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Serotonin, food intake, and obesity

Summary The role of serotonin in food intake has been studied for decades. Food intake is mainly regulated by two brain circuitries: (i) the homeostatic circuitry, which matches energy intake to energy expenditure, and (ii) the hedonic circuitry, which is involved in rewarding and motivational aspects of energy consumption. In the homeostatic circuitry, serotonergic signaling contributes to the integration of metabolic signals that convey the body's energy status and facilitates the ability to suppress food intake when homeostatic needs have been met. In the hedonic circuitry, serotonergic signaling may reduce reward‐related, motivational food consumption. In contrast, peripherally acting serotonin promotes energy absorption and storage. Disturbed serotonergic signaling is associated with obesity, emphasizing the importance to understand the role of serotonergic signaling in food intake. However, unraveling the serotonin‐mediated regulation of food intake is complex, as the effects of serotonergic signaling in different brain regions depend on the regional expression of serotonin receptor subtypes and downstream effects via connections to other brain regions. We therefore provide an overview of the effects of serotonergic signaling in brain regions of the homeostatic and hedonic regulatory systems on food intake. Furthermore, we discuss the disturbances in serotonergic signaling in obesity and its potential therapeutic implications.


Summary
The role of serotonin in food intake has been studied for decades. Food intake is mainly regulated by two brain circuitries: (i) the homeostatic circuitry, which matches energy intake to energy expenditure, and (ii) the hedonic circuitry, which is involved in rewarding and motivational aspects of energy consumption. In the homeostatic circuitry, serotonergic signaling contributes to the integration of metabolic signals that convey the body's energy status and facilitates the ability to suppress food intake when homeostatic needs have been met. In the hedonic circuitry, serotonergic signaling may reduce reward-related, motivational food consumption. In contrast, peripherally acting serotonin promotes energy absorption and storage. Disturbed serotonergic signaling is associated with obesity, emphasizing the importance to understand the role of serotonergic signaling in food intake. However, unraveling the serotonin-mediated regulation of food intake is complex, as the effects of serotonergic signaling in different brain regions depend on the regional expression of serotonin receptor subtypes and downstream effects via connections to other brain regions.
We therefore provide an overview of the effects of serotonergic signaling in brain regions of the homeostatic and hedonic regulatory systems on food intake. Furthermore, we discuss the disturbances in serotonergic signaling in obesity and its potential therapeutic implications. reproduction. An energy deficit is counteracted by an increase in food intake, a behavioral response that is orchestrated by the brain. Studies in the early 20th century showed that hypothalamic lesions in rats exerted region-specific effects on food intake, either resulting in obesity or severe anorexia that ultimately led to death. [1][2][3][4] These findings pointed to an important role for the hypothalamus in the regulation of food intake. Since then, decades of basic and clinical research have Abbreviations: 5-HT, 5-hydroxytryptamine; AgRP, agouti-related protein; ARC, arcuate nucleus; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; BMI, body mass index; CCK, resulted in the identification of complex neuronal networks that are involved in the regulation of food intake and body weight.
Briefly, two major pathways regulate feeding behavior: the hedonic or reward pathway and the homeostatic pathway. Hedonic pathways are mainly located in the corticolimbic areas, and homeostatic pathways include the hypothalamus and brainstem. The main roles for the hedonic system are to promote food-seeking behavior and signal reward after a meal; the homeostatic pathways integrate metabolic feedback about energy stores into an appropriate feeding response and adjustment in energy expenditure. Multiple neurotransmitters, including gamma-aminobutyric acid (GABA), glutamate, acetylcholine, dopamine, and serotonin (5-hydroxytryptamine ), are involved in these processes. With the discovery of leptin, an adipose tissue-secreted neuroendocrine hormone that increases in parallel with adipose mass and adipocyte size, it became clear that metabolic signals from the body directly modulate neuronal cell activity and influence food intake. 5 In addition to leptin, energy deficit and surplus are signaled to the brain by hormones, substrates, and afferent input from organs involved in nutrient processing. The constellation of metabolic signals that reflect the body's energy state is complex. In terms of substrates, during fasting, glucose levels drop, and free fatty acids (FFAs) and ketone bodies increase. 6 This is accompanied by low insulin and leptin levels and increased glucagon, growth hormone, and catecholamines. 7,8 Also, gastrointestinal hormone levels are low in the fasting state, except for ghrelin, which signals hunger and is secreted by the stomach. 9 The metabolic signature of fasting thus provides the brain with feedback to restore energy levels by food-seeking behavior and increasing food intake. An opposite response occurs in the satiated and energy-sufficient state.
Given the current obesity epidemic, it has become apparent that central body weight regulation can be-and often is-overruled, and resistance to metabolic feedback likely underlies this phenomenon. In that regard, much attention has been given to leptin resistance, because humans with obesity are characterized by high leptin levels, but do not decrease food intake. 10,11 Resistance to other metabolic signals that reflect the energy state has also been studied intensively. Overall, it has been shown that reward and homeostatic pathways are altered in individuals with obesity, with multiple effectors and neuronal pathways involved. [12][13][14] This review will focus on the role of the neurotransmitter serotonin in the regulation of food intake and development of obesity.

