Brain Serotonin and Energy Homeostasis

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Brain Serotonin and Energy Homeostasis

15 Pingwen Xu, Yanlin He, Yong Xu

USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States

1. INTRODUCTION Serotonin or 5-hydroxytryptamine (5-HT), a monoamine neurotransmitter, plays essential roles in the regulation of a number of behaviors including depression, anxiety, feeding, mood, learning, and memory [1]. 5-HT actions are mediated by seven 5-HT receptor (5-HTR) families, 5-HT1Re5-HT7R [2]. These 5-HTRs are either G-proteinecoupled receptors (GPCRs) or ligand-gated ion channels (LGICs), contributing to excitatory or inhibitory neurotransmissions. These receptors are expressed in both the central nervous systems (CNS) and peripheral nervous systems (PNS) and modulate the release of many other neurotransmitters including glutamate, gamma-aminobutyric acid (GABA), dopamine, epinephrine/norepinephrine, and acetylcholine. Additionally, 5-HTRs also regulate the production of many hormones, such as cortisol, prolactin, corticotrophin, and oxytocin. Because 5-HTRs are involved in the regulation of various biological and neurological processes, a variety of pharmaceutical drugs have been developed to target 5-HTRs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and empathogens [2]. The role of central 5-HT system in feeding and energy homeostasis has been studied for decades in both animals and humans. While the overall effects of enhanced serotonergic neurotransmission are to increase satiety and reduce energy intake and body weight [3,4], the detailed mechanisms for each 5-HT receptors or their downstream neurocircuits are complex and can be opposing. Development of genetic mouse models and chemogenetic/optogenenetic techniques, together with more conventional 5-HTereceptor pharmacology, have facilitated advances in understanding how the brain 5-HT system regulates feeding behavior and metabolism. In this chapter we outline (1) the roles of 5-HT receptors in the regulation of feeding behavior and energy balance, (2) 5-HTeresponsive neurocircuits that are relevant for feeding and body weight control, and (3) drugs targeting 5-HT receptors for the treatment of obesity.

Serotonin. https://doi.org/10.1016/B978-0-12-800050-2.00015-2 Copyright © 2019 Elsevier Inc. All rights reserved.

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2. SEROTONIN RECEPTORS REGULATE FEEDING BEHAVIOR AND ENERGY EXPENDITURE 5-HTRs are widely expressed throughout the CNS and divided into seven big families according to the sequence homology, intracellular effectors, and evolutionary lineage, named from 5-HT1R to 5-HT7R [2]. Beside these seven big families, another novel 5-HT receptor called pree5-HT8R was recently identified in white butterfly [5], which will not be discussed here.

2.1 5-HT1R FAMILY The 5-HT1R family is comprised of five subtypes, namely 5-HT1AR, 5-HT1BR, 5-HT1DR, 5-HT1ER, and 5-HT1FR. “5-HT1CR” was originally reported in the year 1988, but it was found to have more in common with the 5-HT2R family and was clarified as the 5-hydroxytryptamine 2C receptor (5-HT2CR). Among these 5-HT1R subtypes, 5-HT1AR and 5-HT1BR, which served as inhibitory feedback of 5-HT, were reported to regulate food intake and energy expenditure. The 5-HT1AR subtype is reported to be expressed both on the cell soma and neural terminals, whereas the 5-HT1BR subtype is expressed exclusively on neural terminals [6]. 5-HT1BRs are also present on some nonserotonergic neurons, where they could inhibit the release of other types of neurotransmitters and neuropeptides [7]. A 5-HT1AR agonist, 8-OH-DPAT, increases food intake in fed rats, without altering drinking, grooming, rearing, or locomotion behavior [8]. Interestingly, the same compound was reported to inhibit food intake in rats that have been fasted for 22 hours [8,9]. Thus, these pharmacological studies support a model in which the 5-HT1AR stimulates food intake in the fed state but prevents overeating in the fasted state. Given that hunger decreases 5-HT release whereas eating rapidly increases it [10], the biphasic actions of the 5-HT1AR are consistent with its autoreceptor properties that may regulate 5-HT release at different nutritional states in a negative-feedback fashion. However, the physiological functions of the 5-HT1AR on feeding are not fully supported by observations from genetic mouse models. While one report indicated that 5-HT1AR knockout mice show reduced food intake and fat pad mass without altering the locomotor activities [11], these phenotypes were not replicated by others [12e14]. Thus, more detailed analyses of 5-HT1AR knockout mouse models are needed to further reveal the functions of the 5-HT1AR on feeding (especially at various nutritional states) and body weight balance. A selective 5-HT1BR agonist, CP-94253, causes hypophagia in animals [15,16]. The mechanism of these effects is likely though the heteroreceptor action on nonserotonin neurons, which is different from 5-HT1AR agonists. It is further confirmed by infusion of CP-94253 into the parabrachial nucleus of the pons, which potently resulted in selective reduction of food intake [17]. Further, 5-HT1BR inhibits the orexigenic hypothalamic neurons that coexpress agouti-related peptide (AgRP) and neuropeptide Y (AgRP/NPY neurons), an action that leads to suppression of

