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Unraveling the serotonin saga: from discovery to weight regulation and beyond - a comprehensive scientific review

Cell & Bioscience volume 13, Article number: 143 (2023) Cite this article

Abstract

The prevalence of obesity is rapidly increasing worldwide, while the development of effective obesity therapies lags behind. Although new therapeutic targets to alleviate obesity are identified every day, and drug efficacy is improving, adverse side effects and increased health risks remain serious issues facing the weight-loss industry. Serotonin, also known as 5-HT, has been extensively studied in relation to appetite reduction and weight loss. As a result, dozens of upstream and downstream neural targets of 5-HT have been identified, revealing a multitude of neural circuits involved in mediating the anorexigenic effect of 5-HT. Despite the rise and fall of several 5-HT therapeutics in recent decades, the future of 5-HT as a therapeutic target for weight-loss therapy looks promising. This review focuses on the history of serotonin, the state of current central serotonin research, previous serotonergic therapies, and the future of serotonin for treating individuals with obesity.

Introduction

The global prevalence of obesity is steadily increasing, with a growing number of affected individuals worldwide. According to the World Health Organization (WHO), obesity is defined as having a body mass index (BMI) greater than 30. In 2016, the WHO estimated that approximately 13% of the world’s adult population had obesity, which is three times higher than the rate in 1975. This estimation accounted for 11% of men and 15% of women [1].

While an imbalance of increased energy intake and reduced physical activity is considered the primary cause of obesity, research in this field has also highlighted genetics, disease, and environmental factors as significant contributors to its development [2,3,4]. Consequently, diet and exercise, although the most effective weight management therapy, may not yield the same results for everyone. Obesity is associated with an elevated risk of various health conditions such as heart disease, diabetes, depression, cancer, and reproductive impairment, leading to rising healthcare costs. In 2021 alone, the estimated cost of diabetes-related healthcare reached $966 billion, and it is projected to increase to $1,054 billion by 2045 [5].

In recent years, a new injectable glucagon-like peptide 1 agonist called Semaglutide has emerged as a widely prevalent and popular therapy in the weight-loss treatment industry. Clinical trials have demonstrated the effectiveness of Semaglutide in reducing BMI when combined with lifestyle intervention, with once-weekly treatment for adults and adolescents [6, 7]. However, it is important to note that Semaglutide, like any medication, carries associated side effects, including hypoglycemia, gastrointestinal, pancreatic, thyroid, gallbladder, and cardiovascular effects, as well as acute kidney injury, complications related to diabetic retinopathy, and injection-site allergic reactions [8].

While weight-loss therapies have improved over time, serotonergic therapies remain among the leading approaches for effective weight management with new targets continually being discovered. This review focuses on the history of serotonin, the state of current central serotonin research, previous serotonergic therapies, and the future of serotonin for treating individuals with obesity.

The discovery and diverse roles of serotonin

Serotonin, also known as 5-hydroxytryptamine (5-HT), was initially isolated in 1937 by an Italian pharmacologist named Vittorio Erspamer from the gastric mucosa of a rabbit. At that time, Erspamer referred to it as an “enteramine“[9]. Almost a decade later, in 1948, this enteramine was isolated from bovine serum and given the name “serotonin” due to its vasoconstrictive properties [10]. Serotonin is a highly conserved monoamine. Erspamer successfully identified 5-HT in the gut of various vertebrate animals, including primates, pigeons, frogs, and fish. This finding demonstrated the widespread presence of 5-HT across varied species [11,12,13,14,15,16,17].

In mammals, serotonin plays multiple diverse roles. It is involved in regulating various physiological processes, such as gut homeostasis, mood, body temperature, glucose homeostasis, feeding (both homeostatic and hedonic aspects), energy balance, locomotion, migraine, social behavior (including aggression), and circadian rhythm, among others [11,12,13,14,15].

Serotonin synthesis, storage, and metabolism

5-HT is synthesized from the essential amino acid tryptophan, which is obtained from food. 5-HT is produced in both the peripheral and central nervous systems, and cannot cross the blood-brain barrier [18]. The conversion of tryptophan to 5-hydroxytryptophan is facilitated by the rate-limiting enzyme tryptophan hydroxylase (TPH) [19, 20]. TPH exists in two isoforms, TPH1, found in peripheral serotonin-producing tissues such as the gut, pineal gland, spleen, and thymus, and TPH2 is found in central serotonin-producing neurons like the raphe nuclei [21]. Subsequently, 5-hydroxytryptophan is converted to 5-hydroxytryptamine (5-HT or sertonin) by aromatic l-amino acid decarboxylase [22].