| SEROTONIN SIGNALING AFFECTS EATING BEHAVIOR
Several lines of evidence support a role for serotonin signaling in the regulation of eating behavior and long-term body weight. Firstly, the experimental modulation of multiple serotonin receptor subtypes has been shown to affect food intake and/or body weight regulation in animal models. The subtype-specific effects of receptor knockout, agonism, or antagonism are summarized in Table 1 16 Fourthly, treatment with antidepressants, including the selective serotonin reuptake inhibitors (SSRIs), affects food intake in both animals and humans, and a recent meta-analysis showed that these therapies are associated with increased risk of weight gain over 10-year follow-up. 17 Finally, several novel weight loss drugs selectively influence the serotonin system. 18,19 Notably, the serotonin system spans across the central and peripheral nervous system, and the central and peripheral components have opposing effects on energy homeostasis. [20][21][22] Overall, central serotonergic signaling is anorexigenic, and it increases energy expenditure via the stimulation of thermogenesis in brown adipose tissue. 21,23 In contrast, peripheral serotonergic signaling promotes energy absorption and storage; peripheral effects may account for the SSRIassociated increase in body weight. 22 For in-depth discussions of the role of peripheral serotonergic signaling in energy homeostasis, we refer to the available literature. 22 In the following sections, we will discuss the (neuro)anatomy and physiology of central serotonin-mediated regulation of food intake as well as its role in obesity development.

| FUNCTIONAL ORGANIZATION OF SEROTONERGIC SIGNALING IN EATING BEHAVIOR
Eating behavior is regulated by a complex, partially elucidated interplay between numerous brain regions, neurotransmitters, neuropeptides, and peripheral input and effectors. To understand the physiological mechanisms by which serotonin signaling influences energy intake, we first need to provide an overview of the involved brain circuits.
Food intake can be driven by homeostatic and/or hedonic stimuli.
The homeostatic regulatory circuit aims to match energy intake to energy expenditure in order to maintain a stable energy balance and body weight. In contrast, the hedonic motivation for food intake is driven by the reward circuit. In times of body energy depletion, these regulatory systems work synergistically to increase the likelihood of food consumption. Evolutionarily, a high motivational drive for food is beneficial, because this increases the chance to survive and reproduce during times of scarcity. Nowadays, obesity is thought to develop when the hedonic drive overrides the homeostatic regulation and when the homeostatic system is resistant to metabolic feedback, thereby promoting the consumption of food beyond nutritional needs.
Therefore, in the modern obesogenic environment, where high-energy nutrients are readily available, a strong hedonic drive for food has become a disadvantage.
Serotonin signaling is involved in multiple brain regions that play a role in the homeostatic and hedonic circuits of food intake regula- tion. An overview of the brain regions and their proposed functions in serotonin-mediated regulation of feeding behavior is provided in Table 2. A schematic overview of the interconnections between these brain regions is presented in Figure 1.

| Serotonin signaling in the homeostatic circuitry
Failure to appropriately suppress food intake when body energy stores are sufficient results in the (over)consumption of food beyond nutritional needs and, subsequently, weight gain. Decreased serotonin signaling in the homeostatic circuit has been suggested to contribute to this pathophysiological state. 58 In fact, due to its assumed role in obesity development, serotonin and the homeostatic regulation of food intake have been extensively studied over the past decades. We note, however, that this functional circuit involves multiple neurotransmitters across multiple brain regions.
The hypothalamus and brainstem are considered the primary brain regions of the homeostatic regulation of food intake. 21 In these key regions, central and peripheral inputs on hunger, satiety, and whole-body nutrient availability are integrated in order to adequately adapt subsequent feeding behavior to the present nutritional state.

