Octopamine (OA) and tyramine (TA) are closely related biogenic monoamines that act as signalling compounds in invertebrates, where they fulfil the roles played by adrenaline and noradrenaline in vertebrates. Just like adrenaline and noradrenaline, OA and TA are extremely pleiotropic substances that regulate a wide variety of processes, including metabolic pathways. However, the role of OA and TA in metabolism has been largely neglected. The principal aim of this Review is to discuss the roles of OA and TA in the control of metabolic processes in invertebrate species. OA and TA regulate essential aspects of invertebrate energy homeostasis by having substantial effects on both energy uptake and energy expenditure. These two monoamines regulate several different factors, such as metabolic rate, physical activity, feeding rate or food choice that have a considerable influence on effective energy intake and all the principal contributors to energy consumption. Thereby, OA and TA regulate both metabolic rate and physical activity. These effects should not be seen as isolated actions of these neuroactive compounds but as part of a comprehensive regulatory system that allows the organism to switch from one physiological state to another.

Octopamine (OA) and tyramine (TA) are biogenic amines that are derived from the amino acid tyrosine and are of the utmost importance in invertebrates. These neuroactive substances fulfil the physiological roles that adrenaline and noradrenaline (NA) perform in vertebrates (Roeder, 1999, 2005). Like adrenaline and NA, both OA and TA are highly pleiotropic – they are involved in regulating a wide range of behaviours, physiological variables and, more specifically, metabolic pathways. Similarities exist between these two signalling systems in invertebrates and vertebrates at various levels. First, it should be noted that these signalling substances have strikingly similar structures: NA differs from OA only in the presence of an additional hydroxyl group at position three of the phenolic ring (Roeder, 1999; Roeder et al., 2003). Furthermore, TA is the biological precursor of OA and adrenaline is produced from NA; thus, each signalling system comprises two messenger substances that are not completely independent of one another. The respective receptors, the α- and β-adrenergic receptors of vertebrates and the OA and TA receptors of invertebrates, also share substantial sequence similarity, suggesting that they have common evolutionary origins (Fig. 1). However, this interpretation was recently questioned (Bauknecht and Jékely, 2017). The authors claim that α- and β-adrenergic receptors as well as OA and TA receptors were part of the ancestral receptor repertoire of primordial metazoans; therefore, final clarification of this issue is still pending. Finally, similarities in these systems also exist at the level of the physiological processes that they control. The famous ‘fight-or-flight’ response, which is activated in vertebrates by adrenaline and/or NA, and in invertebrates by OA and TA, is the most obvious example of these physiological similarities. Fight-or-flight responses use adrenaline/NA or TA/OA to induce the relevant physiological effects, but they are also characterised by complex regulatory inputs that enable their efficient execution. For example, in vertebrates, the bone-derived osteocalcin system suppresses parasympathetic activities in response to fear, thus strengthening the fight-or-flight response (Berger et al., 2019).

Glossary

Circadian clocks

Most animals have a circadian rhythm that is controlled by a central circadian clock, which enables the maintenance of rhythm even in the absence of external Zeitgebers (‘time-givers’). Peripheral clocks are present in a number of different peripheral organs to regulate local circadian processes.

Cytoprotective response

A response induced in cells after exposure to stress that increases cellular stress resistance. Hunger and reduced food intake are among the most important inducers of a cytoprotective response. This response is characterised by the induced expression of a defined set of genes.

Lipolysis

The process of releasing fatty acids from storage triglycerides present in storage organs (fat bodies in insects, intestinal cells in nematodes). This release is necessary to provide energy when needed and is regulated by hormones.

Metabolic rate

The metabolic activity and associated energy consumption that occur in the absence of physical activity in an organism. It is one of the major components contributing to the overall energy expenditure.

Mushroom bodies (corpora pedunculata)

Regions in the insect (arthropod) brain that have a mushroom-like appearance. The structure is mainly made of fibres of so-called Kenyon cells and it is known to play a central role in olfactory learning and memory.

Neurohormones

Messenger compounds that are produced by neurons and reach their target organs via the blood/body fluid. Tyramine and octopamine as well as adrenaline and noradrenaline are classic neurohormones, as they are (mostly) produced by nerve cells and address peripheral targets. In invertebrates, insulin-like peptides and adipokinetic hormones (AKHs) are also neurohormones, as the sites of production are nerve cells.

Oenocytes

Specialised cells present in insect larvae and adults that are closely associated with fat body cells; they are segmentally organised and show a distinct morphology. Oenocytes are hepatocyte-like cells that are involved in energy metabolism and the biosynthesis of cuticular hydrocarbons and pheromones.

Supraoesophageal and suboesophageal ganglion

The two main parts of the insect brain, which can exist either as structurally independent units or as fused brain. Most of the higher brain functions are provided by structures of the supraoesophageal ganglion, while one of the main functions of the suboesophageal ganglion is in the control of the mouth parts.