In the brain, 5-HT is stored in vesicles until exocytosis is triggered, leading to its release into the synaptic cleft. In the periphery, the gut is the primary site of 5-HT synthesis; however, platelets will uptake 5-HT from the plasma via the serotonin transporter (SERT), making platelets the fundamental regulators of plasma 5-HT concentration [23]. Platelets store 5-HT in dense granules and release 5-HT into circulation upon stimulation. Once 5-HT is no longer bound to one of its receptors, it is transported back into cells via SERT [24]. Following reuptake, 5-HT is rapidly metabolized by monoamine oxidase into 5-hydroxyindole acetaldehyde, which is further broken down into 5-hydroxindile acetic acid (5-HIAA). The measurement of 5-HIAA, the major metabolite of 5-HT, in urine is a commone and non-invasive method for determining 5-HT levels [25].

Central serotonin and the raphe nuclei: a complex network

In the brain, the synthesis of 5-HT primarily occurs in the raphe nuclei, which were initially classified into nine nuclei (named B1-B9) in the 1960s [26]. Neurons involved in 5-HT synthesis are present in both the midbrain and hindbrain. The dorsal raphe nucleus (B7 or DRN) located in the midbrain is the main producer of central 5-HT. Interestingly, the DRN has also been implicated as a significant regulator of body weight and feeding [27].

The 5-HT cell groups are numbered in a caudal-to-rostral direction, starting with B1-3 in the medulla, followed by B4-9 in the pons and midbrain. Each number corresponds to a specific nucleus, such as B1 (raphe pallidus), B2 (raphe obscurus), B3 (raphe magnus), B4 (dorsal to prepositus hypoglossi), B5 (raphe pontis), B6 (caudal part of raphe dorsalis), B7 (raphe dorsalis), B8 (centralis), and B9 (supralemniscal nucleus). However, it is worth noting that these nuclei also produce other neurotransmitters, such as Gamma-aminobutyric acid (GABA) and glutamate [28]. Additionally, even within the primary site of central serotonin production, the DRN, there are approximately twice as many non-5-HT neurons as there are neurons that synthesize 5-HT [29, 30].

Serotonin beyond the blood-brain barrier

Due to its size, serotonin (5-HT) faces difficulty crossing the blood-brain barrier, and therefore its functions in the central nervous system and peripheral tissues are generally considered separate [31]. However, it is important to note that precursors and metabolites of 5-HT may have an easier time crossing the blood-brain barrier [32] and 5-HT can also influence the barrier’s permeability [33,34,35].

The majority of 5-HT in the body (~ 95%) is produced in the periphery [9, 16, 17, 36]. It is primarily synthesized in enterochromaffin cells of the gut mucosa located in the stomach, and to a lesser extent in the pineal gland and other tissues [37]. In the 1960s, Gershon et al. conducted radioautography experiments using mice and identified that several peripheral tissues, including the adrenal, gastric, thyroid, pancreas, lung, liver, splenic tissues, and blood platelets, take up and store 5-HT [38].

The roles of peripheral 5-HT are diverse, but it primarily regulates gut motility and plays a role in hemodynamics and vasoconstriction [20]. Interestingly, individuals taking Selective Serotonin Reuptake Inhibitor (SSRI) medication commonly prescribed for the treatment of depression, experience gut irregularities such as nausea, constipation, and diarrhea, which can be attributed to the alteration in the gut microbiome caused by the imbalance of 5-HT [39].

The diverse landscape of 5-HT receptors

There are seven classes of 5-HT receptors, with a current consensus of 14 receptor subtypes in total (Table 1) [40]. The first family of 5-HT receptors consists of five subclasses: 5-HT1A, 1B, 1D, 1E, and 1F. These receptors are Gi-coupled receptors, and binding of 5-HT to these receptors inhibits adenylate cyclase and reduces cyclic adenosine monophosphate (cAMP) [40, 41]. Additionally, they can indirectly regulate G-protein inwardly rectifying potassium channels, resulting in neuronal hyperpolarization and reduced neuronal activity [40]. Agonism of these receptors leads to anxiolytic and anti-depressant effects.

