioth, 2005; Figure 2). GPCRs are characterized by a signature motif of seven conserved transmembrane spanning helix domains (TM) in vertebrates and non-vertebrates. Receptor activation is mediated by the extracellular N-terminal domain and also by TM and extracellular loops (receptor core domain) that interact with diverse types of molecules. The cellular response is provoked by the receptor C-terminal domain which activates a series of intracellular signaling cascades via the G-protein coupled pathway complex (Bockaert and Pin, 1999; Marinissen and Gutkind, 2001). Other molecular mechanisms such assembly of receptor heterodimers and allosteric receptor–receptor interactions in the cell membrane are also involved in GPCR regulation, activation and signaling (Prinster et al., 2005; Langmead and Christopoulos, 2006; Fuxe et al., 2012).

G-protein coupled receptors are ubiquitous and involved in many different physiological functions. The glutamate receptors are involved in synaptic plasticity and participate in numerous functions in the central nervous system (CNS; Niswender and Conn, 2010). Rhodopsin receptors include receptors for hormones, neurotransmitters and photons and they are involved in taste, smell, and also regulate metabolism, reproduction, and neural function (Simoni et al., 1997; Murdoch and Finn, 2000; Gaillard et al., 2004; Waldhoer et al., 2004). Adhesion receptors participate in cell adhesion, signaling, and immune function (Bjarnadottir et al., 2007; Yona et al., 2008). Frizzled receptors are involved in the Wnt signaling pathway and in the control of cell proliferation and embryogenesis (van Amerongen and Nusse, 2009; Schulte, 2010). In contrast to other GPCRs, secretin family members are only activated by peptide hormones and they are implicated in brain-gut functions, calcium homeostasis, and in the stress response (McDermott and Kidd, 1987; Harmar, 2001; Bale and Vale, 2004; Moody et al., 2011). Due to their conserved structure and presence in many phyla, GPCRs are suggested to have a common evolutionary origin and to have arisen via gene/genome duplication early in the species radiation (Krishnan et al., 2012). With the exception of the glutamate family members, they are proposed to share a common ancestor with the cAMP receptors of primitive eukaryote species (Nordstrom et al., 2011).

In humans, more than 700 GPCR genes are predicted and a large proportion are orphans with unknown function (Figure 2). The rhodopsin family (a.k.a family A or class 1 GPCRs) comprise the most diverse receptor group and in humans they account for more than 80% of GPCRs and include members that are involved in regulation of feeding (Joost and Methner, 2002; Fredriksson et al., 2003). Rhodopsin family members possess a short N-terminal domain and are characterized by the presence of several conserved amino acid motifs such as N-S-x-x-N-P-x-x-Y within TM7 and the DRY (D(E)-R-Y(F)) motif between TM3 and intracellular loop (IL) 2 (Schioth and Fredriksson, 2005; Suwa et al., 2011). Based upon sequence similarity the human rhodopsin receptors are sub classified into four main groups (α, β, γ and δ; Figure 2; Fredriksson et al., 2003). The α-group contains clusters for the prostaglandin, amine, opsin, melatonin, melanocortin, endothelial, cannabinoid, and adenosine binding receptors. Members of the β-group include a subfamily of receptors for which known ligands are peptides such as orexin (OX), neuropeptide FF (NPFF), neurokinin (NK), gastrin-cholecystokinin (CCK), neuropeptide Y (NPY), endothelin-related (EDN), bombesin and related peptides (BB), neurotensin (NTS), ghrelin and obstatin, neuromedin (NMU), thyrotropin releasing hormone (TRH), arginine vasopressin (AVP), gonadotropin-releasing hormone (GNRH), and oxytocin (OXT). The γ group includes receptors for somatostatin (SST), opioids, galanin (GAL), melanin concentrating hormone (MCH), and chemokine peptides. The δ group contains the olfactory receptors (highly diverse > 400 members) as well as the glycoprotein, purine, and the MAS-related receptor clusters. In humans, twelve members of the rhodopsin family, which are activated by peptide hormones, play an important role in feed intake and stimulate or reduce food consumption (Table 1). The majority of these receptors are β group members and their role in the regulation of feed intake in mammals will now be briefly considered.