Fig. 1.

Structure of the octopaminergic/tyraminergic system of invertebrates and the noradrenergic/adrenergic system of vertebrates. The chemical structures of octopamine (OA), tyramine (TA), noradrenaline (NA) and adrenaline are given on the left. The corresponding receptors are listed on the right. For the invertebrate OA/TA systems, receptors from Drosophila melanogaster and Caenorhabditiselegans are displayed; for vertebrates, the canonical set of adrenergic receptors is given. With the exception of Lgc-55, which is a TA-gated chloride channel, all other receptors belong to the G-protein coupled receptor (GPCR) superfamily. Oct-TyrR, octopamine–tyramine receptor; TyrR, tyramine receptor; OctR, octopamine receptor; Ser-2, tyramine receptor 1; Tyra, tyramine receptor; Lgc-55, tyramine-gated chloride channel 55; Octr-1, octopamine receptor 1; Ser-3, octopamine receptor; Ser-6, octopamine receptor; α, alpha-adrenergic receptor; β, beta-adrenergic receptor.

Fig. 1.

Structure of the octopaminergic/tyraminergic system of invertebrates and the noradrenergic/adrenergic system of vertebrates. The chemical structures of octopamine (OA), tyramine (TA), noradrenaline (NA) and adrenaline are given on the left. The corresponding receptors are listed on the right. For the invertebrate OA/TA systems, receptors from Drosophila melanogaster and Caenorhabditiselegans are displayed; for vertebrates, the canonical set of adrenergic receptors is given. With the exception of Lgc-55, which is a TA-gated chloride channel, all other receptors belong to the G-protein coupled receptor (GPCR) superfamily. Oct-TyrR, octopamine–tyramine receptor; TyrR, tyramine receptor; OctR, octopamine receptor; Ser-2, tyramine receptor 1; Tyra, tyramine receptor; Lgc-55, tyramine-gated chloride channel 55; Octr-1, octopamine receptor 1; Ser-3, octopamine receptor; Ser-6, octopamine receptor; α, alpha-adrenergic receptor; β, beta-adrenergic receptor.

Numerous studies have shown the regulatory effects of TA and, especially, OA on almost all aspects of an animal's life, and a number of comprehensive reviews summarise these data (Chase and Koelle, 2007; Roeder, 1999, 2005; Roeder et al., 2003). However, there has been relatively little progress in the differentiation of the effects of OA and TA to date. In some systems, opposing effects of these substances have been identified, which implies that the various functions may be regulated differently according to the proportions of OA and TA present (Alkema et al., 2005; Damrau et al., 2018; Saraswati et al., 2004; Vierk et al., 2009). These specific and, in some cases, antagonistic effects of OA and TA will be discussed in different parts of this Review. For TA, a particular role as a neuroactive substance has been highlighted in a number of studies and reviews (Blenau and Baumann, 2003; Cazzamali et al., 2005; Lange, 2009; Roeder et al., 2003). However, what at first glance appears to be a surprising variety of effects, largely induced by OA, merges into a coherent overall picture on closer inspection. In most instances, OA seems to be the messenger that coordinates the activities of a number of organs, orchestrating a change from a resting state to a state of higher activity. This concerted action involves behavioural changes, metabolic adjustments and the optimisation of the performance of various organ systems (Adamo et al., 1995; Stevenson and Rillich, 2012). The processes that are regulated in this way include those that require substantial resources, such as egg laying (Avila et al., 2012; Lee et al., 2003; Li et al., 2015).

Central to the combined actions of OA are effects on the circulation, with changes in the heart rate being the most important outcome. Effects of OA, but also of TA, on heart rate have been reported for a number of different species (Fig. 2). In most cases, these amines act to increase the heart rate, whereas for some preparations an inhibitory effect has been shown (Chowanski et al., 2017; Papaefthimiou and Theophilidis, 2011; Pryce et al., 2015). Increased heart rate makes all exchange processes more efficient. Graham Hoyle proposed a hypothesis that describes OA as a messenger compound that modulates a number of different behavioural and physiological properties in order to transform the animal into a state of higher activity; this is known as the orchestration hypothesis (Hoyle, 1985; Libersat and Pflueger, 2004). These disparate OA-mediated effects serve to coordinate organ function, enabling a coherent physiological response at the organismal level. However, to date, the focus of most studies has been on the behavioural and motor effects of OA and TA, whereas their influence on metabolism has been little studied. Nevertheless, there is considerable evidence that this aspect of OA/TA action is important for the overall performance of the organism (Li et al., 2016; Roeder, 2005). Therefore, this Review focuses on the effects of both of these neuroactive amines on metabolism. Aspects of their activity that affect behaviour will be considered if they are directly connected to energy gain or energy expenditure. The relationship between energy intake and energy expenditure is of central importance for the regulation of metabolic processes, and both of these variables are directly and indirectly influenced by OA and TA. Therefore, I first discuss the different contributions of OA and TA to energy intake and move on to discuss their roles in modulating the most important components of energy expenditure, namely metabolic rate (see Glossary) and physical activity (Fig. 3). Whenever information is available, I will discuss the effects of the two monoamines separately.