2. Serotonin Receptors Regulate Feeding Behavior and Energy Expenditure

food intake [18]. Consistently, 5-HT1BR knockout mice show increased body weight and length [12e14]. However, 5-HT1BR knockout mice are also reported to display increased exploratory activity compared with that of wild types, without altering food intake at all stages in the behavioral satiety analysis [19]. Thus, most of early studies using pharmacology and genetic mouse models appear to support an anorexigenic role of the 5-HT1BR.

2.2 5-HT2R FAMILY The 5-HT2R family is widely expressed in the humans and animals including blood vessels, CNS, platelets, smooth muscle, etc. These receptors play important roles in the regulation of anxiety, appetite, cognition, imagination, mood, learning, and memory [20e22]. Three subtypes of 5-HTRs are the 5-HT2AR, 5-HT2BR, and 5-HT2CR. The 5-HT2AR is widely expressed throughout the CNS. It is expressed near most of the serotoninergic terminal, including prefrontal cortex, somato sensory cortex, and the olfactory tubercle. It is reported that high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex could modulate cognitive processes, working memory, and attention through enhancing glutamate release [23,24]. Activation of the 5-HT2AR in the hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin [25,26]. High fat diet feeding decreases the expression of the 5-HT2AR in hippocampus [27], suggesting a role of 5-HT2AR in the regulation of energy balance. However, neither 5-HT2AR nor 5-HT2BR knockout mice show changes in food intake and energy expenditure [28,29]. However, a recent report indicated that selective deletion of the 5-HT2BR exclusively in pro-opiomelanocortin (POMC) neurons reduces food intake and fat pad mass but does not alter locomotor activity [11,30]. Thus, the 5-HT2BR may play a role in feeding control, but these effects warrant further investigations. The 5-HT2CR is perhaps the most studied 5-HT receptor in the context of energy balance. Numerous pharmacological studies demonstrated that activation of 5-HT2CR suppresses food intake in animals [31e33]. The D-fenfluramine, a compound that stimulates 5-HT release and inhibits its reuptake, induces potent hypophagia in rats [34], and these effects of D-fenfluramine are attenuated by 5-HT2CR antagonist SB-242084 [35]. Activation of the 5-HT2CR in the arcuate nucleus of the hypothalamus (ARH) also increases expression of POMC, a gene precursor that can be cleaved into a-melanocyte stimulating hormone (a-MSH). a-MSH could act on the melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVH) neurons to induce satiety [36]. Pharmacological blockade of the 5-HT2CR increases food intake [37]. 5-HT2CR agonists also reduce locomotor activity, whereas 5-HT2CR antagonists increase locomotor activity [33,38]. Notably, a selective 5-HT2CR agonist, lorcaserin, is also reported to reduce binge-like eating behavior in mice by acting on dopamine neurons [39]. Consistent with these pharmacological observations, 5-HT2CR knockout mice show life-long hyperphagic phenotype, with increased meal size, which result in

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late-onset obesity [40,41]. 5-HT2CR knockout mice also show a delayed behavioral satiety sequence and delayed onset of resting behavior [42], suggesting the importance of role of 5-HT2CR signals in the regulation of satiety. Furthermore, mice lacking 5-HT2CR also display increased locomotor activity [43,44]. To date, the 5-HT2CR is the only serotonin receptor where genetic deficiency results in hyperphagia and obesity, indicating that it plays a crucial role in the serotonergic coordination of food intake and body weight.