Receptors for melatonin (MT), gastrin-cholecystokinin (CCK), neurokinin (NK), neuropeptide FF (NPFF), bombesin and related peptides (BB), and neuromedin (NMU) have an inhibitory role in feed intake in vertebrates. Melanocortin receptors (MCR) are activated by melanocortin (ACTH, MSH, and lipotropin) peptides and administration of receptor agonists significantly reduces food consumption in rats (Irani and Haskell-Luevano, 2005). In addition mutant MC3R mice have increased fat mass (Coll et al., 2007) and ablation of the MC4R gene results in severe obesity (Coll et al., 2004; Millington, 2007). In rats, mutations of CCK1R are associated with obesity (Kopin et al., 1999) and peripheral administration of an NK1R antagonist leads to reduced weight gain after a high-fat diet (Karagiannides et al., 2011). Injection of NPFF provokes anorexia in mice and induces satiety (Murase et al., 1996; Bechtold and Luckman, 2006, 2007; Cline et al., 2009). BB peptides also mediate satiety (Hampton et al., 1998; Yamada et al., 2002; Gonzalez et al., 2008) and knockout BB2R mice have increased body weight (Ladenheim et al., 2002) and BB3R-deficient mice exhibit a mild obesity phenotype and increased food intake (Ohki-Hamazaki et al., 1997). Mice lacking the NMU gene are hyperphagic and have increased adiposity and obesity and amino acid variants in NMU are associated with human obesity (Brighton et al., 2004; Hainerova et al., 2006).

In contrast, orexin (OXs), neuropeptide Y (NPYs), galanin (GAL), and melanin concentrating hormone (MCH) receptors are activated by orexigenic peptides which stimulate feeding (Sakurai, 1999; Branchek et al., 2000; Chamorro et al., 2002; Lecklin et al., 2002; Lang et al., 2007; Wong et al., 2011). Administration of orexin-A and B stimulates food consumption in a dose-dependent manner (Sakurai et al., 1998; Matteri, 2001). NPY is one of the most potent orexigenic factors and NPY-induced feeding is markedly reduced in Y1-knockout mice and NPY Y1 receptor deficient mice lack appetite (Mercer et al., 2011; Pjetri et al., 2012). GAL1R-KO mice display increased food intake and body weight gain in response to an acute 3 day high-fat challenge (Zorrilla et al., 2007). MCH is a hypothalamic appetite-stimulating peptide that is high in obese mice (Kawauchi, 2006; Coll et al., 2007) and deletions in MCH1R confer resistance to diet-induced obesity (DIO) and MCH1R antagonists are effective in reducing body weight (Chung et al., 2011).

The role of SSTR and their activating peptides in vertebrates is unclear. In rats SSTR can stimulate or inhibit appetite although peptide injections in chickens have an orexigenic effect (Tachibana et al., 2009). In addition receptors for ghrelin-obestatin have opposing effects on feeding and ghrelin is associated with hunger scores and plasma ghrelin levels increase during fasting and decrease after food intake (Rocha-Sousa et al., 2010). Treatment of rats with obestatin suppresses food intake and decreases body weight gain (Zhang et al., 2005).

Other GPCR families activated by peptide hormones may also play a role in food intake and include members of the secretin receptor family: pituitary Adenylate-Cyclase Activating Peptide/Vasoactive Intestinal Peptide (PACR/VIPR; Morley et al., 1992; Chance et al., 1995); Glucagon and related peptide (GCGR/GLPR; McMahon and Wellman, 1997, 1998; Tang-Christensen et al., 2001; Woods et al., 2006); Calcitonin (CTR; Riediger et al., 2004) and Corticotrophin Releasing Factor (CRFR) receptors (Heinrichs and Richard, 1999; Bradbury et al., 2000; Richard et al., 2002). However, the secretin receptor family will not be considered in the present review.