Fig. 2.

Interaction of OA and TA with different peripheral organs and with the central clock. Effects of OA (blue arrows pointing towards the target organs) and TA (red arrows pointing towards the target organs) are shown. For some of these interactions, both OA and TA affect the corresponding peripheral organ. Very few systems (intestine, hormones, central clock) have been shown to influence the level of either of these compounds or of the enzymes that are responsible for OA and TA synthesis. Symbols close to the targets indicate whether a positive (+) or a negative (−) effect has been reported. Question marks indicate either that it is not known in which direction the modulation occurs or that the terms activation and inhibition are not meaningful. The arrow with the mixed colours from the circadian clock to the OA/TA system indicates that the activity of the enzyme producing both compounds cycles in a circadian rhythm. ILP, insulin-like peptide; AKH, adipokinetic hormone; JH, juvenile hormone.

Fig. 2.

Interaction of OA and TA with different peripheral organs and with the central clock. Effects of OA (blue arrows pointing towards the target organs) and TA (red arrows pointing towards the target organs) are shown. For some of these interactions, both OA and TA affect the corresponding peripheral organ. Very few systems (intestine, hormones, central clock) have been shown to influence the level of either of these compounds or of the enzymes that are responsible for OA and TA synthesis. Symbols close to the targets indicate whether a positive (+) or a negative (−) effect has been reported. Question marks indicate either that it is not known in which direction the modulation occurs or that the terms activation and inhibition are not meaningful. The arrow with the mixed colours from the circadian clock to the OA/TA system indicates that the activity of the enzyme producing both compounds cycles in a circadian rhythm. ILP, insulin-like peptide; AKH, adipokinetic hormone; JH, juvenile hormone.

Fig. 3.

Effects of OA and TA on the most important components contributing to either energy expenditure or energy intake. OA (blue arrows) and TA (red arrows) affect systems contributing to energy expenditure (metabolic rate and physical activity) as well as those responsible for energy intake (feeding rate, appetite, food choice). Symbols indicate whether positive (+) or negative (−) effects have been reported.

Fig. 3.

Effects of OA and TA on the most important components contributing to either energy expenditure or energy intake. OA (blue arrows) and TA (red arrows) affect systems contributing to energy expenditure (metabolic rate and physical activity) as well as those responsible for energy intake (feeding rate, appetite, food choice). Symbols indicate whether positive (+) or negative (−) effects have been reported.

The control of food intake is of central importance to all metabolic processes because it regulates the supply of energy. This means that the interaction of hunger and satiation, and the resulting regulation of food intake, is of great significance when considering metabolism. OA has numerous physiological effects that are important during a period of hunger. Hunger triggers the release of OA, which induces a suitable physiological response (Tao et al., 2016). Early studies revealed that the administration of exogenous OA phenocopies the effects of starvation in Caenorhabditiselegans (Horvitz et al., 1982), and higher body concentrations of OA have been observed during starvation – Tao and colleagues (2016) reported a 3–4 times higher OA concentration in fasted C. elegans compared with well-fed ones.

Invertebrates have evolved a number of different strategies to prevent starvation. Starvation activates behavioural responses aimed at increasing food intake. During starvation, food availability, rather than the capacity for feeding, is usually the limiting factor. Therefore, movement to locate new food sources is an appropriate response. Consequently, starvation-induced behavioural responses include greater locomotor activity. In D. melanogaster, this starvation-induced hyperactivity depends on neuronal OA production (Yang et al., 2015), as observed previously in C. elegans, where it acts antagonistically to serotonin (5-HT). Interestingly, in C. elegans, OA and TA seem to control different aspects of the worms' complex behaviour in response to starvation, thus acting differentially (Fig. 3). TA promotes reduced locomotion to allow feeding, and OA promotes increased locomotion in response to fasting to allow searching for new food sources (Churgin et al., 2017). However, the role of OA in the context of feeding in invertebrates is still controversial, because food intake is a multifaceted behaviour: starvation-induced hyperactivity is obviously a very important aspect of the overall response to starvation, but it is not necessarily causally related to increased food intake. Despite the numerous different approaches that have been developed to quantify food intake, it is only very recently that reliable and reproducible approaches have been published (Shell et al., 2018). Previous difficulties in reliably monitoring daily food intake might be one reason why some studies show that food intake indeed depends on OA in D. melanogaster (Li et al., 2016), whereas other studies do not show this dependency (Yang et al., 2015).