| Raphe nuclei
Almost all ascending serotonergic projections involved in nutritional homeostasis originate from the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN). 59 The activity of serotonergic neurons in the DRN increases directly after food intake, whereas the activity of serotonergic neurons in the MRN does not. This suggests that the DRN is specifically involved in postprandial satiation signaling. 60 In contrast, MRN serotonergic neurons may be involved in the motivational control of eating behavior, because these project to several brain regions in the reward system. 61 The DRN and MRN, sometimes referred to as the rostral caudate nuclei, contain the majority of central serotonergic neurons; much smaller, the caudal raphe nuclei, including the raphe pallidus, the raphe magnus, and raphe obscurus nuclei, are also activated under satiated conditions. 62 Serotonergic projections from the latter nuclei project to the NTS and contribute to the suppression of food intake. 63 Raphe nuclei serotonergic neurons are under regulatory control of central and peripheral input. Prominent projections to the DRN and MRN include pathways from the hypothalamus, prefrontal cortex (PFC), amygdala, ventral tegmental area (VTA), and the basal ganglia, which include the striatum, globus pallidus, and substantia nigra. 64 The caudal raphe nuclei receive innervation from the amygdala and hypothalamic nuclei. 65 These connections likely enable higher brain functions to influence the sensitivity of homeostatic control. In addition, peripheral input on the body's nutritional state van GALEN ET AL.
is integrated with the serotonin system within the raphe nuclei. 66 The gastrointestinal hormones cholecystokinin (CCK) and glucagonlike peptide 1 (GLP1) are secreted from the gastrointestinal tract in response to nutrient ingestion. These hormones stimulate serotonergic neurons in the DRN and mediate anorexigenic effects. 67,68 In contrast, ghrelin is secreted from the stomach during fasting and stimulates food intake; it may also interact with serotonin receptors in the DRN. 69 Finally, there is also evidence that serotonin signaling toward the DRN may be involved in food intake regulation: experimental administration of serotonin or SSRI to the DRN stimulates food intake in rats, presumably via the activation of inhibitory autoreceptors on DRN serotonergic neurons in the homeostatic circuit. 70

| Arcuate nucleus and nucleus tractus solitarius
The ARC in the hypothalamus and NTS in the brainstem are among those brain regions that receive serotonergic projections from the DRN. The ARC is in close proximity to the third ventricle and has a leaky blood-brain barrier (BBB). It is optimally equipped to read out T A B L E 2 Overview of brain regions involved in the serotonergic modulation of feeding behavior Leptin also stimulates POMC ARC . 80 The AgRP/NPY neurons in the ARC mediate an opposite, orexigenic effect via a dual mechanism. Firstly, activation of AgRP/NPY neurons promotes the release of AgRP, which is a direct antagonist of the melanocortin pathway. 35

| Paraventricular nucleus
Lesions to the hypothalamic PVN result in hyperphagia and obesity, suggesting an important role for this nucleus in the regulation of food intake and energy homeostasis. 82

| Ventral medial nucleus
The VMN was once regarded as the "satiety center" of the hypothalamus: an early study found that destruction of this hypothalamic nucleus resulted in voracious eating behavior. 91 This was later refuted: lesions restricted to the VMN were neither sufficient nor necessary for hyperphagia, and the previously observed effect was attributed to damage outside of the VMN. 92 More recent studies have attributed specific functions related to nutritional homeostasis, thereby "resurrecting" interest in this region. 93 One neuronal population of interest expresses steroidogenic factor 1 (SF-1). 94 These neurons are exclusively found in the VMN, express the 5-HT 2C receptor, and are directly targeted by serotonergic projections from the brainstem. 24,94 However, SF-1 neurons seem to primarily contribute to energy homeostasis by modulating energy expenditure and glucose homeostasis (rather than energy intake). 94 The VMN also receives POMC ARC and AgRP/NPY neuronal projections from the ARC. 95 Here, POMC ARC are believed to activate VMN brain-derived neurotrophic factor (BDNF)-expressing neurons via the MC 4 R. 95 Administration of BDNF to the VMN decreases food intake and body weight, and this effect was most pronounced for NPYinduced feeding. 96 Finally, direct VMN administration of serotonin selectively reduces carbohydrate preference, 97 whereas direct administration of a 5-HT 1B/2C receptor agonist reduces overall food intake. 36 It is likely that other and/or more specific functions of the VMN have yet to be discovered.