The 5-HT type 2 receptors consise of three subclasses: 5-HT2A, 2B, and 2C. These are primarily Gq/11-coupled receptors, and their activation increases inositol phosphate and intracellular calcium concentration. Agonism of 5-HT type 2 receptors exhibits anti-obesity (anorexigenic) and some anti-depressant and anti-physcotic effects [12, 42]. Of note, the 5-HT2C receptor was originally classified as 5-HT1C, however it was reclassified due a shared pharmacological profile with the type 2 receptors [43, 44].

The 5-HT type 3 receptor is typically a ligand-gated ion channel, and binding of 5-HT to this receptor rapidly depolarizes neurons through non-selective influx of sodium and calcium [44]. Agonists of the 5-HT 3 receptor remain largely unexplored, but may have anti-psychotic and anti-anxiety properties. Antagonists of the 5-HT 3 receptor are more widely used as an anti-emetic [45].

The 5-HT type 4, 6, and 7 receptors preferentially couple with Gs receptors, triggering a second messenger cascade mediated by protein kinase A and increasing cAMP [41, 44]. Agonism of these receptors range from a gastroprokinetic to increase gut motility (5-HT type 4) to anxiolytic and anti-depressant (5-HT type 6) and a potential analgesic (5-HT type 7). Less is known about 5-HT type 5 receptors. There are two subtypes, 5-HT 5A and 5B. They have generally been found to be Gi/o coupled, resulting in decreased cAMP. Agonism of 5-HT type 5 receptors may have anxiolytic and anti-depressant effects [41].

Table 1 5-HT Receptor Summary
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Serotonin and appetite: implications for obesity and eating disorders

While 5-HT in the brain only accounts for about 3–5% of the body’s serotonin, it plays a crucial role in regulating appetite [46, 47]. Generally, an increase in 5-HT reduces food intake, while a reduction in 5-HT increases food intake [47, 48]. In fact, after a meal, extracellular 5-HT levels increase in the medial hypothalamus of rats [49]. Notably, 5-HT neurons in the DRN project to the arcuate nucleus of the hypothalamus (ARH), a region well known for its involvement in regulating food intake, energy homeostasis, and body weight [50, 51]. 5-HT agonists provided directly into the brains of rats suppresses food intake and body weight [52]. On the contrary, depleting central 5-HT in rodents leads to a reduction in thermoregulation, a marked decrease in uncoupling protein 1 expression in brown and white adipose tissue, and a sharp increase in blood glucose, free fatty acids and triglycerides [53]. Furthermore, central 5-HT depletion results in increased hyperphagia and body weight gain, eventually leading to obesity [46, 47].

Several investigators have identified neural circuits that may explain the link between psychiatric illness and eating disorders [54, 55]. One of these circuits involves a dysregulated 5-HT system, which is accompanied not only by symptoms of common mood disorders, like depression, but also disordered eating [56]. In fact, mice with mutated or ablated 5-HT2C receptors commonly exhibit hyperphagia, type 2 diabetes, and seizures [57, 58]. For example, patients prescribed atypical antipsychotics, such as olanzapine, often experience noticeable weight gain. Further investigation into olanzapine found that it acts through the 5-HT2C receptor and is suspected to act as an antagonist. Adding Lorcaserin, a high-affinity 5-HT2C receptor agonist mitigates weight gain effect of olanzapine in a mouse model [59]. Karth et al., found that reduced brain 5-HT alters responses to a high-fat diet, such as reduced depression-like behavior and increased anxiety-like behavior, which could explain the correlation between obesity and some mental illnesses [60]. Dieting and malnutrition can reduce the intake of diet-derived tryptophan, leading to reduced serotonin production and availability [61]. In fact, in the 1970s, Breisch and Staller demonstrated that reducing 5-HT synthesis in the brain promotes weight gain and eventually leads to obesity [46, 62]. Furthermore, a reduction or mutation in the 5-HT2C receptor can lead to binge eating behaviors that perpetuate the restricting and binging cycle commonly observed in patients with anorexia nervosa and bulimia [58]. Conversely, overconsumption and obesity can also contribute to a dysregulated 5-HT system. Changes in 5-HT signaling often occur prior to the development of obesity. Mice on a high-fat diet were observed to have an increase in central 5-HT, which may partially contribute to the faster satiating effect of a calorie-dense diet [63]. Additionally, in a study of rats with obesity, 5-HT neurons in the DRN exhibited elevated excitability and had a greater feeding response compared to lean rats [49]. Infusing these rats with 5-HT directly to the ventromedial nucleus of the hypothalamus (VMH), a known feeding-control center of the brain, reduced food intake, but only in lean rats, not obese rats [49, 64]. Furthermore, 5-HT neurons in the DRN (5-HTDRN) projecting to the ventral tegmental area (VTA) inhibit hedonic feeding via 5-HT2C receptor and reduced potassium channel currents [51]. Additional studies have also shown that in rats made obese by feeding a high-fat diet exhibit an increase in 5-HT transporter binding in the DRN, ultimately reducing 5-HT availability in the brain [65, 66], which may contribute to an increased feeling of hunger. All of this research demonstrates that obesity can dysregulate the 5-HT pathways in the brain, therefore, making 5-HT an excellent candidate target for anti-obesity treatment. Furthermore, evidence that 5-HT2C receptor agonists have therapeutic potential as a type 2 diabetes medication due to their ability to produce effects on blood glucose and insulin sensitivity independent of weight loss [67, 68].