The behavioural response to starvation is complex. As discussed above, starvation-induced hyperactivity enables the search for new food sources. Therefore, persistence in following an odour trace that leads to a food source is an adaptive response, but it is necessary to inhibit odour tracking in order to start feeding. In D. melanogaster, the activation of OA-containing VPM4 neurons reduces persistent odour tracking, which might be the signal to start feeding (Sayin et al., 2019). Moreover, targeted manipulation of octopaminergic VPM4 neuron activity shows that these neurons promote feeding by increasing the proboscis extension response in adult flies (Youn et al., 2018). Buckemüller and colleagues (2017) observed a similar effect of octopaminergic signalling on proboscis extension, and therefore on feeding, in honey bees. Indeed, this OA-induced increase in feeding appears to be a general phenomenon in insects (Cohen et al., 2002). In D. melanogaster larvae, neuronal circuits involving octopaminergic VUM neurons in the suboesophageal ganglion (see Glossary) are involved in the increase in feeding in response to hunger, while sub-circuits also comprising octopaminergic neurons prevent overfeeding and are therefore associated with satiety (Zhang et al., 2013).

Besides the initiation of feeding, additional behaviours are altered in response to starvation that are highly relevant for food intake (Fig. 3). For example, prior to the start of feeding, an organism must decide what to eat and what not to eat. Starvation influences this decision in two different ways: it sensitises sugar taste and desensitises bitter taste (Lin et al., 2019). Thus, starvation changes the acceptance of food sources dramatically, which leads to acceptance of otherwise rejected food, increasing energy intake in periods of food scarcity. Drosophila melanogaster, like most animals, avoid bitter food sources because this taste is often associated with toxicity. However, starvation reduces the sensation of bitterness and therefore increases the acceptance of bitter-tasting food sources. OA- and/or TA-secreting neurons (OA-VL) potentiate this bitterness sensation, and upon starvation they reduce their activity, thereby reducing the sensation of bitterness (LeDue et al., 2016). A similar adjustment of food source-associated sensory inputs was described for C. elegans, which can react differently to CO2 such that is it attractive, repulsive or neutral. CO2 is thought to represent an ambiguous signal as it is produced not only by the normal food bacteria C. elegans depends on but also by potential pathogens. Therefore, shifting from aversion to attraction increases the possible food range, but it is associated with a higher risk of infection. This shift towards a more comprehensive food range (albeit one that is associated with a certain risk) seems to be a general mechanism in response to starvation. OA is the neurohormone (see Glossary) that mediates a shift towards attraction to a greater range of foods, which is observed during starvation (Rengarajan et al., 2019). Furthermore, OA appears to foster decision making in situations where various options are available (Claßen and Scholz, 2018). For example, mated females require food with a relatively high protein content in order to optimise their fecundity; in D. melanogaster, they show protein-seeking behaviour that is mediated by octopaminergic neurons in response to starvation (Tian and Wang, 2018). In summary, it can be concluded that OA is a classic hunger signal that modulates various aspects of food intake. Its secretion leads to the ingestion of larger quantities of food to provide the required amount of energy.

As discussed above, OA plays a crucial role in the control of food intake and therefore in the regulation of energy supply. However, energy intake is normally balanced by energy consumption, which comprises two main components: physical activity and metabolic rate. Physical activity is easy to measure and is subject to behavioural control mechanisms, but the regulation of metabolic rate is far less well understood. In this section, I will discuss the effects of OA and TA on physical activity, which directly impacts energy expenditure. It should be mentioned that the body of information dealing with the effects of OA on the regulation of physical activity is much more comprehensive than that of TA on the corresponding behaviours (Fig. 2).

Flight is the most energy-intensive means of movement in insects. OA regulates flight behaviour at a number of levels, thus contributing to this important component of energy expenditure (Orchard et al., 1993). Drosophila melanogaster, like other insects, fly at a relatively constant cruising speed, independent of hormonal influences (and thus also mostly independent of OA levels). However, OA affects the rate of acceleration, thus altering the time taken to reach the appropriate flight speed. This is especially relevant for more complex flight manoeuvres, as they are characterised by frequent changes in direction and flight speed. Thus, although OA has no impact on normal flight speed, through its effects on acceleration it should have a major impact on overall flight speed and performance (van Breugel et al., 2014). Flies deficient in the production of OA show significant changes in additional major components of flight behaviour: important parameters of flight control, namely flight initiation and length of flight episodes, critically depend on this amine. Interestingly, TA also appears to be an integral part of the flight control system in insects; at high concentrations, TA acts antagonistically to OA. Nevertheless, these differential effects of OA and TA on these flight-related traits are not simply antagonistic, as they could only be observed at high TA and concurrent low OA concentrations (Brembs et al., 2007). Thus, long periods of uninterrupted flight that are necessary to find new places and new resources critically depend on high OA concentrations. These flight periods are particularly energy demanding.