2.3 5-HT3R FAMILY The 5-HT3R family belongs to the Cys-loop superfamily of LGICs and therefore its structure and function are different from all other 5-HT receptors that are GPCRs [45,46]. The 5-HT3R channels are cation-selective and mediate neuronal depolarization and excitation within the central and PNSs [47]. The 5-HT3R family has five different subtypes, namely the 5-HT3AR, 5-HT3BR, 5-HT3CR, 5-HT3DR, and 5-HT3ER [48]. Increasing evidence indicates that 5-HT3R regulates feeding behavior and energy expenditure [49e52]. However, the effect of 5-HT3Rs in feeding behavior remains controversial to a great extent. On one hand, many feeding-related neurons were reported to be regulated by 5-HT3Rs, including POMC neurons [50], catecholamine neurons [52], and AgRP/NPY neurons [51]. The 5-HT3Rs also play important roles in interacting with other feeding related peptide-mediated signaling. For example, a selective 5-HT3R antagonist, ondansetron, was reported to reduce the cholecystokinin-induced satiety and c-Fos in the dorsal medulla [53]. Furthermore, 5-HT reduces sucrose intake through 5-HT3Rs [54], whereas selective blockade of 5-HT3Rs leads to decreased satiation [55e57]. Activation of 5-HT3Rs exerts an inhibitory effect on feeding behavior in fasted mice [58]. However, the peripheral 5-HT3R agonist, 2-methyl-5-HT, was reported to have no effect on food intake in rat [59]. Furthermore, ondansetron reduces palatable food consumption in fed rats but not in fasted rats [25,56]. Therefore, the roles of 5-HT3Rs on feeding at different nutritional states may vary and these require further investigations.

2.4 5-HT4R FAMILY The 5-HT4Rs are expressed in both the peripheral and CNS to modulate the release of various neurotransmitters. It is reported to have multiple functions including feeding and mood behavior, learning and memory as well as gastrointestinal transit. Direct stimulation of 5-HT4Rs in the nucleus accumbens (NAc) reduces the physiological drive to eat and increases cocaine- and amphetamine-regulated transcript (CART) mRNA levels in fed and fasted mice [60]. Consistently, injecting a 5-HT4R antagonist or siRNA-mediated 5-HT4R knockdown into the NAc induces hyperphagia in fed mice [60]. The 5-HT4R knockout mice display attenuated stress-induced hypophagia without altering the basal food intake [61], suggesting that 5-HT4Rs are involved in stress-induced anorexia. Collectively, these results demonstrate that 5-HT4Rs play important roles in feeding behavior.

2. Serotonin Receptors Regulate Feeding Behavior and Energy Expenditure

2.5 5-HT5R FAMILY The 5-HT5R family is probably the least understood among all 5-HTR families. There are two subtypes, the 5-HT5AR and 5-HT5BR. The initial 5-HT5AR cDNA sequence was generated from a mouse brain library using degenerate oligo-nucleotides [62] corresponding to the regions encoding the highly conserved putative transmembrane domains III and VI of metabotropic 5-HTRs [63]. Subsequently, another related receptor, 5-HT5BR, was reported by the same group, again derived from a mouse brain cDNA library [64]. Both the rat 5-HT5AR and 5-HT5BR were also identified by other researchers [65,66] using cDNA libraries derived from brain tissue, whereas report of the human 5-HT5AR sequence followed shortly after [67]. The mice lacking the 5-HT5AR display increased locomotor activity and exploratory behavior compared with wild-type animals [68,69], although this did not manifest as a difference in the anxiety-like behavior of these animals in the elevated plus maze [70].

2.6 5-HT6R FAMILY The 5-HT6R was cloned from striatal tissue by two groups following identification of a cDNA sequence that encodes a 5-HTesensitive receptor with a novel pharmacological properties [71,72]. The rat 5-HT6R gene encodes a protein of 438 amino acids and shares around 89% homology to the human 5-HT6R [72]. It is exclusively expressed in multiple brain regions including the ARH, the ventromedial nucleus of the hypothalamus (VMH), the PVH, and the nucleus of the solitary tract (NTS) [73]. The 5-HT6R has been implicated in obesity [74], epilepsy, anxiety, and depression [75]. A 5-HT6R antagonist, SB-399885, induces hypophagia through activation of PVH and NTS neurons [76]. In addition, 5-HT6R antagonists reduce food intake [74,77,78] and intracerebroventricular (i.c.v.) administration of a 5-HT6R antisense oligo-nucleotide reduces food intake [78]. Although 5-HT6R knockout mice showed normal food intake when fed on regular chow diet [79], these mice are hypophagic and resistant to diet-induced obesity when exposed to a high fat diet [80]. Thus, the 5-HT6R produces orexigenic signals to promote body weight gain.

