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Harris RBS, editor. Appetite and Food Intake: Central Control. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2017. doi: 10.1201/9781315120171-1

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Appetite and Food Intake: Central Control. 2nd edition.

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Chapter 1 Appetite Control in C. elegans

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1.1. Introduction

1.1.1. Caenorhabditis elegans Feeding

Caenorhabditis elegans is a 1-mm-long free-living nematode that feeds on bacteria. The feeding organ of C. elegans is a pharynx, a neuromuscular tube responsible for sucking bacteria into the worm from outside, concentrating them, and grinding them up (Doncaster 1962, Seymour et al. 1983). The basic mechanics and the neurons and muscles used to execute feeding motion are important for understanding several feeding behaviors and are therefore briefly described. More details regarding cellular and nuclear composition, the structure, electrophysiology, and the molecular components can be found in Avery and You (2012).

The motions of the pharynx are largely regulated by its embedded nervous system. It contains 20 neurons of 14 different types (Albertson and Thomson 1976). Three of these 14 are particularly important for feeding motions: MC, M3, and M4. MC and M3 control the timing of pumping, a full cycle of contraction and relaxation of the pharyngeal muscle (Avery 1993a): MC controls when a contraction starts (Raizen and Avery 1994, Raizen et al. 1995), and M3, when it ends (Avery 1993b, Raizen and Avery 1994). M4 is necessary for the peristaltic movement within the pharynx to transport trapped bacteria to the grinder, where the bacteria are crushed (Avery and Horvitz 1987). The pumping frequency has been shown to be altered by external cues and the neurons outside the pharynx (Greer et al. 2008). However, the exact connections between extrapharyngeal neurons and the pharynx that control feeding rates or motion are not clearly known.

Pharyngeal neurons contain both neuropeptides and small-molecule neurotransmitters. The most important of the small transmitters are acetylcholine, glutamate, and serotonin. Acetylcholine is released from MC to the pharyngeal muscle to initiate the muscle contraction via a nicotinic channel receptor, EAT-2 (Raizen et al. 1995, McKay et al. 2004). Acetylcholine also regulates a hunger response by controlling pharyngeal muscle responsiveness during starvation via a muscarinic receptor GAR-3 (You et al. 2006). GAR-3 is a C. elegans homolog of mammalian M3 muscarinic receptor (Steger and Avery 2004). M3 receptor knockout mice eat less and become skinny, showing conservation in controlling feeding via a similar molecular mechanism (see Section Glutamate is released from M3 to end pharyngeal muscle contraction via an invertebrate-specific glutamate gated chloride channel, AVR-15 (Dent et al. 1997). Serotonin is released from either a neurosecretory-motor neuron (NSM) inside the pharynx or from extrapharyngeal neurons (e.g., ADF) to increase the pumping frequency (Niacaris and Avery 2003, Song et al. 2013). Neuropeptides play important roles, but they are still, for the most part, poorly understood. Recently, Cheong et al. (2015) discovered that one type of neuropeptide homologous to mammalian opioids regulates a hunger response in C. elegans (see Section

1.1.2. C. elegans as a Model to Study Appetite Control

Studies from the past 50 years found several fundamental mechanisms of appetite control: specific brain regions integrate signals from the gut, assess the body’s nutritional status, and control feeding. Although it has been well known that the hypothalamus in mammals is the executive center for appetite control, it receives input from all over the brain. Because feeding is essential, animals have to use all perceptions to get food. Yet feeding is also dangerous. An animal needs to learn what to eat and what not to eat. Under certain conditions, an animal needs to suppress feeding in order to avoid an immediate danger even if it is still hungry. Indeed, feeding is controlled by input from multiple areas including the reward circuits consisting of the nucleus accumbens and the limbic system including the amygdala. Thus, decoding the circuitry controlling appetite and identifying the neurotransmitters working among the components of the circuit involve the entire brain. This makes the study in animals with a complex brain extremely difficult. Humans are considered to have approximately 100 billion neurons, resulting in as many as 1000 trillion possible synapses (Micheva et al. 2010). Figuring out which connections result in a particular circuit to control appetite and related feeding behaviors is certainly a daunting task.