Regulation of serotonin, satiation, and the network of feeding control

Satiation triggers increases 5-HT activity in both the gut and brain [51, 69]. However, the activation of 5-HT neurons begins long before satiation, likely starting with the smell and anticipation of food. For instance, in drosophila, serotonergic neurons respond to the gustatory detection of food, which then signals to downstream insulin-producing cells and enteric neurons (Fig. 1) [70]. This 5-HT activity also communicates with enteric neurons in the gut, promoting gastric motility and initiating the digestion process [70]. It is speculated that this mechanism serves to communicate potential nutrient availability or intake. The signaling of 5-HT continues during the mastication process leading to the increase in 5-HT spike activity [71].

Fig. 1
figure 1

Projections to and from 5-HT ORN neurons. Projections to the DRN are illustrated with a green arrow and from the DRN are red. Reciprocal projections are purple. Abbreviations are as follows: ARH, Arcuate Nucleus of the Hypothalamus, BNST, Bed nucleus of the stria terminalis, DRN, Dorsal Raphe Nucleus, LHb, Lateral Habenula, LH, Lateral Hypothalamus, NTS, nucleus tractus solitarius, STR, Striatum.Globus pallidus and substantia nigra are not pictured. Created with BioRender.com

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In addition to the 5-HTDRN neurons, dopaminergic neurons in the VTA (DAVTA), also receive dense projections from orexin neurons originating from the lateral hypothalamus (LH) and dorsal medial hypothalamus. Orexin neurons, also known as hypocretin neurons, contribute to feeding behavior and body weight homeostasis. In models of orexin deficiency, mice become obese despite consuming fewer calories compared to their lean counterparts [72]. 5-HTDRN neurons receive some of densest projections from orexin neurons (Fig. 1) [73] and are known to project to and inhibit orexin neuronal activity [74]. Additionally, in rats, 5-HTDRN neurons express orexin receptors, OX1R and OX2R [75,76,77]. In response to orexin, 5-HTDRN neurons exhibit increased inhibitory post-synaptic currents via GABADRN neurons [78, 79]. Orexin-A and B also inhibit depolarization-stimulated 5-HT release [80]. Moreover, the medial prefrontal cortex has been shown to project to 5-HTDRN neurons, and stimulation of this circuit using optogenetics in rats has a profound effect on depression-like behavior [81]. The DRN also receives input from the lateral habenula which is implicated psychiatric disorders, motivation behavior and depression (Fig. 1) [82, 83]. Viral tracing studies indicate that the DRN is innervated by the striatum, globus pallidus, and substantia nigra [84,85,86,87], which regulate autonomic, emotional, aversion and reward-related information. Other inputs to the DRN include the anterior cortex and cerebellar nuclei, which play roles in coordinating sensation, motor control, and cognitive function [88]. Another important player in feeding regulation is the GABALH neurons that project to the paraventricular hypothalamic nucleus (PVH). Optogenetic stimulation of PVH-projecting GABALH neurons increases inhibitory post-synaptic current (IPSC) in PVH neurons, leading to increased feeding, while disruption of GABA receptors in the PVH reduced feeding [89]. Notably, GABALH neurons simultaneously project to 5-HTDRN neurons (Fig. 1) [28], which also increases feeding [51], suggesting a parallel pathway for feeding regulation.