2.7 5-HT7R FAMILY The 5-HT7R is the most recently identified 5-HTR [81,82]. 5-HT7R cDNAs have now been identified from a number of species (e.g., Xenopus laevis, mouse, rat, guinea pig, human) [71,72]. The 5-HT7R is a Gs-coupled receptor and is highly expressed in many human tissues, including the brain, the gastrointestinal tract, and the various blood vessels [72]. The 5-HT7R is most abundant in the thalamus and hypothalamus. It is reported to be involved in the regulation of animal thermoregulation, circadian rhythm, learning and memory, and sleep. 5-HT7R knockout mice exhibit normal body weight [83]. No alternations in food intake have been reported from this knockout mouse. However, the 5-HT7R has been implicated in regulating feeding motivation and satiety processes through its actions in the striatum [84].

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3. NEUROANATOMY OF SEROTONIN CIRCUITS WITH RELEVANCE TO ENERGY HOMEOSTASIS Serotonergic cell bodies are mainly located in the midbrain raphe nuclei, which received afferent signals from many parts of the forebrain and brain stem and project to almost all regions of the forebrain and brain stem [85e88]. Serotonin neurons play an important role in integrating and transmitting signals to brain regions implicated in the regulation of energy balance, including both hypothalamic centers and extrahypothalamic structures (Figure 15.1). Within the hypothalamus, a significant amount of research has been focused on the arcuate nucleus of the hypothalamus (ARH) and the paraventricular nucleus of the hypothalamus (PVH) nucleus of the hypothalamus and the lateral hypothalamic area (LHA). Several other extrahypothalamic regions including parabrachial nucleus (PBN), NTS, and ventral tegmental area (VTA) have also been shown to participate in serotonergic control of energy balance.

3.1 HYPOTHALAMIC SEROTONIN CIRCUITS 3.1.1 Arcuate Nucleus of the Hypothalamus There are at least two distinct neural populations in the ARH that are essential for the regulation of energy balance and body weight control. One population of neurons, which express the melanocortin precursor POMC and CART, suppress food intake and increase energy expenditure through downstream projecting sites including PVH, VMH, LHA, and sympathetic preganglionic neurons in spinal cord [89e91]. On the other hand, another population of neurons, which express AgRP

FIGURE 15.1 5-HTeresponsive neurocircuits relevant in energy homeostasis. This figure shows representative fibers indicating major serotonergic pathways contributing to body weight regulation. Different colors represent different serotonergic cell groups. ARH, arcuate nucleus of the hypothalamus; CRN, caudal raphe nuclei; DRN, dorsal raphe nucleus; LHA, lateral hypothalamic area; MRN, median raphe nucleus; NTS, nucleus of the solitary tract; PBN, parabrachial nucleus; PVH, paraventricular nucleus of the hypothalamus; SN, substantia nigra; VTA, ventral tegmental area.