Mechanistically, OA-containing neurons are part of a complex neuronal network also comprising dopaminergic and GABAergic neurons within the mushroom bodies (see Glossary). OA-containing neurons located in the sub-oesophageal ganglion activate dopaminergic neurons that, in turn, control these GABAergic mushroom body output neurons (MBON). Either inhibition of the octopaminergic or dopaminergic neurons or activation of the GABAergic neurons reduces the duration of flight episodes (Manjila et al., 2019). These positive effects of OA on various aspects of flight performance occur concurrently with modulation of visual information processing (Suver et al., 2012). This means that OA enables efficient insect flight because many essential aspects of this behaviour are under direct octopaminergic control. Thus, there is a clear and direct relationship between OA/TA and the most energy-intensive means of insect movement.

Terrestrial locomotion is another major cause of energy expenditure. Higher OA concentrations are associated with an increase in walking activity in flies and other arthropods, and in movement speed in C. elegans. In C. elegans, this effect of OA on movement has been reported several times (Churgin et al., 2017; Donnelly et al., 2013). As discussed above, starvation-induced, OA-dependent higher physical activity seems to be a general phenomenon in insects. A series of very elegant experiments performed in Graham Hoyle's laboratory set the stage for a better understanding of the role of OA in the initiation and maintenance of all kinds of insect movement. This work showed that local application of OA into defined regions of the thoracic ganglia of locusts induces different types of rhythmic behaviours, such as flight, walking or egg deposition (Sombati and Hoyle, 1984). Only very recently, comparable studies with Drosophila melanogaster have elucidated the cellular circuitries underlying these responses. Based on the early studies performed in the Hoyle lab, Jay Hirsh's laboratory showed that exogenous OA induces stereotypic movement programmes, even in a highly reduced, ‘headless’ Drosophila melanogaster model (Yellman et al., 1997). Thus, in many insects and other arthropods, OA increases movement and general arousal, thereby substantially increasing energy expenditure.

The effects of OA on movement induction and maintenance in invertebrates are paralleled by those observed in studies of human physiology. As observed in humans, flies respond to endurance training with improvements in walking speed and cardiac performance. This adaptive reaction is completely dependent on OA and can be mimicked by the intermittent, daily application of this neuroactive substance (Sujkowski et al., 2017; Sujkowski and Wessells, 2018).

Surprisingly, in D. melanogaster, the presence of an intestinal microbiome also affects movement activity, and this link requires octopaminergic signalling, representing an impressive example of a functional gut–brain axis, in which OA is of central importance (Schretter et al., 2018). The authors showed that germ-free animals exhibit hyperactive locomotor activity. This phenotype is rescued by reassociation with a functional microbiota, and even by monoassociation with a particular member of the microbiota, namely with Lactobacillus brevis. Furthermore, a single bacterial enzyme, the xylose isomerase, recapitulates this rescue. Ectopic application of OA, as well as activation of octopaminergic neurons, abrogates these effects of the xylose isomerase (Schretter et al., 2018). It has to be kept in mind that the relevance of the microbiota for different physiological processes differs vastly between insect species (Hammer et al., 2017).

Metabolic activity (or more precisely, the basal or resting metabolic rate) is defined as the rate of energy expenditure at rest (McNab, 1997). This definition was introduced for endothermic animals, but it applies also to exothermic animals, including all invertebrates. The resting metabolic rate is the sum of metabolic activities of all organ systems in an animal in the absence of movement activity. Usually, the metabolic rate accounts for a large percentage of the overall energy expenditure. OA-deficient D. melanogaster show several different metabolic adaptations. For example, these flies develop severe obesity, which is characterised by a body fat mass that is substantially higher than the average (Bullman et al., 2017; Li et al., 2016). This phenotype probably results from an imbalance in energy intake and expenditure. Interestingly, these OA-deficient animals show lower energy intake than average, because of lower dietary intake, but they also demonstrate lower energy expenditure because of lower physical activity and resting metabolic rate (Li et al., 2016). However, the underlying molecular mechanisms have yet to be established. Ectopic activation of OA release by thermogenetic activation of octopaminergic neurons induces the opposite phenotype, which is characterised by substantially lower body fat mass (Li et al., 2016). This phenotype resembles the situation observed in humans who have a dysregulation of adrenergic signalling, because adrenaline and NA directly regulate lipolysis (see Glossary) in fat cells (Bartness et al., 2014; Lafontan and Berlan, 1993).

Fasting in vertebrates induces an increase in NA/adrenaline release from autonomous neurons, which mirrors the situation in invertebrates, where OA is also released in response to starvation (Wang et al., 2016). However, the molecular mechanisms that underlie the transduction of the modulatory effects of OA and/or TA on body fat mass are poorly characterised in invertebrates. At present, direct effects on the storage organ (the fat body) and indirect effects via, for example, peptide hormone release, cannot be differentiated. Adipokinetic hormones (AKHs), which are the invertebrate equivalents of glucagon, are the most potent lipolytic hormones (Arrese and Soulages, 2010). Similar to glucagon release, AKH release provides energy-rich substances, such as fatty acids and carbohydrates. AKH directly acts on the fat body via specific receptors (Grönke et al., 2007), thereby inducing release of fatty acids. In experimentally amenable insects, such as locusts, a direct effect of OA on lipolysis from the fat body has been reported (Orchard et al., 1982). This direct effect resembles the situation observed in C. elegans, where OA, together with 5-HT, can induce lipolysis directly from the major storage organs (Noble et al., 2013). I discuss the interaction between OA and the release of AKHs in more detail below.