Luckily, because control of food intake and the related behavior are essential to survival, many aspects of appetite-controlling behavior and the molecular pathways are highly conserved in simpler organisms, including C. elegans (You et al. 2008, Valentino et al. 2011, Arshad and Visweswariah 2012, Grimmelikhuijzen and Hauser 2012). This simple model system has contributed to several breakthrough discoveries such as cell death, RNA inference, and use of green fluorescent protein (GFP) as a biomarker. Each of these discoveries led to a Nobel Prize, showing the value and appreciation of the model system.

C. elegans after experiencing starvation and full-refeeding often rests, mimicking the behavioral sequence of satiety and postprandial sleep in rodents (Antin et al. 1975, You et al. 2008, Gallagher et al. 2013a,b, Gallagher and You 2014). For the molecular mechanisms, the satiety quiescence behavior is regulated through transforming growth factor β (TGFβ), insulin and, cyclic guanosine monophosphate (cGMP) pathways that are also conserved in mammals (Valentino et al. 2011).

In addition to conserved behavior and mechanisms, the simplicity of the nervous system of C. elegans makes it a great model to study neuronal mechanisms of appetite control. C. elegans has only 302 neurons (in a hermaphrodite), each of which is identifiable through differential interference contrast microscopy. The function of each neuron can be studied by selective ablation of that neuron by laser (Bargmann and Avery 1995). In addition, it is the only organism whose entire neural network is mapped by electron microscopy reconstruction, which allows researchers to decode the circuits for simple behaviors such as backward and forward movement as well as for complex learning behaviors such as chemotaxis and thermotaxis (Bargmann 2006, Mori et al. 2007, Zhen and Samuel 2015).

Most importantly, C. elegans is a powerful genetic model; they are self-fertilizing hermaphrodites. From egg to adult takes about 3 days. Each worm lays about 300 eggs, which allows large numbers of worms to be bred cheaply, easily, and quickly. The advantage of getting a large number of progeny (easily millions or billions) in a small space within a week is a key feature in genetics; it makes possible large-scale unbiased genetic screens to cover the entire genome. Also the haploid genome size of C. elegans is only 100 megabase pairs (Mb) (Coghlan 2005), compared to about 3200 Mb in humans (Morton 1991, International Human Genome Sequence Consortium 2004).

In addition, it is easy to generate transgenic worms that carry a gene of interest (Praitis and Maduro 2011). C. elegans researchers have built various transgenic lines where calcium sensors (such as GCaMP) or channel rhodopsin are expressed in the targeted neurons then their neuronal activity is monitored or manipulated in real-time under various conditions. Another beneficial feature is the ease of RNA interference (RNAi) that can be used to knock down gene expression and assess the role of specific genes. Because C. elegans feed on bacteria, simply feeding them bacteria that expresses the RNAi of choice can knock down the gene of interest.

It has to be noted that however simple the genome and the nervous system are, studies of metabolism and energy homeostasis in worms reveal conserved fundamental processes and mechanisms, from signaling molecules and receptors to metabolic enzymes (Ashrafi et al. 2003). Insulin signaling plays roles in fat storage, dauer formation, and life span (Kimura et al. 1997). A worm homolog of 5′ adenosine monophosphate-activated protein kinase (AMPK) and a homolog of a nuclear hormone receptor, nhr-49, are also engaged in energy homeostasis: mutations in these genes alter fat storage and life span (Apfeld et al. 2004, Van Gilst et al. 2005). Furthermore, neurotransmitters such as serotonin and dopamine, which are known to be important in high-level control of mammalian feeding, are also important in worms, illustrated by the isolation of mutations in biosynthetic enzymes and receptors for these transmitters in screens for mutants with altered fat storage as well as food preference (Sze et al. 2000, Ashrafi et al. 2003, Chase et al. 2004, Song et al. 2013). These findings show that worms and mammals share common mechanisms for signaling, metabolic pathways, and even information processing for energy homeostasis and fat metabolism. Finally, several feeding behaviors and the molecular mechanisms underlying them are also conserved between C. elegans and other animals. Through the study of a much simpler model organism such as C. elegans, the core molecular basis of appetite-controlling behavior can be unraveled without the complexity that comes with mammalian models.

In this chapter, we describe two main appetite control behaviors, hunger and satiety, in C. elegans and discuss the molecular mechanisms underlying them. Then we describe two other food-related behaviors, which show that feeding behavior can be modified by previous experiences and potentially by learning. The integration of molecular mechanisms and learning is summarized in Figure 1.1.