3. Neuroanatomy of Serotonin Circuits

and NPY, increase food intake and inhibit energy expenditure through projections to PVH, LHA, the PBN [92e94]. Both AgRP, an antagonist for endogenous melanocortin receptors (MCRs) and POMC, a MCRs agonist precursor, are involved in serotonergic control of feeding and energy balance. A subpopulation of ARH POMC neurons express 5-HT2CR and can be activated by serotonin augmentation with D-fenfluramine or mCPP, a combined 5-HT2CR and 5-HT1BR agonist via the putative transient receptor potential C channels [36,95,96]. Conversely, a subpopulation of ARH AgRP neurons express 5-HT1BRs and can be inhibited by serotonin and 5-HT1BR agonist [18]. Thus, serotonin appears to reciprocally activate POMC neurons and inhibit AgRP neurons to stimulate melanocortin circuits, which in return decreases food intake. The essential role of melanocortin system in anorexigenic effects of serotonin is further supported by the evidence that the inactivation of melanocortin circuits in mice by either pharmacological pretreatment with MCR antagonist or genetic deletion of MC4R diminished the anorexigenic effects of D-fenfluramine and mCPP [18,95]. 5-HT2CR expressed by POMC neurons is essential for serotonin’s effects on energy balance. Recent studies utilized transgenic strategies to specifically delete or reexpress 5-HT2CR in POMC neurons. In particular, global deletion of 5-HT2CR leads to hyperphagia, diet-induced obesity, and attenuated anorexigenic response to serotonergic drugs, whereas selective reexpression of 5-HT2CR only in the POMC neurons is sufficient to rescue these metabolic syndrome [44]. One the other hand, 5-HT2CR loss in POMC neurons during an embryonic stage or adulthood led to diet-induced obesity and insensitivity to the anorectic effects of serotonin agonists, similar to those observed in the mice globally lacking 5-HT2CR [97]. These data indicate that 5-HT2CR on POMC neurons is required and sufficient to mediate 5-HT2CR effects on energy balance. 5-HT1BR expressed by AgRP neurons have also been implicated in the serotonergic inhibition of feeding. AgRP neurons produce three different neurotransmitters, inducing AgRP, an endogenous MC4R and MC3R antagonist, NPY, and GABA [98]. Both NPY and GABA released by AgRP neurons provide local inhibitory inputs to POMC neurons in the ARH [89]. 5-HT1BR is a Gi-coupled autoreceptor, which inhibits adenylyl cyclase and hyperpolarize neurons to reduce the release of neurotransmitters [18]. It has been shown that 5-HT1BR agonists reduce food intake and produces satiety [15]. Heisler and colleagues provided evidence that the anorexigenic effects of 5-HT1BR agonists involve both AgRP and POMC neurons: 5-HT1BR expressed by AgRP neurons acts as an autoreceptor to directly inhibit orexigenic AgRP neurons or indirectly activates POMC neurons by suppressing the inhibitory inputs from AgRP to POMC neurons [18]. Unlike anorexigenic 5-HTR2CR and 5-HTR1BR, another serotonin receptors 5-HT1AR may promote feeding through POMC mechanism. The agonists of 5-HT1AR promote feeding whereas antagonists inhibit feeding [99e101]. Mice lacking 5-HT1AR specifically in POMC neurons showed hypophagia that led to decreased body weight at 6 months of age [102], indicating that serotonin acts through 5-HT1AR expressed by POMC neurons to promote feeding. Because 5-HT1AR is

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known as an inhibitory autorecetpor, the hypophagia phenotype is likely attributed to the reduced inhibitory serotonergic tone to postsynaptic POMC neurons. Thus, stimulatory 5-HT2CR and inhibitory 5-HT1AR provide a coordinated and complementary serotonergic control of POMC circuits. What is puzzling is 5-HT2BR, a Gq-coupled and excitatory receptor such as 5-HT2CR. Selective deletion of 5-HT2BR in POMC neurons decreased food intake and fat mass, which associated with increased hypothalamic mRNA expression of MC4R [11]. These results support a model in which 5-HT2BR promotes feeding through POMC neurons, a well-established anorexigenic neural modulator. Except the ARH in the brain, POMC is also expressed in peripheral tissues, such as cardiomyocytes in heart, and inactivation of 5-HT2BR gene decreased survival and proliferation of cardiomyocytes and led to impaired cardiac development [103]. This raises the possibility that the loss of 5-HT2BR in peripheral POMC cells contributes to the decreased body weight observed in the POMC-specific deletion model. Another possibility is that 5-HT2BR activates POMC neurons to release the opioid peptide b-endorphin, another POMC-derived peptide. A previously unsuspected role of POMC neurons in promoting feeding has been recently identified by Horvath and his group [104]. It has been demonstrated that b-endorphin produces orexigenic effects and cannabinoids activates POMC neurons to increase release of b-endorphin, which in return promotes feeding [104]. So it is possible that 5-HT2BR promotes feeding through stimulating POMC neurons to increase b-endorphin release.

3.1.2 Paraventricular Nucleus of the Hypothalamus Aside from the ARH, PVH also receives serotonergic innervation from dorsal and median raphe nuclei [86]. Early indications of serotonergic regulation of energy balance through PVH came from pharmacological studies. Site-specific injection of serotonin into the PVH decreased food intake by suppressing meal size and frequency [105,106]. Later studies more specifically identified corticotropinreleasing hormone (CRH), an anorectic neuropeptide, as one of the mediators for serotonergic control of energy balance in the PVH. For example, PVH CRH neurons receive direct serotonergic innervation [107] and can be activated by serotonin drugs [108,109]. Consistent with these, the mRNA levels of CRH in the PVH were increased by D-fenfluramine treatment and decreased by global deletion of 5-HT2CR [110]. Importantly, the anorexigenic effects of serotonin drugs were blocked by pretreatment with an anti-CRH antibody, suggesting a physiological role of CRH in serotonergic regulation of feeding [111]. Besides the direct stimulatory effects on CRH neurons, serotonin may also indirectly activated CRH through a melanocortin-dependent mechanism. PVH CRH neurons express MC4R and are activated by the agonists of MCRs [112]. Considering the regulatory effects of serotonin on AgRP and POMC neurons [18,44,97], which project to PVH and release MC4R-binding neuropeptides, it is likely that serotonin acts through AgRP and POMC neurons to stimulate PVH CRH neurons in a MC4R-dependent mechanism. Oxytocin, another neuropeptide produced in the PVH neurons, is also involved in the regulatory effects of serotonin on energy balance. Besides the role in female