| Dorsomedial nucleus
Although lesion studies strongly support a role for the DMN in feeding, drinking, and body weight regulation, 98  nuclei serotonergic neurons also project to the LHA, 103 and extracellular serotonin levels in the LHA increase upon food intake. 104 Notably, serotonin inhibits orexin neurons, 105,106 an LHA-exclusive neuronal population that promotes reward-related behavior and arousal. 107 Orexin neurons are involved in hedonically motivated feeding. [108][109][110][111] The effect on energy homeostasis seems to be context specific, that is, under hypoglycemic conditions, activation of orexin neurons increases short-term food intake, 112,113 whereas under (longterm) high-fat diet conditions, the activation of orexin neurons may actually protect against diet-induced weight gain by enhancing spontaneous physical activity. 114 Orexin neurons express several serotonin receptor subtypes, 115 but blocking the 5-HT 1A receptor is sufficient to completely negate serotonin-mediated inhibition of orexin neurons. 106 Orexin neurons, in turn, activate serotonergic neurons in the DRN and may thus partake in a complex negative feedback loop within the homeostatic circuit. 116 Another neuronal population in the LHA expresses melanin-concentrating hormone (MCH). Intracerebroventricular MCH injections increase food intake, 117 whereas MCH receptor antagonists reduce food intake and may even cause weight loss. 118 Serotonin hyperpolarizes MCH neurons, thereby desensitizing this mechanism. 119

| Parabrachial nucleus
This brainstem nucleus consists of several subpopulations of neurons that relay sensory information to other forebrain structures. 120 Interest in the role of the PBN in nutritional homeostasis was first stirred following the observations that dexfenfluramine, an indirect serotonin agonist, increased c-Fos immunoreactivity in the lateral PBN 121 and bilateral PBN lesions attenuated dexfenfluramine-induced anorexia. 122 The 5-HT 2C receptor is required for the anorexic effects of dexfenfluramine. 123 In addition, infusion of a 5-HT 1B receptor agonist into the PBN dose-dependently reduces food intake. 37 Thus, anorexic effects of serotonergic signaling in the PBN may be partially mediated by the 5-HT 1B and 5-HT 2C receptors, but the downstream mechanisms remain to be determined.
More recently, another anorexigenic neuronal population, one that expresses calcitonin gene-related peptide (CGRP), has been identified in the PBN. 124 These are inhibited by ARC AgRP neurons and project to the central nucleus of the amygdala (CeA). 125

| Thalamus
The paraventricular thalamic nucleus (PVT) receives serotonergic projections from the raphe nuclei 103 as well as extensive feeding-related input from the hypothalamic nuclei. 126 It is unknown how thalamic serotonin signaling is functionally involved in the regulation of feeding behavior. Human neuroimaging studies that compare lean subjects against subjects with obesity do not show consistent trends to support increased or decreased serotonergic activity in this region, 15 and it is likely more complicated. Thalamic SERT availability is decreased in insulin-resistant humans, as compared with insulin-sensitive humans with obesity, 127 suggesting that the relationship between obesity and thalamic SERT availability may, at least in part, be driven by changes in metabolic health. Weight loss and weight gain also affect thalamic SERT availability, but these effects are dependent on meal timing during weight loss and meal composition during weight gain. The consumption of a large breakfast and small dinner during weight loss is associated with increased thalamic SERT availability, 128 suggesting that serotonin signaling may contribute to reported favorable effects of meal timing on weight maintenance. In contrast, a 6-week high-fat/ high-sugar snacking diet decreases SERT availability. 129 Because this occurs early during weight gain, it potentially contributes to the progression of obesity. Interestingly, the PVT has dense connections with the limbic system, 130 suggesting that it may play a role in the relaying or integration of homeostatic and reward circuitries.