Figure 1.1. Appetite control in C.

Figure 1.1

Appetite control in C. elegans. Hunger and satiety are opposite metabolic states potentially antagonizing each other when one state is achieved (shown as the dashed line in dark gray). Hunger evokes signals such as opioid and muscarinic signals to induce (more...)

1.2. Behaviors and Mechanisms

Satiety and hunger produce opposite behaviors in animals. Hungry animals seek food, increase exploratory behavior, increase alertness, and continue feeding once they encounter food. Satiated animals decrease exploratory behavior, take rest, and stop feeding. This fact suggests that in a broad sense, there are two feeding states: satiated and hungry. If so, two pathways must converge at some point for the animal to make a decision about whether it is hungry or full and whether to continue feeding or to stop. In mammals, the signaling of nutritional status originates in the liver, which monitors the level of both glucose and fatty acids via the hepatic portal vein from the small intestine. The vagus nerve conveys this signal from the liver to the nucleus of the solitary tract (NST) in the medulla. From the NST, nutrient-related information is passed on to the arcuate nucleus of the hypothalamus. Projections from the arcuate nucleus then pass to the paraventricular nucleus of the hypothalamus and the lateral hypothalamic area. Two important neurotransmitters are released from this projection, neuropeptide Y (NPY) and agouti-related peptide (AgRP). In addition to these two neurotransmitters, proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcripts are released from a group of neurons adjacent to NPY/AgRP neurons. These signals are critical for the delivery of nutritional inputs as well as to integrate and communicate between the nuclei to finally have the animal eat or not. (See reviews by Elmquist et al. 1999 and Schwartz et al. 2000.) The hypothalamus receives input from other brain areas, which could override the energy demands or satisfaction signaled from the gut. These are the general brain areas for motivation and reward such as the nucleus accumbens, ventral tegmental area, dorsal striatum, amygdala, hippocampus, orbitofrontal cortex, cingulate gyrus, and insula. The pleasurable aspect of food is conveyed via cannabinoid and opioid signaling in these areas (Volkow et al. 2011).

In C. elegans, the designated area to integrate the signals to regulate appetite has yet to be identified. However, as described in the next section, the relevant feeding behaviors such as satiety or hunger responses and the molecular mechanisms underlying them are conserved.

1.2.1. Hunger

Hunger is the internal state that results from a lack of nutrients and that motivates the behavioral response. Hungry animals seek food and are eager to eat when they encounter food. Dysregulation of the sensation of hunger often leads to unhealthy conditions; patients with no functional leptin (a fat-derived signal; Masuzaki et al. 1995) feel hungry all the time regardless of their nutritional status, whereas patients with anorexia or cachexia do not feel hungry. In both cases, their brains shut off their bodies’ input because of dysregulation of the hunger sensation. Muscarinic Signal