3. Neuroanatomy of Serotonin Circuits

reproduction, oxytocin has been reported to decrease food intake via projections to dorsal vagal complex [113,114]. The treatment of serotonin drugs including D-fenfluramine and 5-HTRs agonists stimulate oxytocin neurons and increase the release of oxytocin [115e117]. Similar to CRH neurons in the PVH, the stimulatory effects of serotonin on oxytocin neurons may involve indirect mechanisms. For example, a-MSH, an endogenous MC4R agonist, activates PVH oxytocin neurons and increases dendritic oxytocin release [118] whereas MARLON-0004, a selective MC4R antagonist, inhibits PVH oxytocin neurons [119]. Considering the stimulatory effects of serotonin on a-MSH release, it is likely that serotonergic control of oxytocin is secondary to the activation of melanocortin circuits.

3.1.3 Lateral Hypothalamic Area LHA is well-recognized as a control center for reward and feeding, which integrates diverse information arising from ARH, cortical, amygdala networks to generate a motivated feeding behavior via LHA projection sites, such as NAc, VTA, and PBN [120e122]. Serotonin may influence energy balance through direct effects at LHA. For example, LHA receives serotonergic innervation from dorsal or median raphe nuclei [123] and has a high expression level of 5-HT2CR and 5-HT1AR [124]. Importantly, a subgroup of LHA neurons expressing orexin, an orexigenic neuropeptide, is hyperpolarized and inhibited by serotonin through the 5-HT1ARemediated mechanism [125]. One the other hand, the LHA also receives direct projections from ARH AgRP and POMC neurons [126], and photostimulation of AgRP neuronal projections to the LHA promotes feeding [94]. These suggest another possibility that serotonin may exert negative and indirect effects on LHA neurons through ARH AgRP and POMC neurons.

3.2 EXTRAHYPOTHALAMIC SEROTONIN CIRCUITS 3.2.1 Brain Stem While substantial efforts have been made to understand how serotonergic circuits in the hypothalamus regulate energy homeostasis, some additional extrahypothalamic brain sites also appear to be involved in serotonergic control of body weight. Back in the late 20th, Kaplan et al. first indicated an important role of serotonergic inputs to brain stem in feeding control. When injected into the fourth ventricle, mCPP, an agonist of 5-HTRs inhibits feeding whereas an antagonist of 5-HTRs applied into the fourth ventricle blocks the anorexigenic effects of systemic mCPP injection [127]. Within the brain stem, two distinct nuclei, NTS and PBN, have been shown to mediate the regulatory effects of serotonin on energy homeostasis regulation. The NTS, the primary relay center receiving visceral gastrointestinal information, is innervated by the caudal serotonin neurons and systemic mCPP treatment activates NTS neurons releasing catecholamine, known as a neuromodulator for feeding [128,129]. Additionally, blockade of 5-HT3R signaling in the NTS increases food intake and protests against starvation induced by inactivation of AgRP neurons [51], suggesting a physiological role of NTS serotonergic tone in feeding control.

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The PBN is another brain stem nucleus particularly relevant to the regulation of feeding and energy balance [51,130,131] and received direct innervation from serotonin neurons in the dorsal raphe [123]. Both 5-HT2CR and 5-HT1BR are expressed in the PBN [132,133] and the 5-HT1BR agonist infused into the PBN decreases food intake whereas the 5-HT1BR antagonist applied into the PBN diminishes the anorexigenic effects of systemic D-fenfluramine injection [134], suggesting a direct serotonergic control of PBN neurons. Besides direct effects on the PBN, serotonin also modulates feeding through the NTS / PBN brain circuits. Recent optogenetic results revealed that NTS neurons directly engage PBN neurons to promote anorexia [135]. More specifically, caudal serotonergic neurons stimulate NTS glutamatergic neurons to increase glutamate release, which in return increases the excitability of PBN neurons to inhibit feeding [51].