Whether there is a direct physiological effect of OA and/or TA that is mediated by specific receptors present on target tissues such as the fat body or the oenocytes (see Glossary) is still a matter of debate; in D. melanogaster, such an interaction remains to be unequivocally shown. The major storage organ of insects, the fat body, which is the functional equivalent of vertebrate adipose tissue, is a direct target of OA, at least in a number of experimentally more amenable insects, such as locusts or cockroaches. For example, OA was shown to induce the release of fatty acids from fat bodies isolated from locusts in a dose-dependent manner (Orchard et al., 1982). Other data obtained with locusts, crickets or moths complemented this finding, showing that, as in vertebrates, OA (the invertebrate equivalent of an adrenergic signalling compound) directly activates fatty acid and carbohydrate release from this major energy-storing organ (Arrese and Soulages, 2010; Fields and Woodring, 1991; Meyer-Fernandes et al., 2000; Orchard et al., 1993; Park and Keeley, 1998). OA also regulates the liberation of carbohydrates from glycogen stored in the fat body of cockroaches (Fig. 2). In vitro incubation of isolated fat bodies with OA results in the activation of glycogen phosphorylase, which is required for the release of trehalose, one of the most important energy-containing compounds in the haemolymph (Park and Keeley, 1998). It has to be kept in mind that, in D. melanogaster, such a direct effect has yet to be shown. One particular OA receptor, Octβ-2R, is expressed at significant levels in the fat bodies of larvae and adults (El-Kholy et al., 2015; Leader et al., 2018); this receptor could mediate the direct effect of OA on the fat body. In addition, a study that comprehensively mapped the potential release sites of OA-containing neurons in D. melanogaster revealed that almost all organs can be targeted by these neurons. This implies that almost all insect organs can be direct targets of OA (and TA) action (Pauls et al., 2018). Despite the uncertainties regarding whether OA can directly induce the release of fatty acids from peripheral stores in D. melanogaster, this appears to be the case for other invertebrates, including locusts, crickets, cockroaches and moths (see above), as well as C. elegans. In this last species, OA is released from RIM neurons in response to starvation, and it seems to interact with Ser-3 receptors in the intestine, an important storage organ (Noble et al., 2013; Tao et al., 2016).

The most important means whereby OA and TA regulate the metabolic status of an animal are likely to be through their effects on the release of other hormones (Fig. 2). Insulin and glucagon in vertebrates and insulin-like peptides and AKH in invertebrates are central players in the control of metabolic traits. Whereas the release of insulin and insulin-like peptides triggers the switch towards the storage of energy, glucagon and AKH induce exactly the opposite (Ahmad et al., 2019; Gáliková et al., 2015; Hoffmann et al., 2013; Nässel and Vanden Broeck, 2016; Straub and Sharp, 2012). Thus, modulation of the release of either insulin-like peptides (ILPs) or AKH by OA and TA should have a major impact on the metabolism of the organism. Consequently, the regulation of insulin-secreting cells appears to be the most important mechanism whereby adrenergic/octopaminergic/tyraminergic signalling systems exert their effects on major metabolic parameters (Ahmad et al., 2019; Nässel et al., 2015; Straub and Sharp, 2012). Indeed, NA and adrenaline have long been known to inhibit the release of insulin from pancreatic islets (Porte and Williams, 1966). The blunting of adrenergic signalling in vertebrates induces a set of predictable phenotypic changes, including the induction of obesity, and OA-deficient D. melanogaster also show an obese phenotype, with lower haemolymph glucose concentrations, which are presumably caused by the higher circulating insulin concentrations. Therefore, OA may reduce insulin secretion (Bullman et al., 2017; Li et al., 2016). Regarding the underlying mechanisms, it has been proposed that OA binds to specific receptors, especially the OAMB receptor (Octα-1R), which is present on insulin-like peptide 2 (dILP2)-expressing cells in the pars intercerebralis (PI) of the adult fly brain (Crocker et al., 2010); dILP2 is the most important insulin-like peptide in D. melanogaster (Park et al., 2014). However, it remains unclear whether the inhibitory effects of OA on dILP release from the PI cells are indeed mediated by the OAMB receptor or whether other receptors are also involved; it is also unclear how this signalling system operates to control ILP release (Nässel et al., 2013, 2015).