There are only a few molecules known to mediate hunger. The best understood hunger signal in mammals is ghrelin, an endogenous ligand for growth hormone receptor. It is released from the stomach upon fasting and stimulates the orexigenic center in the hypothalamus via the bloodstream and passing through the blood–brain barrier in addition to influencing the tone of the vagus nerve (Date 2012, Scopinho et al. 2012). Subsequently, enhanced NPY release in the hypothalamus motivates the animal to eat (Asakawa et al. 2001, Wren et al. 2001a,b). In C. elegans, the muscarinic receptor → MAPK (mitogen-activated protein kinase) pathway is a part of hunger signaling in the pharynx (You et al. 2006). When MPK-1, the C. elegans homolog of MAPK-1/2, is activated, its two designated residues (threonine and tyrosine) are phosphorylated. This dual phosphorylation is essential for MAPK activation and thus the marker for MAPK activation (Canagarajah et al. 1997). Specific antibodies for this dual phosphorylation have been used to measure MAPK activation. Endogenous MPK-1 is highly expressed in neurons and muscles including pharyngeal muscles. To measure the phosphorylation of MPK-1 in the pharyngeal muscle specifically, You et al. (2006) targeted the expression of a GFP-tagged MPK-1 to the pharyngeal muscle using a pharynx muscle specific promotor. Starvation and a muscarinic agonist, arecoline, activated pharyngeal muscle MPK-1, but serotonin, also known to act on pharyngeal muscle, did not. Because a Gq-coupled muscarinic receptor, GAR-3, mediates arecoline action in C. elegans feeding (Steger and Avery 2004), they tested whether the starvation signal and the muscarinic signal may act on the same GAR-3 and Gq pathway and whether the muscarinic signal could be a starvation signal. Mutations in gar-3 reduce MPK-1 activation by starvation and by arecoline treatment. In contrast, hyperactivation of Gq (by means of a gain of function mutation of Gq or removal of a negative regulator of Gq) increased MPK-1 activation compared to wild type. If the muscarinic signal mediates a starvation signal, these hyperactive Gq mutants should be more sensitive to starvation than wild type are. Indeed, these mutants are extremely sensitive to starvation, compared with wild type. Inhibiting the pathway either by introducing a mutation in the gar-3 receptor or by treating the hyperactive Gq mutants with an MAPK inhibitor rescued the sensitivity, showing that the muscarinic signal-Gq-MAPK pathway mediates a starvation response. It has been suggested that the normal muscarinic signal functions to initiate general starvation responses in the pharyngeal muscle, such as to change the pumping rate or pharyngeal muscle responsiveness in preparations for when the animal encounters food later. Overactivation of this pathway for a prolonged time in the hyperactive Gq signaling mutants causes lethality due to a pharyngeal muscle that directly interferes with feeding motion. In fact, wild-type worms initially pump slowly when they are taken off food, but they gradually increase the pumping rate in the first 2 hours of starvation. When the pharyngeal muscle GAR-3 → MPK-1 pathway is blocked with a gar-3 mutation, the increase in pumping rate is reduced. Conversely, the hyperactive Gq mutants pumping rate increases more in response to starvation. These data suggest that activation of the muscarinic receptor during starvation contributes to the increase in starvation-induced pharyngeal activity. This study also suggests that fine-tuned regulation of this pathway is essential for worm survival during starvation. Subsequently, Kang and Avery (2009) showed that one of the downstream processes that the muscarinic signal initiates as a starvation response is autophagy. Overactivation of the signal leads to excessive autophagy that contributes to early death in the mutants. Opioid Signal

Opioids have been used as analgesics for longer than any other drug. The opioid system is composed of μ-opioid receptors (MORs), δ-opioid receptors, and κ-opioid receptors (KORs) and endogenous ligands for these receptors. Enkephalins, dynorphins, and β-endorphin peptides are produced by proteolytic cleavage of large protein precursors known as preproenkephalin (Penk), preprodynorphin (Pdyn), and POMC, respectively. All opioid peptides share a common N-terminal YGGF signature sequence, which interacts with opioid receptors (Holtzman 1974, Akil et al. 1998).

Many studies have shown that the opioid system modulates food intake; blocking the opioid receptor by naloxone, an opioid receptor blocker, decreases food intake. On the other hand, treating animals with an agonist of the opioid receptor increases food intake (Martin et al. 1963), and β-endorphin stimulates food intake when administrated directly into the ventromedial hypothalamus (Grandison and Guidotti 1977). Selective agonists for the μ receptor (DAMGO), the δ receptor (DADLE), and the κ receptor (U50448) also increase food intake (Tepperman and Hirst 1983, Gosnell et al. 1986, Jackson and Cooper 1986). In addition to the homeostatic regulation, opioids also regulate the hedonic food intake, by modulating the palatability of food. Naloxone suppresses intake of sucrose solution and blocks the preference for saccharin solution (Levine et al. 1982, Lynch and Burns 1990). An opioid agonist, DAMGO, increases saccharin intake (Zhang and Kelley 2002).

The opioid system has been observed in invertebrates; biochemical approaches such as immunocytochemistry and radioimmunoassay detected opioids in many invertebrate animals including planarians (Phylum Platyhelminthes) and a parasite trematode, Schistosoma mansoni (Venturini et al. 1983, Duvaux-Miret et al. 1990). Treatment with naloxone inhibits a wide range of opioid-mediated responses such as stress-induced analgesia, feeding, mating behavior, and social aggression in invertebrates (Zabala et al. 1984, Kavaliers and Hirst 1986, Kavaliers et al. 1987, Nieto-Fernandez et al. 2009).