3.2.2 Ventral Tegmental Area Another extrahypothalamic effect of serotonin occurs through midbrain structure, VTA and substantia nigra (SN), known as dopamine (DA) centers. Dopamine is a neurotransmitter controlling reward-motivated behaviors, including feeding. The first evidence for interaction between serotonin and dopamine system came from neuroanatomical studies. The presence of 5-HTecontaining nerve fibers were first identified in VTA and SN in the early 1960s [136] and the monosynaptic inputs from dorsal and medial raphes serotonin neurons to VTA and SN were further confirmed by monosynaptic rabiesetracing method [137]. Additionally, high expression levels of 5-HT1BR, 5-HT2AR, 5-HT2CR, and 5-HT3R are present in the VTA and SN [138e141] and VTA-specific perfusion with a 5-HT3R agonist or serotonin increases dopamine (DA) release in the VTA or accumbens [142, 143]. Recently electrophysiological evidence showed that a selective 5-HT2C agonist activates VTA dopamine neurons via 5-HT2Cemediated mechanisms [39]. Notably, activation of serotonin to VTA dopamine neural circuit effectively suppresses binge-like eating, suggesting a role of VTA 5-HT2CR in the control of feeding [39]. This point of view is further supported by the evidence generated from mouse models with 5-HT2CR specifically manipulated in dopamine neurons. The inhibitory effects of serotonin drugs on binge-like eating are blocked in the mice lacking 5-HT2CR globally or specifically in dopamine neurons, whereas reexpression of 5-HT2CR selectively in dopamine neurons in a 5-HT2CR null background rescues the inhibition on binge-like eating [39].

4. SEROTONIN DRUGS AND OBESITY The impotency of serotonin system in energy hemostasis regulation is reflected by its corresponding fluctuation with different nutritional status. For example, long-term malnutrition is associated with a significant reduction in serotonin levels in several areas of the brain [144], whereas short-term food deprivation increases serotonin turnover in almost all brain areas [145,146] and reduces serotonin-responding neurons in the VMH [147], suggesting alterations in

4. Serotonin Drugs and Obesity

5-HTRs expression. Plasma serotonin decreased significantly in high fat diet-induced obese mice and obese Zucker rats [148,149], indicating an impaired serotonin system. Human clinical studies also demonstrated that hypocaloric diet decreases plasma levels of serotonin precursor, tryptophan [150]. Additionally, moderate dieting causes 5-HT2CR supersensitization, indicating a decline in the actual serotonin ligand [151]. Hence, serotonin-mediated actions in the brain are highly relevant to body weight control and energy homeostasis and several serotonin-based compounds have been clinically used as antiobesity medicine.

4.1 FENFLURAMINE AND DEXFENFLURAMINE Fenfluramine is a selective serotonin reuptake inhibitor (SSRI), which increases serotonin content in the brain’s synapses to decrease caloric intake. Anorexia and weight loss induced by fenfluramine have been demonstrated in numerous early therapeutic trials [152]. Despite the variation in the duration of the trial, the target population, the dose of fenfluramine and the additional dietary advice, a robust clinical effect has been shown [152]. It was approved by FDA in 1973 to be used as an anorecitc drug. When combined with a norepinephrine stimulant, phentermine, it became part of the antiobesity medication Fen-phen. The former brand names for fenfluramine include Pondimin, Ponderax, and Adifax. After more than 20 years of circulation, fenfluramine was withdrawn from the US market in 1997 after severa adverse side effects were reported. The main side effects of fenfluramine are cardiovascular complications, including heart valve disease, pulmonary hypertension, and cardiac fibrosis [153,154], which may be caused by the serotonin-mediated actions on heart valve 5-HTRs. Similarly, dexfenfluramine, the active isomer of fenfluramine, was approved by FDA in the mid-1990s for the purpose of weight loss and withdrawn in 1997 following the same concerns about the cardiovascular side effects as fenfluramine [155].