Modification of insulin secretion is a powerful and effective way of regulating the metabolic state of an animal. Flies missing the most important ILPs have a lower basal metabolic rate, implying that the regulation of insulin secretion affects this important aspect of energy expenditure (Zhang et al., 2009). Such regulation also occurs in parallel with the effects of nutritional interventions, such as dietary restriction, which lead to a reduction in circulating insulin concentration and lower resting metabolic rate (Romey-Glüsing et al., 2018). A lower circulating insulin concentration would result in metabolic changes, including lower glucose uptake and greater mobilisation of fat and glycogen.

Recent studies with C. elegans have shown that TA affects insulin signalling not only at the TA release site but also at the level of the insulin-responsive cells. In C. elegans, TA is released in response to short but potent stress signals, which induce the fight-or-flight response (Alkema et al., 2005; Roeder, 1999, 2005). This release of TA activates insulin signalling in C. elegans, especially targeting the intestinal cells, thereby inhibiting the nuclear translocation of FoxO/daf-16, which blunts the cytoprotective response (see Glossary) usually induced by these proteins (De Rosa et al., 2019). Initial studies imply that this interaction between the octopaminergic/tyraminergic and insulin systems is not unidirectional, but organised in a reciprocal fashion. The activity of chico, the major insulin receptor substrate, regulates OA/TA metabolism, which adds a level of complexity (Adonyeva et al., 2016).

In addition to release of insulin, that of other hormones is also regulated by OA/TA. The corpora allata, which produces the juvenile hormone of insects, expresses OA receptors. In honey bee larvae, OA stimulates the release of juvenile hormone (Rachinsky, 1994), and this may also occur in D. melanogaster, because OA secretion from sites close to the corpora allata has been reported (Pauls et al., 2018). Higher juvenile hormone concentrations may be associated with higher metabolic rate and therefore with energy expenditure. This proposition is supported by studies conducted in the beetle Dermestes maculatus, which showed that juvenile hormone analogues substantially upregulate metabolic rate (Sláma and Krypsin-Sørensen, 1979). In burying beetles, a correlation between juvenile hormone concentration and metabolic rate (Trumbo and Rauter, 2014) was also identified, which further supports the hypothesis that OA affects metabolic status by regulating juvenile hormone release. The corpora cardiaca, another hormone-secreting structure that substantially affects metabolism in D. melanogaster, produces and releases AKHs, which (as discussed above) are the most important energy-liberating hormones in insects. However, it remains to be confirmed whether OA induces AKH release from the corpora cardiaca. A series of studies performed more than 20 years ago utilizing experimentally amenable insects such as locusts showed that OA application induces cAMP production in the corpora cardiaca as well as AKH release from this organ (Orchard et al., 1993; Downer et al., 1984). This dependency could not be demonstrated in D. melanogaster (Ahmad et al., 2019). Interestingly, a different type of interaction between the octopaminergic and the AKHergic systems has recently been elucidated. AKH release, which is triggered by starvation, induces a set of behavioural responses. Among them, hyperactivity takes a central role as it allows the search for new resources. Here, AKH directly controls OA-containing neurons that are necessary to translate starvation into hyperactivity (Yu et al., 2016).

Circadian rhythms consisting of rest/sleep phases and activity phases are seen throughout the entire animal kingdom. At the cellular level, the rhythm is controlled by an evolutionarily conserved system composed of only a few components that regulate the periodic activation of transcription (Allada and Chung, 2010). The pioneering work in D. melanogaster that led to the identification of the clock genes was honoured in 2017 with the Nobel prize awarded to Jeff Hall, Michael Rosbash and Michael Young (Sehgal, 2017). Circadian clocks (see Glossary) usually show a hierarchical organisation, with a central clock located in the brain controlling various peripheral clocks operating in different organs (Dibner et al., 2010). These clock systems are responsive to a number of different hormonal signals, which naturally have a major influence on metabolic processes. Moreover, the clock output and the control of sleep/wake periods is interconnected with feeding behaviour: starvation suppresses sleep, and sleep deprivation promotes food intake (Keene et al., 2010). Therefore, the circadian rhythm and the associated sleep/wake cycle are of central importance to the performance of metabolic systems. The resting phase, and especially sleep, are associated with substantial reductions in energy expenditure, which is important for the minimisation of metabolic waste.

In vertebrates, adrenaline and NA not only affect circadian rhythm and sleep quality but also their plasma concentrations cycle in a circadian manner (Linsell et al., 1985) and regulate important physiological functions accordingly (Scheer et al., 2010). Adrenaline/NA secretion modulates peripheral clock systems (Terazono et al., 2003), implying that there is a complex feedback between the circadian clock and adrenergic/noradrenergic signalling. In D. melanogaster, OA promotes wakefulness via regulation of protein kinase A activity, whereas OA deficiency promotes sleep (Crocker and Sehgal, 2008). These wakefulness-promoting effects of OA are mediated by octopaminergic ASM neurons and require their interaction with insulin-producing cells, in which binding to the OAMB receptor (Octα-1R) alters potassium conductance and increases cAMP levels (Crocker et al., 2010). The wakefulness-promoting effects that are mediated through OA secretion, the OAMB receptor and insulin-producing cells are known to be independent of insulin, because alterations in insulin secretion have no effect on sleep (Erion et al., 2012). These effects of OA on sleep have also been found in D. melanogaster larvae, in which an increase in OA signalling reduces sleep. In this scenario, sleep allows the maintenance of stem cell activity, which ensures proper development (Szuperak et al., 2018).