Invertebrates are one of the most diverse animal groups and they represent more than 95% of the species on Earth. Protostomia comprise the majority of the species identified and are of both ecological and economic importance as they are involved in the nutrient cycle, plant fertilization, and include agricultural pests and vectors of human disease, such as malaria and sleeping sickness. The divergence of Protostomes from Deuterostomes occurred more than 700 million years ago (MYA) and their success is associated with adaptations to a variety of ecological niches and modifications in their feeding habits that allow them to live, survive and reproduce in many different environments. Invertebrates can be herbivores (eating plant tissue, nectar, and pollen), carnivores (feeding on other invertebrates as well as larger animals), parasites (living on plant and animals), and detritus feeders (eating dead animal and plants). Surprisingly few studies exist about the regulation of feed intake in invertebrates, despite its importance for their success and this is also a neglected target for alternative control strategies. The genome of several invertebrates has been sequenced and in the metazoan Ensembl genome database (www.ensemblgenomes.org) 48 invertebrate genomes are available. Comparative molecular studies represent an invaluable mechanism to better understand invertebrate biology and to characterize endocrine factors associated with feeding.

Homologs of the vertebrate GPCR repertoire have been described in many invertebrates and representatives of the five distinct human GRAFS families are proposed to have emerged before the split of nematodes from the chordate lineage (Table 2; Fredriksson and Schioth, 2005). The model organisms, the nematode roundworm C. elegans and the fruit fly D. melanogaster are the most studied Prostostomes. Their genomes have been completely sequenced and are fully annotated and a vast range of functional resources exists and numerous GPCRs have been characterized (Consortium, 1998; Adams et al., 2000; Keating et al., 2003). In the roundworm, GPCRs account for approximately 5% of the genome (there are more than 1000) and the chemoreceptor genes, which are involved in chemoreception of environmental stimuli are unique in nematodes and are also the most abundant and diverse (Schioth and Fredriksson, 2005; Robertson and Thomas, 2006; Nagarathnam et al., 2012). In the fruit fly, approximately 200 GPCRs (1% of the genome) are predicted and the gustatory/taste receptors (Montell, 2009) are specific to insects although a quarter share sequence homology with vertebrate neurohormone receptors (Keating et al., 2003; Fredriksson and Schioth, 2005; Hauser et al., 2006; Nagarathnam et al., 2012). Recently GPCRs were also characterized in the genome of two Platyhelminthes, the blood fluke Schistosoma mansoni and the planarian Schmidtea mediterranea and a similar gene repertoire to vertebrates has been characterized. A platyhelminth-specific rhodopsin subfamily (PROF1) and a planarian-specific Adhesion-like family (PARF1) have been identified suggesting lineage specific GPCRs evolved in invertebrates (Suwa et al., 2011; Zamanian et al., 2011).

Comparison of the neuroendocrine GPCR complement in the fruit fly and the honey bee Apis mellifera (A. mellifera) revealed that a similar gene complement is present (Hauser et al., 2006). In the malaria vector, the mosquito Anopheles gambiae (A. gambiae) genome, a total of 276 GPCRs are predicted and approximately 30 correspond to putative neuropeptide receptors (Hill et al., 2002). With the exception of C. elegans, very little is known about GPCRs in other nematodes despite availability of molecular data in public databases. The activating molecules for the roundworm and fruit fly GPCRs in common with other organisms are in general neurohormones (biogenic amines, protein hormones, and neuropeptides) and they play a central role in the control of behavior, reproduction, development, feeding, and many other physiological processes. This suggests that GPCR signaling has been conserved during evolution and that neuropeptide signaling plays a key role in both Proto and Deuterostomes (Grimmelikhuijzen and Hauser, 2012).

The present review provides a general overview of the evolution of the rhodopsin GPCR members that are implicated in feeding regulation. It will start by identifying and describing sequence homologs of human rhodopsin GPCRs in the model invertebrate organisms C. elegans and D. melanogaster followed by the characterization of their homologs in other nematodes and arthropods with distinctive feeding habits and life styles (Table 4). The C. elegans and D. melanogaster rhodopsin GPCR repertoire was obtained from published data and to enrich and confirm the dataset it was complemented with appropriate database searches using the human homologs (Table 3). A total of 35 rhodopsin GPCRs are present in C. elegans and 22 in D. melanogaster genomes (Table 2) and a conserved role in feeding regulation has been demonstrated.