Despite all these observations, however, the first invertebrate opioid system with the molecular identities and defined pathway was discovered in C. elegans, where it regulates a hunger response (Cheong et al. 2015). This study shows that neuropeptide like proteins (NLP)-24 is a worm opioid and neuropeptide receptor (NPR)-17 is a worm opioid receptor.

C. elegans have 115 neuropeptide genes. Among them, 10 NLPs (nlp-24, nlp-25, nlp-27, nlp-28, nlp-29, nlp-30, nlp-31, nlp-32, nlp-33, and nlp-34) have an YGGY motif, which is similar to the YGGF motif in the opioid peptides of mammals. The frequency of C. elegans pumping is regulated mainly by the firing rate of MC (see Section 1.1.1), a motor neuron embedded in the pharyngeal muscle. MC releases acetylcholine, and its binding to a nicotinic receptor on the pharyngeal muscle initiates an action potential followed by muscle contraction. In the wild-type C. elegans, in the presence of food, the usual pumping frequency is over 200 times per minute. This high-frequency pumping absolutely requires MC. Once MC is either genetically or surgically ablated, the frequency decreases to an average of 50 times per minute. Because worms do not pump at a high frequency in the absence of food, it has been assumed that MC fires only when food is present in order for worms to eat as much as possible. Therefore, the MC minus state could represent a hunger state (or absence of food) for the worms. It is also suggested that the residual pumping in the absence of food is probably to survey the environment to increase the chances of taking in food (C. elegans are practically blind and they presumably use olfaction to find food). To identify what mediates this MC minus state pumping (or starvation pumping), each of the 115 neuropeptide genes was knocked down by RNAi in MC minus mutants. Cheong found that knocking down nlp-24 in MC minus worms reduced the pumping rate further. She also found that NPR-17, a G-protein-coupled receptor that shares homology with mammalian opioid receptors and functions in pain suppression (Nieto-Fernandez et al. 2009, Harris et al. 2010), is the functional opioid receptor to mediate this starvation pumping.

The conservation of the signaling system at the molecular level is incredible; morphine induces pumping during starvation, mimicking the NLP-24 role in MC minus worms. The morphine effect on pumping is completely abolished in NPR-17 mutants, strongly suggesting that NPR-17 is the receptor that morphine acts on. Finally, heterologously expressed NPR-17 is activated by specific MOR-1 (loperamide) and KOR-1 (U69593) agonists used in mammals, and this activation is blocked by naloxone (Cheong et al. 2015). This proves that NPR-17 is an opioid receptor and NLP-24 is an endogenous opioid of C. elegans.

Based on known opioid roles, we speculate that the opioid during starvation may provide two benefits. First, as the muscarinic signaling does during starvation, opioids stimulate feeding motion to help worms to survey environment and to increase chances of finding food. Second, as a pain reliever, opioids might help the worms feel less stressed during starvation so that they can endure and survive starvation better.

1.2.2. Satiety Satiety Quiescence

Satiated animals stop eating, decrease exploratory behavior, and often fall asleep, a pattern called the “behavioral sequence of satiety” (Antin et al. 1975). C. elegans also display the same behavioral sequence (You et al. 2008). When satiated, they stop eating (measured by pumping rate), stop moving, and become quiescent. The quiescence is the result of satiety because (1) the quiescence is dependent on food quality—worms become quiescent on good food but not on poor food; (2) a decrease in food intake (in feeding mutants) or a decrease in food absorption in the intestine (in absorption mutants) reduces quiescence; and (3) the behavior is dependent on the animal’s past experience of starvation—worms that have experienced starvation show enhanced satiety quiescence compared to worms that have not. Satiety quiescence is regulated by neuropeptide signals since egl-21 mutants, which lack a carboxypeptidase to process neuropeptides, do not produce most peptide signals (Husson et al. 2007), and are completely defective in satiety quiescence. Consistent with the evidence for neuropeptide signaling, insulin and TGFβ signals are also necessary for worms to show satiety quiescence.