Although this list is not exhaustive, it highlights the regulation of the central serotonergic system by various brain regions and the crucial role played by the 5-HTDRN neurons in controlling and coordinating multiple physiological functions. Notably, while several of these circuits have been studied, few have examined their impact on feeding behavior and body weight, creating an unaddressed gap in knowledge in the field.

Downstream of 5-HT neurons

Numerous studies have focused on the role of 5-HTDRN neurons projecting to the ARH in inhibiting homeostatic food intake and regulating body weight. Specifically, the innervation of ARH proopiomelanocortin (POMC) and Agouti-related Protein (AgRP) neurons by upstream 5-HTDRN neurons has been extensively studied (Fig. 1) [12, 50, 90, 91]. It has been established that 5-HT2C and 5-HT1B receptors mediate this inhibitory activity [51, 92]. Interestingly, feeding reduces 5-HT responsiveness to GABA inhibitory input, resulting in increased activity of 5-HT neurons [51]. The release of GABA from neurons expressing leptin receptor (LepR) has also been implicated in body weight regulation. Disrupted GABA release from LepR-expressing neurons has been shown to contribute to mild obesity and sensitivity to diet-induced obesity in mice [93]. This mechanism may also play a role in the regulation of 5-HT, but further studies are required to make this determination.

Within the DRN itself, a local circuit has been identified as a regulator of feeding behavior. Neurons expressing vesicular GABA and glutamate transporters (Vgat and VGLUT3) have opposing effects on food consumption, with VgatDRN neurons increasing and VGLUT3DRN neurons suppressing food intake [27]. Additionally, VgatDRN neurons inhibit VGLUT3DRN neurons, and 5-HT1A receptor agonist can inhibit TPH2-expressing VGLUT3DRN neurons [27].

The interaction between 5-HT and dopamine activity is also important for feeding regulation. Activation of 5-HT2C receptor stimulates dopamine neural activity and effectively inhibits binge-like eating behavior in mice [94]. Moreover, 5-HT has been shown to control reward processing in the brain through dopamine regulation [95]. The nucleus of the solitary tract (NTS), which expresses 5-HT2C receptors and may receive projections from 5-HTDRN neurons, is involved in feeding behavior (Fig. 1). Activation of POMC neurons via 5-HT2C receptors, in the NTS decreases feeding and mediates acute reduced food intake in response to the selective 5-HT2C receptor agonists, like lorcaserin [96].

Furthermore, selective activation of 5-HTDRN projections to the LH and bed nucleus of the stria terminalis (BNST) triggered by food access and satiety hormones suppresses feeding by increasing extracellular 5-HT (Fig. 1) [97], suggesting redundant circuits mediating the suppression of food intake by 5-HT. In addition, studies have explored the diverse projections of 5-HTDRN neurons to different brain regions, with individual neurons responding to different cues and displaying distinct anatomical subpopulations projecting to reward-related or anxiety-related structures [98,99,100,101].

Exploring serotonergic therapies for weight-loss: progress, challenges, and future directions

Given the extensive communications of the neural 5-HT system with brain regions involved in regulating feeding behavior and body weight homeostasis, it represents a promising target for therapeutic interventions aimed at alleviating obesity. To improve current serotonergic therapies, it is crucial to gain a deeper understanding of their development and current usage [102,103,104].

SSRIs are commonly used to increase 5-HT availability in the brain by blocking the reuptake of serotonin through SERT. These medications are primarily employed for the treatment of depression. Interestingly, mice deficient in SERT expression develop characteristics such as glucose intolerance, insulin resistance, and obesity, despite reduced food intake [24]. Serotonin reuptake inhibitors, like sibutramine and fluoxetine, as well as monoamine oxidase inhibitors like clorgyline and pargyline, have demonstrated effectiveness in reducing food intake [105,106,107]. This highlights serotonin as a potential candidate for weight-loss therapies, particularly for individuals who do not respond adequately to diet and exercise alone.

However, it is important to note that many of these serotonin-targeted weight-loss therapies require an intact melanocortin system in order to be effective [108]. Therefore individuals with mutations or deficits in melanocortin receptor expression may not respond favorably to these treatments.