Similar to the role of adrenaline in vertebrates, the modulation of peripheral physiology in D. melanogaster, which is subject to circadian rhythms, appears to depend on OA (Schendzielorz et al., 2015). However, the role of OA in mediating the effect of the circadian clock on peripheral targets is more complex than expected, because the expression of OA receptors, such as OA2 (Octβ-1R) and OAMB (Octα-1R), cycles in cells responsible for the central clock of D. melanogaster (Kula-Eversole et al., 2010). Indeed, OA has substantial time- and light-dependent effects on the properties of parts of the central circadian clock of flies. Large lateral–ventral neurons (l-LNvs) are important parts of the central clock in D. melanogaster, and they are wake promoting. They integrate information from light and OA-containing neurons, but also from dopamine (DA)-containing neurons. OA, similar to DA, modulates the cAMP level in these cells, thereby modulating their properties substantially. The action of these two transmitters is strongly context dependent; for example, light and the clock cycle alter the modulatory effect of OA (Shang et al., 2011). The network that exists between the central clock and OA/TA production and OA/TA action is even more complex, as it was demonstrated that Tdc2, the enzyme that produces TA from tyrosine and that is also required to produce OA, is present in central clock neurons (Fig. 2). Furthermore, Huang and colleagues (2013) showed that Tdc2 cycles with a circadian rhythmicity, both at the transcript and the protein level (Huang et al., 2013).

The two monoamines OA and TA play a central role in the regulation of invertebrate metabolism. As for almost all systems and behaviours, the number of studies explicitly showing effects of TA in the control of metabolic traits is much lower than those showing effects of OA. It is still unclear whether this discrepancy reflects actual differences in the importance of the two compounds for controlling metabolism or whether this imbalance results from biased study designs that focus more strongly on OA. The effect of OA on metabolic traits seems to be in changing from a behavioural and metabolic state of rest to a state of high activity. This change affects the two most important states of metabolism: basal metabolic rate and motor activity. As a result, energy consumption increases, and the storage of energy as fat and glycogen decreases. These effects parallel quite closely those of NA and adrenaline in vertebrates. Moreover, OA increases wakefulness, which is commonly associated with an increase in metabolic activity. In addition, OA and TA directly affect energy intake. Because OA is a starvation signal, one of its major roles is to fulfil energy demands by increasing food intake. In summary, OA and TA are signalling compounds that release invertebrates from an economical resting state and direct their metabolism towards a more active state that requires more energy.

Despite the importance of metabolism for overall fitness, the impact that OA and TA have on it is understudied and certainly deserves much more attention than it has received so far. A major weakness of studies performed in this field is the exclusive focus on the two major models, the fruit fly Drosophila melanogaster and the soil nematode Caenorhabditis elegans. Thus, studies using other organisms, including representatives of the large and mostly unexplored group of lophotrochozoans, are highly appreciated; it is important to know whether specific mechanisms identified in D. melanogaster or C. elegans are of general relevance or whether they are specific for these models. In addition, some major questions in the field remain to be answered. These questions cover various facets of octopaminergic and tyraminergic neurotransmission, ranging from understanding the general organisation of these systems to determining the effects induced at particular target sites. At a higher organisational level, it is still not understood whether the corresponding systems have a hierarchical organisation or whether OA and TA are transmitters in a complex system of inter-organ communication with multiple feedback loops. How do OA/TA-containing cellular systems interact with other hormonal systems in invertebrates, and how does this interaction give rise to a concerted and expedient response of the organism? Possibly the most enigmatic issue is how octopaminergic and tyraminergic signalling systems are controlled in the animal. Are the two compounds released together or is there a differential release allowing for a differential control of the two systems? Last but not least, our understanding of the different roles of the numerous specific receptors for OA and TA is still very limited. This is especially puzzling in those systems where different receptors are expressed in the same cells. As already mentioned, studies from a variety of animals should be excellently suited to ultimately clarify these unresolved problems.

I would like to thank my group (the Department of Molecular Physiology at the University of Kiel), especially Britta Laubenstein and Christiane Sandberg for their continuous support.

Funding

The research in the laboratory was supported by the Deutsche Forschungsgemeinschaft (DFG, SFB 1182, Project C2) and the Bundesministerium für Bildung und Forschung (Project DroLuCa).

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Competing interests

The author declares no competing or financial interests.