Previous studies found that a gain of function mutant of egl-4, which encodes a cGMP-dependent protein kinase, shows excessive quiescence under conditions where the wild-type worms do not show quiescence (Avery 1993a, Raizen et al. 2006). You et al. (2008) found that egl-4 loss of function mutants show no satiety quiescence, whereas the gain of function mutation shows excessive satiety quiescence. This finding suggested a role for cGMP signaling in satiety quiescence, confirmed by the fact that the membrane guanylate cyclase and C. elegans homolog of a natriuretic peptide (NP) receptor, DAF-11, and the cGMP-gated cation channel are necessary for satiety quiescence (You et al. 2008). In C. elegans, insulin, TGFβ, and cGMP pathways are used in sensing a favorable environment and in making the developmental decision to keep growing and reproducing instead of becoming a dauer, a nonreproductive form specialized for long-term survival (Riddle et al. 1981). In other words, these signals are used to ensure that worms will be in nutritionally favorable conditions. The findings of You et al. imply that these same signals of favorable conditions are used to exhibit satiety quiescence in adults. The Mechanisms: TGFβ and cGMP Pathways in ASI Neurons Regulate Satiety

TGFβ signaling is well studied in cell proliferation, differentiation, and tumor formation (Feng and Derynck 2005). In addition, studies suggest a role of TGFβ in food intake and fat metabolism: (1) Overexpressing a TGFβ family member (MIC-1/GDF-15) in the brain inhibits food intake in wild-type mice and causes weight loss by reducing food intake in leptin-deficient ob/ob mice (Johnen et al. 2007). Deficiency of MIC-1, on the other hand, causes an increase in food intake (in females) and induces obesity (in both genders) (Tsai et al. 2013). (2) Exercise activates TGFβ in the brain, and this increase of TGFβ correlates with increased fat mobilization (Shibakusa et al. 2006). (3) Orexin, a neuropeptide that increases appetite, upregulates expression of four sets of signaling genes including TGFβ/SMAD (Sikder and Kodadek 2007). (4) In C. elegans, neuronal TGFβ signaling controls fat metabolism (Greer et al. 2008) as well as satiety quiescence (You et al. 2008). These studies suggest that TGFβ signaling regulates food intake and fat metabolism in both mammals and worms. In C. elegans, TGFβ is released from a pair of head sensory neurons ASI, which is known to regulate several nutrition-related behaviors such as calorie restriction-dependent longevity (Bishop and Guarente 2007). Gallagher et al. (2013b) found that nutrients directly activate ASI and feeding increases the expression of TGFβ in ASI. These results suggest that nutrients activate ASI and lead to the activation of the TGFβ pathway to induce satiety quiescence.

The cGMP signaling pathway is involved in many essential functions; it regulates phototransduction in the eyes, hypertension, reproduction, attention and hyperactive behavior, vasodilation, circadian rhythms, intestinal homeostasis, and cancer progression (Januszewicz 1995, Oster et al. 2003, Yau and Hardie 2009, Francis et al. 2010, Zhang et al. 2010, Gong et al. 2011, Arshad and Visweswariah 2012, Kim et al. 2013). In addition, it regulates body size, exploratory behavior, stress-induced development, sleep, and feeding in invertebrates (Fujiwara et al. 2002, Raizen et al. 2008, You et al. 2008). Its role in appetite control and obesity was first discovered in C. elegans and later in mammals (Valentino et al. 2011). In mammals, a gut peptide, uroguanylin, is released upon feeding and binds to GUCY2C, its receptor in the hypothalamus, to suppress feeding (Valentino et al. 2011). GUCY2C is a membrane guanylyl cyclase (GCY) that produces cGMP upon its activation. Interestingly, there are several previous studies that suggest cGMP functions in obesity. For instance, sildenafil, a medicine that inhibits degradation of cGMP to treat erectile dysfunction, has protective effects in weight gain on a high-fat diet (Ayala et al. 2007, Mitschke et al. 2013). NPs that bind to NP receptors (also GCYs) to produce cGMP are not only important to control blood pressure and heart function (Takei 2001) but also play an important role in lipolysis in adipose tissue via phosphorylation of hormone sensitive lipase by cGMP-dependent protein kinase (PKG) (Sengenes et al. 2000). Furthermore, epidemiological studies show that a certain allele of the NP receptor type C gene is associated with a lean phenotype (Sarzani et al. 2004), suggesting a critical role of NP in fat metabolism.

In C. elegans, the cGMP signal is used to perceive most sensations, including temperature, smell, and light (Komatsu et al. 1996, Ward et al. 2008). The cGMP signal is essential for worms to show satiety quiescence; lack of functional PKG led to increased fat storage and a defect in satiety quiescence (You et al. 2008). Together, these findings in mammals and worms highlight an essential role for cGMP signaling in appetite control and metabolism.