Fenfluramine and d-fenfluramine, which are derivatives of amphetamine, elevate extracellular 5-HT levels by disrupting the vesicular storage of 5-HT, leading to increased release. Unlike amphetamines, which increase multiple monoamines like dopamine and norepinephrine, fenfluramine exhibits greater selectivity in increasing 5-HT and has shown lower addictive potential [109, 110]. Fenfluramine was approved as a weight loss treatment in 1973, followed by the approval of dexfenfluramine (d-fen) in 1996. These drugs exert their effects by increasing energy expenditure and reducing body weight, by targeting the lateral hypothalamus [52, 111,112,113,114]. In addition, they also target POMCARH 5-HT2C receptors and downstream melanocortin 4 receptors (Mc4R) in PVH neurons, which are responsible for the appetite-suppressing effects of d-fen [115]. In mouse studies, d-fen dose-dependently reduced the consumption of palatable food, and mice lacking 5-HT2C receptor were less sensitive to these effects [116]. However, chronic treatment with d-fen becomes less effective over time due to a reduction of 5-HT uptake [117,118,119]. Interestingly, baboons administered repeated fenfluramine did not develop tolerance to its effects on food intake [120]. As a result, these drugs were commonly prescribed in combination with phentermine, an amphetamine, referred to as fen-phen, for short-term weight loss. In human studies, meal microstructure differed between fenfluramine and amphetamine treatments. Both treatments reduce food intake, but fenfluramine specifically reduces the rate of feeding, while amphetamine increases the latency to consume [121, 122]. This study emphasizes the importance of meal microstructure as an often-overlooked aspect of studying appetite in humans. This combination of amphetamine and fenfluramine posed an increased risk for developing pulmonary hypertension and heart disease [123,124,125]. Consequently, the Food and Drug Administration (FDA) withdrew both fenfluramine and dexfenfluramine from the market in 1997 (Table 2) [42, 115, 125].

Sibutramine, which gained approval as an obesity treatment in 1997, replaced fenfluramine, but was subsequently withdrawn in 2010 due to an elevated risk for cardiovascular complications. This drug is a monoamine reuptake inhibitor, primarily used for the treatment of depression. By inhibiting the reuptake of monoamines, such as dopamine, norepinephrine, and serotonin in the central nervous system, Sibutramine increases their concentration [106, 126,127,128]. While Sibutramine is less effective for depression treatment, it is effective in reducing food intake and increasing energy expenditure, resulting in sustained weight loss [129,130,131]. However, alongside weight loss, Sibutramine also raises heart rate and blood pressure, thereby increasing the cardiovascular risk for individuals with obesity [132, 133]. Despite an effective reduction in body weight, the associated 16% increase in cardiovascular events prompted its withdrawal (Table 2) [129].

After the withdrawal of Sibutramine, a very promising weight-loss therapeutic called Lorcaserin, emerged as a replacement. Lorcaserin is a high-affinity 5-HT2C receptor agonist [134], offering more specific actions compared to the previous serotonin-targeting drugs. The use of a more selective drug aims to minimize off-target side effects associated with non-specific action, such as those observed with Sibutramine. Lorcaserin has shown improvements in glucose tolerance, insulin sensitivity, reduced food intake, and weight loss in obese mouse models, positioning it as a potential candidate for weight-loss therapy [135]. Its mechanism of action involves the downstream Mc4R [68]. Mice lacking Mc4R are not responsive to lorcaserin-induced hypophagia, indicating that melanocortins acting on Mc4R are essential for altering food intake in response to 5-HT2C receptor agonists [14, 134]. Additionally, Lorcaserin has been found to rely on preproglucagon (PPG) neurons in the NTS (PPGNTS) to mediate its therapeutic effects on reducing food intake as demonstrated by the lack of response in mice in which PPGNTS neurons are ablated [136].

In human clinical trials, Lorcaserin treatment resulted in modest weight loss and fewer cardiovascular events compared to previous 5-HT-targeted therapies [137, 138], leading to its approval by the FDA as a weight-loss therapeutic [139]. However, rodent toxicology studies revealed abnormal tissue masses in mammary and brain tissues of rats treated with remarkably high doses of Lorcaserin (30 and 100 mg/kg) [140]. At a low dose (3 mg/kg), Lorcaserin was effective in inducing hypophagia and weight loss with minimal side effects [141, 142]. Due to the modest and unsustainable weight loss outcomes and potential carcinogenicity concerns, the FDA ultimately withdrew its approval as a weight-loss aid in 2020 (Table 2) [143,144,145]. However, Lorcaserin is currently showing potential for treating Dravet Syndrome due to its anti-seizure effects, and clinical trials in this context are ongoing [146].