4.2 FLUOXETINE Another member of SSRI family, fluoxetine or commercially called Prozac, which was originally approved by FDA in 1987 for treatment of depression, also showed robust inhibitory effects on food intake and body weight gain. Rodent studies first demonstrated that chronic administration of fluoxetine reduced chow intake and body weight throughout the treatment period in normal rats [156] whereas only showed transient beneficial effects on feeding and weight gain in ob/ob mice [157]. Similarly, clinical trials also found significant decreases in food intake and body weight after chronic treatment with fluoxetine in healthy male subjects [158e160], whereas body weight was decreased during the first few weeks but subsequently regained during fluoxetine maintenance in obese individuals [161]. Based on the anorexigenic and antidepression effects of fluoxetine, it has been used to treat bulimia nervosa, binge eating disorder, obesity, and depression [162,163]. Fluoxetine treatment is often associated with multiple side effects, such as anxiety, dizziness, mania, seizures [164e166].

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4.3 SIBUTRAMINE After fenfluramine and dexfenfluramine were removed from US market, sibutramine, a centrally acting serotoninenorepinephrine reuptake inhibitor, was approved by FDA as an adjunct in the treatment of exogenous obesity along with diet and exercise. Evidence from both basic and clinical studies demonstrated sibutramine treatment induces robust reduction in food intake and body weight [167e173]. Although initially considered as a safer alternative to both fenfluramine and dexfenfluramine, sibutramine was likewise withdrawn from US market because of the concerns on increased risk of heart attacks and strokes in 2010 [174].

4.4 MCPP mCPP, generally considered as a psychoactive drug, was initially developed in the late 1970s for scientific research as an agonist for 5-HTRs [175]. mCPP is still not approved at the federal level in the United States, but it has been sold as a designer drug mimicking the pharmacological effects of another psychoactive drug, benzylpiperazine, in the mid-2000s [175]. Although mCPP binds to most serotonin receptors, including 5-HT1AR, 5-HT1BR, 5-HT1DR, 5-HT2AR, 5-HT2BR, 5-HT2CR, 5-HT3R, and 5-HT7R [175,176], its discriminative cue is primarily mediated by 5-HT2CR [177]. As expected, as a preferential agonist for 5-HT2CR, mCPP long-term treatment has been shown to reduce body weight in both rat [178,179] and obese patients [180]. mCPP also acts through other 5-HTRs to generate negative side effects such as anxiety, headaches, psychedelic effects, and nausea [181,182].

4.5 LORCASERIN To produce more potent antiobesity effects and avoid main side effects of mCPP, a selective 5-HT2CR agonist, lorcaserin, or commercially called Belviq, was recently developed as a weight-loss drug in an addition to a reduced-calorie diet and exercise for chronic weight management [183]. Although other agonist properties at 5-HT1A and 5-HT2A were found [184], lorcaserin showed reasonable selectivity for 5-HT2CR over other 5-HTRs [183]. The efficacy and safety of lorcaserin for weight loss in obese patients have been confirmed in different clinical trials and lorcaserin was found to reduce body weight primarily through decreasing energy intake but not energy expenditure or respiratory quotient [185e188]. The high selectivity of lorcaserin reduces patient risk for serious adverse cardiovascular complications, which were associated with nonselective 5-HT agonist medicines, such as fenfluramine or sibutramine [189]. On June 27, 2012, the FDA officially approved lorcaserin as an antiobesity drug for adults with body mass index (BMI)  30 or adults with BMI  27 having high blood pressure, type 2 diabetes, or high cholesterol [190].

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5. CONCLUSIONS While the brain 5-HT system has an overall inhibitory effects on feeding behavior, the detailed neurobiological mechanisms for 5-HT actions are quite complex. As we discussed above, numerous 5-HTRs show potential effects on the regulation of food intake, energy expenditure, and/or physical activity, which may produce physiologically relevant effects on body weight balance. However, their effects are not always in concert with each other, with some 5-HTRs (e.g., 5-HT1BR and 5-HT2CR) being anorexigenic, while some others (e.g., 5-HT6R) being orexigenic. In addition, effects of the same 5-HTR could vary depending on various nutritional states (satiated or fasted) and/or diets (chow or high fat diet). The complexity also stems from the intermingled neurocircuits downstream of 5-HT neurons, which spread throughout the brain. However, the brain 5-HT system carries a great deal of therapeutic potentials for human diseases, including obesity. This is highlighted by a few effective antiobesity regimens, including D-fenfluramine and more recently, lorcaserin. Thus, we suggest that continuous research to unravel the complex 5-HTRs actions and the 5-HTeresponsive neurocircuits in the context of feeding and body weight control may lead to development new antiobesity therapies.

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