How does it regulate appetite and satiety? ASI neurons, whose ablation impairs satiety quiescence and which are activated by nutrients and release TGFβ when the worms are satiated, are also directly activated by 8-Br-cGMP, a membrane permeable form of cGMP. DAF-11, homologous NP receptors, and a GCY expressed in several head neurons including ASI, are necessary for satiety quiescence. Expressing daf-11 in ASI rescues the defect in satiety quiescence of daf-11 mutants. All this suggests that ASI is the major neuron to sense nutrients and regulate satiety behavior via TGFβ and cGMP signals.

1.3. Food Preference

1.3.1. Quality

Given a choice, C. elegans show a preference toward food that supports their growth better. Avery and Shtonda (2003) characterized the quality of food operationally by measuring the growth of C. elegans. There is a strong inverse correlation between the quality of food and the size of bacteria; better food is smaller so easier to eat (Avery and Shtonda 2003). The size limitation is one of the most common determinants of food an animal feeds on in nature; when only large seeds were available after drought, the finches with small beak sizes could not feed on them and died. Only the finches with a large beak size survived and were selected (Boag and Grant 1981).

This preference can be modified by experience; using three different quality foods (good, mediocre, and bad), Avery and Shtonda (2003) showed that naïve C. elegans L1s that had experienced bad food stayed on the mediocre food and ate it, but the genetically identical naive L1s that had experienced good food from hatching did not stay on the mediocre food. Instead, they left the food a lot more frequently and wandered around, presumably trying to find better food.

Avery and Shtonda (2003) ruled out the possibility that C. elegans made the choice based on primary perceptions (such as olfactory cues) by testing several unrelated species of bacteria of similar quality (i.e., similar ability to support C. elegans growth). Therefore, their studies strongly suggest that C. elegans sense the nutritional value of food to show preference for a better quality of food based on their past experience.

1.3.2. Familiarity

Food can be dangerous for feeders in the wild, mainly because food does not want to be food. Many prey and plants are armed with diverse defense mechanisms such as toxins. Therefore, the feeders would need to make sure what they eat is safe. Familiar food means they are safe so they can eat without experimenting on it. If you have a dog, you should have seen that its responses toward familiar food and nonfamiliar food are as different as day and night. If it is familiar food, the dog is excited from the smell of it. As soon as the food is given, the dog will take a big bite of it without hesitation. On the contrary, if you give the dog a food that it has never experienced before, it hesitates, cautiously tastes it, takes time to eat it.

Song and Avery found that this preference toward familiar food is conserved in C. elegans. Using two equally good qualities of bacteria (let us name them A and B for convenience), they showed that C. elegans that had fed on bacteria A chose A but the C. elegans that had fed on B chose B, when they were given choices between A and B. Song and Avery further discovered that this behavior is mediated by a neuronal serotonin system. Serotonin has been implicated in mimicking food in C. elegans (Horvitz et al. 1982, Sze et al. 2000, Niacaris and Avery 2003), exerting several food-related behaviors such as promoting feeding motions and egg-laying and suppressing locomotion. In mammals, serotonin plays a critical role in controlling appetite and food choices by controlling dopamine pathway reward circuits. Song and Avery’s work suggests that a conserved reward circuit is used to promote feeding after recognizing familiar food.

1.4. Conclusions

Although they are simple, C. elegans show conserved feeding behavior that enables them to survive an uncertain environment; hunger increases locomotive activity and induces pumping to increase the chances of finding food. Satiation causes them to rest. They can learn what to eat and what not to and change their behavior depending on their past experience of the quality of food. Surprisingly, many of the signals for these behaviors are highly conserved, e.g., a muscarinic acetylcholine signal, opioids, and serotonin. With the simple nervous system, powerful genetics, conserved behavior and genes, and rich resources such as the known connectome of neurons and highly collaborative society of researchers, C. elegans proves as an extremely useful model to study fundamental aspects of appetite control behavior and its underlying molecular neuronal mechanisms.


We thank Dr. Leon Avery for his invaluable comments. This work is supported by the School of Medicine, Virginia Commonwealth University.

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Bookshelf ID: NBK453151PMID: 28880514DOI: 10.1201/9781315120171-1


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