Further studies have found that the rebound weight gain in individuals taking Lorcaserin is in part attributed to internalization of the 5-HT2C receptor, a common mechanism of G-protein coupled receptors, which results in reduced sensitivity to the effects of Lorcaserin [141]. The reduced sensitivity can potentially be mitigated by adding a β-arrestin inhibitor, although its efficacy in human clinical trials requires further investigation.

Table 2 5-HT Targeted therapies for weight-loss
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Conclusions and exploring potential therapeutic avenues: innovative approaches in weight-loss

There are several avenues for further research in the field of 5-HT and weight-loss therapies. Exploring upstream signals to 5-HTDRN neurons, such as GABA and dopamine, could provide additional therapeutic targets for alleviating obesity. While 5-HT2C receptor is the most targeted 5-HT receptor for weight-loss, other receptor subtypes remain largely unexplored in the context of body weight and feeding behavior. The 5-HT1B receptor is one such receptor with exciting potential as a future target for the development of obesity therapeutics. Studies have indicated that co-administration of a 5-HT1B receptor agonist enhances the anorectic effect of 5-HT2C receptor compounds by increasing the number of activated POMCARH neurons, although not their magnitude, as observed in electrophysiology studies [147]. Recent research further supports the importance of 5-HT1B receptor activation in mediating the hypophagic effects of 5-HT, particularly in AgRPARH neurons expressing 5-HT1B receptor, which project to the PVH [148].

In the realm of migraine treatment, there have been notable developments with a nasal spray which delivers a highly selective 5-HT1F receptor agonist called lasmiditan. Lasmiditan is the first member of a new drug category of neural acting anti-migraine agents [149]. This therapeutic shows promise as a potential replacement for previous therapies targeting 5-HT1B/1D receptors, which are commonly prescribed for acute migraine attacks. The selective nature, direct nasal delivery, ease of administration for long-term use, and minimal interactions with other 5-HT receptor subtypes makes this type of progressive therapy a potential future approach for weight-loss medications, offering the advantages of targeted efficacy and reduced side effects.

Data Availability

Not applicable.

Abbreviations

5-HIAA:

5-hydroxindile acetic acid

5-HT:

5-hydroxytryptamine

AgRP:

Agouti-related protein

ARH:

Arcuate nucleus of the hypothalamus

BMI:

Body mass index

BNST:

Bed nucleus of the stria terminalis

cAMP:

Cyclic adenosine monophosphate

d-fen:

Dexfenfluramine

DRN:

Dorsal raphe nucleus

FDA:

Food and drug administration

GABA:

Gamma-aminobutyric acid

IPSC:

Inhibitory post-synaptic current

LepR:

Leptin receptor

LH:

Lateral hypothalamus

Mc4R:

Melanocortin 4 receptors

NTS:

Nucleus of the solitary tract

OX1R:

Orexin receptor 1

OX2R:

Orexin receptor 2

POMC:

Proopiomelanocortin

PPG:

Preproglucagon

PVH:

Paraventricular hypothalamic nucleus

SERT:

Serotonin transporter

SSRI:

Selective serotonin reuptake inhibitor

TPH:

Tryptophan hydroxylase

Vgat:

Vesicular GABA transporters

VGLUT:

Vesicular glutamate transporters

VMH:

Ventromedial nucleus of the hypothalamus

VTA:

Ventral tegmental area

WHO:

World health organization

References

  1. Health W, Organization. Obesity and overweighthttps://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight 2021. Accessed 13 February 2023.

  2. Lafia AT, Ketounou TR, Honfoga JNB, Bonou SI, Zime AKB. Dietary habits, prevalence of obesity and overweight in developed and developing countries. Res Soc Dev. 2022;11(10):e249111032769.

    Article  Google Scholar 

  3. Benjamin S, Masai E, Kamimura N, Takahashi K, Anderson RC, Faisal PA. Review: phthalates impact human health: epidemiological evidences and plausible mechanism of action. J Hazard Mater. 2017;340:360–83.