| Serotonin signaling in the reward circuitry
Serotonin and dopamine have been considered the most important neurotransmitters in the homeostatic and hedonic systems, respectively, but emerging evidence supports a role for serotonin in rewardrelated, motivational food consumption as well. 131 In the reward circuitry, serotonergic signaling interplays with dopaminergic signaling and signaling through other neurotransmitters.
The mesolimbic system, including the VTA, the nucleus accumbens (NAc) of the ventral striatum, and the CeA, is sometimes referred to as the reward pathway. These regions have also been proposed to partake in the interaction between homeostatic and hedonic regulation of food intake. In addition, serotonin receptors are expressed in the dorsal striatum, 132 a key region in the development of habitual (eating) behavior. 133 When the availability of food is time restricted, the dorsal striatum is proposed to function as a foodentrained oscillator, resulting in food anticipatory activity with a circadian rhythm that is synced to the food availability time schedule. 134 The role of serotonin signaling in food anticipatory activity is debated: where previous studies have suggested that whole-brain serotonin signaling suppresses the development of food anticipatory activity, 135,136 a more recent study reported food anticipatory activity to be independent of serotonin signaling. 137 Serotonergic signaling in the dorsal striatum is more strongly related to the regulation of motor behavior, and perturbed serotonergic signaling within this region is associated with several pathological motor conditions. 138,139 van GALEN ET AL.

| Ventral tegmental area
Most dopaminergic projections to the mesolimbic brain areas originate from the VTA. Just like the hypothalamic nuclei of the homeostatic system, the VTA itself is innervated by serotonergic neurons from the DRN. The VTA also receives direct projections from the LHA, a neural circuit that controls compulsive sugar consumption. 140 Subsets of both dopaminergic and GABAergic neurons in the VTA express the 5-HT 2C receptor, 46,141,142 and systemic administration of lorcaserin, a 5-HT 2C receptor agonist, increases the activity of GABAergic, but not of dopaminergic, neurons in the VTA. 46 In fact, activation of the 5-HT 2C receptor in the VTA results in decreased dopaminergic signaling 143 and reduced motivational food intake. 46 When specifically activating 5-HT 2C receptor-expressing dopaminergic VTA neurons, they increase their firing rate and suppress binge eating behavior in mice. 141 Such observations indicate that, overall, serotonergic signaling in the VTA may decrease the hedonic drive for eating behavior, primarily via GABAergic inhibition of VTA dopaminergic neurons.

| Nucleus accumbens
The NAc, located in the ventral part of the striatum, is a major target for downstream VTA dopaminergic projections. Dopamine release in the NAc increases the incentive motivation for palatable food. 144 Increases in NAc dopamine levels are induced by food-predictive cues, and this dopaminergic response is amplified in underweight and/or fasted animals. 145,146 A proposed hypothalamic-thalamic-striatal axis links the NAc to the homeostatic system. The NAc receives direct homeostatic input from the raphe nuclei and LHA as well as indirect input via the PVT; the NAc reciprocally projects to the LHA. 130,147 This axis would allow hypothalamic serotonergic signaling to influence NAc dopaminergic signaling, but its precise role remains unclear. Injection of serotonin into the NAc reduces the motivation for food. 148 In addition, injection of either CCK or serotonin into the PVN limits dopamine release and synergistically promotes acetylcholine release in the NAc. 149 However, the modulation of specific serotonin receptors on NAc neurons has differential effects: agonists for the 5-HT 1/7 , 5-HT 2C , and 5-HT 4 receptors decrease food intake, whereas agonists for the 5-HT 3 and 5-HT 6 receptors increase food intake. 30,49,53 This demonstrates the complexity of serotonergic modulation of the hedonic circuitry. Interestingly, experimental stimulation of serotonergic signaling using D-fenfluramine or lorcaserin suppresses the binge-like eating induced by stimulation of μ-opioid receptors in the NAc, 150 pointing to another pathway where serotonin signaling may influence the regulation of food intake via the reward circuitry.

| Central nucleus of the amygdala
The CeA contains many distinct cellular and neurochemical populations, 151 complicating investigations into its role in feeding behavior. At least two known neuronal populations, a GABAergic population that expresses the 5-HT 2A receptor 40 and another GABAergic population that expresses protein kinase Cδ, 152 play a role in the regulation of feeding behavior. Experimental activation of 5-HT 2A receptor-expressing CeA neurons increases food intake, but not the motivational drive for food. 40 It is unknown to what extent endogenous serotonergic signaling to these cells occurs. However, decreased SERT availability in the CeA has been associated with resistance to chronic high-fat diet-induced obesity in mice, providing further evidence that CeA serotonergic signaling may affect the regulation of food intake. 153