Feeding in invertebrates in common with other animals involves a complex combination of physical, chemical, and nutritional factors (Chapman and De Boer, 1995). Taste and smell are important for feeding behavior and provide the CNS with information on quality and quantity of food and feeding behavior occurs mainly in response to both nutrient and nutritional storage status. Once feeding has been initiated and food ingested, the alimentary canal, and its associated glands triturate, lubricate, store, digest, and absorb the food material and excrete and expel unwanted remains (Audsley and Weaver, 2009).

The Nematoda is a highly diverse, complex, and specialized group of metazoans, about 30,000 species are currently known and many are renowned parasites (15%) and have specialized life cycles that depend on their host to survive and reproduce. Their success is associated with a protective, impermeable cuticle and by the diversity of the pharynx and feeding mechanisms (Coghlan, 2005). The shape and presence or absence of teeth, lancets, stylets, or other structures in the mouth reflects their distinct feeding methods. The majority of nematodes are free-living and inhabit soil and water and feed on microorganisms (bacteria, fungi, algae) and organic debris. The parasites feed on animal and plant tissues and some on vertebrate blood.

The Arthropoda represents the most diverse animal phyla and comprises over 80% of the species identified and the Insecta class is the most specious with approximately 920,000 species. Four main classes of feeding habits are recognized: plant feeders, predators (feed on aphids and mites), scavengers (feeding on dead and decaying organic matter), and parasites (of other insects and vertebrates), some of which are hematophagous. Within each of these classes, various types of feeding can be found such as biting and chewing on leaves or animal tissue and sucking from plant or animal cells or tissues. Despite this unique ability to use almost any organic substrate, most insect species restrict themselves to a particular category of food (Posnien et al., 2010) and feed primarily on a fluid diet (Prakash and Steele, 2010). The variety of feeding habits in arthropods is the result of anatomical and physiological adaptations to distinct food sources (Chapman and De Boer, 1995). The alimentary canal is composed of specialized regions that vary according to feeding habit and life stage.

The organisms selected for analysis of rhodospin GPCRs potentially involved in invertebrate feeding are members of different nematode and arthropod lineages. The specific life style and feeding habits of the invertebrates included in the analysis are indicated in Table 4.

The following section describes the evolution and function of rhodopsin family members in nematodes and arthropods. It will start with an overview of those described in C. elegans and D. melanogaster involved in or candidates for feed intake regulation (Tables 2 and 5). Expression data when available from wormbase and flybase is included to provide insight into receptor function. It is followed by a section in which receptor evolution in invertebrates is discussed including homologs from non-model nematode and arthropod species.

In general, no putative melatonin peptide receptors (MCR) or melanin concentrating hormone receptor (MCHR) homologs have been described or were identified in the present study in any of the selected nematodes or arthropods (Figure 3). In addition, in nematodes no homolog of the vertebrate and fruit fly bombesin receptors seem to exist (Table 2). Duplicates of the human receptor genes were identified in the genomes of nearly all target species and phylogenetic analysis suggests specific gene duplication/deletions occurred within the nematode and arthropod lineages (Figure 3).

In general, the physiological processes involving GPCRs are conserved and sequence and function homologs of vertebrate rhodopsin GPCRs are present in invertebrates indicating they emerged early in evolution. In Nematoda and Arthropoda the rhodopsin GPCRs have evolved differently. Gene expansion is observed in nematodes with a free-living stage and specific gene deletions seem to have affected parasitic nematode genomes. In arthropods species-specific gene duplications occurred. We hypothesize that the evolving feeding regime and life style of invertebrates was one of the pressure forcing GPCR evolution and that this may explain some of the specific gene family expansions and deletions. Comparative studies of GPCRs gained or lost in the nematodes and arthropods and their relationship to feeding regulation may provide insights into how GPCRs contributed and shaped adaptation to new ecological niche. Studies of other nematodes and arthropods coupled with experiments to assign function and potential conserved role in feeding will be needed to test this hypothesis.

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.

The Supplementary Material for this article can be found online at http://www.frontiersin.org/Neuroendocrine_Science/10.3389/fendo.2012.00157/abstract