| DISTURBED SEROTONERGIC SIGNALING IN OBESITY AND THERAPEUTIC IMPLICATIONS
Obesity results from an energy intake that exceeds energy expenditure. In this regard, attenuated homeostatic inhibition and/or increased hedonic drive for energy consumption has been postulated to contribute to the consumption of food beyond homeostatic needs.
Because serotonergic signaling fulfills an important role in the regulation of food intake, disruption in serotonergic signaling may contribute to the pathogenesis of disturbed feeding behavior in individuals with chronic overweight or obesity. Indeed, data from multiple studies indicate that serotonergic signaling is disturbed in animals and humans with obesity.
Hypothalamic baseline serotonin release is reduced in animal models of obesity. 154,155 Feeding rats an obesogenic diet for 7 weeks results in changes in binding to 5-HT 1A , 5-HT 1B , and 5-HT 2A receptors (using quantitative autoradiography), 156 in accordance with reduced serotonin release and decreased activity of the serotonergic neurons.
Attenuation of meal-induced hypothalamic serotonin release occurs as early as after 1 week of high-fat feeding, and it progresses over time to a complete absence of meal-stimulated hypothalamic serotonin release. 157 Apparently, diet-induced changes in serotonergic signaling precede the onset of obesity. Given the role for serotonin in food intake, it is not surprising that specific serotonin receptors serve as therapeutic targets to reduce food intake in individuals with obesity.
In humans, it is impossible to study the central serotonin system [SPECT]) have been applied to assess changes in serotonergic signaling associated with human obesity. 15 Decreased levels of SERT protein were observed in the infundibular nucleus (equivalent to the ARC in rodents) in postmortem hypothalamic tissue of humans with overweight/obesity. 158 In addition, women with obesity have lower levels of serotonin and its metabolites in CSF compared with lean women. 159 Interestingly, studies measuring serotonin receptor or SERT availability using either PET or SPECT consistently support decreased serotonin levels/signaling in a variety of brain regions in individuals with obesity. 58,[160][161][162][163][164] Whether these findings are the consequence or cause of obesity remains a point of discussion. Because most studies observe no (curvi) linear correlation between body mass index (BMI) and these indirect measures of central serotonin signaling, it is likely that obesityassociated factors, such as diet composition and meal timing, at least partially account for the obesity-associated changes in serotonin measures. 15 A role for meal timing is supported by the observations that thalamic SERT increased following a 4-week hypocaloric diet when most daily calories were consumed during breakfast and decreased when most daily calories were consumed during dinner. 128 In addition, following a 6-week hypercaloric high-fat/high-sugar snacking diet, a reduction in diencephalic SERT was observed in lean men. 129 These studies indicate that changes in serotonergic signaling may develop early during the overconsumption of food in humans and may therefore contribute to the development and/or persistence of obesity.
On the basis of the evident role of serotonergic signaling in feeding behavior and translational observations supporting reduced serotonergic signaling in human obesity, the stimulation of central serotonergic signaling emerged as a therapeutic target for obesity well over a decade ago. Initially, fenfluramine and, later, dexfenfluramine and sibutramine were successfully marketed as obesity treatments.
Unfortunately, the success of serotonergic drugs in the treatment of obesity has so far been limited by peripheral side effects due to the stimulation of serotonin receptors in peripheral tissues. More recently, the 5-HT 2C receptor agonist lorcaserin was shown to be effective in reducing food intake, body weight, and cardiometabolic complications in individuals with obesity. 165 It was used in clinical practice across the United States from 2012 to 2020, at which time the FDA requested it be withdrawn from the market due to concerns about increased cancer incidence. 166 Finally, given the peripheral side effects of centrally acting serotonin stimulators and given the overall effects of peripheral serotonin stimulation on energy balance per se, the targeted inhibition of peripheral serotonin has also been proposed as a potential therapeutic target for prevention or treatment of obesity, 167 although we are not aware of any clinical trials assessing this mechanism at this moment. In summary, several serotonergic drugs have shown promising results in humans with obesity, but they have also been associated with severe side effects; further research is required to determine if this system can be safely targeted in humans with obesity.

| CONCLUDING REMARKS
The brain's serotonergic system plays a pivotal role in the control of food intake and whole-body energy homeostasis. Multiple complex neuronal networks and serotonin receptor subtypes participate in this regulatory system, together eliciting an appropriate feeding response depending on the actual metabolic state. Human obesity is associated with reduced serotonergic signaling. Early changes in serotonergic signaling occur during overconsumption, and these may contribute to the onset and/or persistence of overweight and obesity. Pharmacotherapy aimed at specific serotonin receptor subtypes affects food intake and body weight, but peripheral side effects have thus far limited their use.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest associated with the manuscript.