    Article  CAS  PubMed  Google Scholar 

  4. Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004;116(2):337–50.

    Article  CAS  PubMed  Google Scholar 

  5. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.

    Article  PubMed  Google Scholar 

  6. Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen OK, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med. 2022;387(24):2245–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002.

    Article  CAS  PubMed  Google Scholar 

  8. Smits MM, Van Raalte DH. Safety of Semaglutide. Front Endocrinol (Lausanne). 2021;12:645563.

    Article  PubMed  Google Scholar 

  9. Erspamer V, Vialli M. Ricerche sul secreto delle cellule enterocromaffini. Boll d Soc Med-chir Pavia. 1937;51:357–63.

    Google Scholar 

  10. Rapport MM, Green AA, Page IH. Partial purification of the vasoconstrictor in beef serum. J Biol Chem. 1948;174(2):735–41.

    Article  CAS  PubMed  Google Scholar 

  11. Backström T, Winberg S. Serotonin coordinates responses to social stress-what we can learn from Fish. Front Neurosci. 2017;11:595.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, et al. Serotonin 2 C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clin Invest. 2013;123(12):5061–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cai X, Liu H, Feng B, Yu M, He Y, Liang C, et al. A D2 to D1 shift in dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice. Nat Neurosci. 2022;25(5):646–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Heisler LK, Jobst EE, Sutton GM, Zhou L, Borok E, Thornton-Jones Z, et al. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron. 2006;51(2):239–49.

    Article  CAS  PubMed  Google Scholar 

  15. Rowland NE, Carlton J. Neurobiology of an anorectic drug: fenfluramine. Prog Neurobiol. 1986;27(1):13–62.

    Article  CAS  PubMed  Google Scholar 

  16. Erspamer V. Pharmacology of indolealkylamines. Pharmacol Rev. 1954;6(4):425–87.

    CAS  PubMed  Google Scholar 

  17. Erspamer V. Über den 5-Hydroxytryptamin-(Enteramin)-Gehalt des Magen-Darmtraktes bei den Wirbeltieren. Naturwissenschaften. 1953;40(11):318–9.

    Article  CAS  Google Scholar 

  18. Nakatani Y, Sato-Suzuki I, Tsujino N, Nakasato A, Seki Y, Fumoto M, et al. Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat. Eur J Neurosci. 2008;27(9):2466–72.

    Article  PubMed  Google Scholar 

  19. Grahame-Smith DG. The biosynthesis of 5-hydroxytryptamine in brain. Biochem J. 1967;105(1):351–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Keszthelyi D, Troost FJ, Masclee AA. Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol Motil. 2009;21(12):1239–49.

    Article  CAS  PubMed  Google Scholar 

  21. Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol. 2003;66(9):1673–80.

    Article  CAS  PubMed  Google Scholar 

  22. Best J, Nijhout HF, Reed M. Serotonin synthesis, release and reuptake in terminals: a mathematical model. Theor Biol Med Model. 2010;7:34.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mercado CP, Kilic F. Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels. Mol Interv. 2010;10(4):231–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen X, Margolis KJ, Gershon MD, Schwartz GJ, Sze JY. Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake. PLoS ONE. 2012;7(3):e32511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Höglund E, Øverli Ø, Winberg S. Tryptophan metabolic pathways and brain serotonergic activity: a comparative review. Front Endocrinol. 2019;10.

  26. Dahlström A, Fuxe K. Localization of monoamines in the lower brain stem. Experientia. 1964;20(7):398–9.

    Article  PubMed  Google Scholar 

  27. Nectow AR, Schneeberger M, Zhang H, Field BC, Renier N, Azevedo E, et al. Identification of a Brainstem Circuit Controlling Feeding. Cell. 2017;170(3):429–42e11.

    Article  CAS  PubMed  Google Scholar 

  28. Luo M, Zhou J, Liu Z. Reward processing by the dorsal raphe nucleus: 5-HT and beyond. Learn Mem. 2015;22(9):452–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gaspar P, Lillesaar C. Probing the diversity of serotonin neurons. Philos Trans R Soc Lond B Biol Sci. 2012;367(1601):2382–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Descarries L, Watkins KC, Garcia S, Beaudet A. The serotonin neurons in nucleus raphe dorsalis of adult rat: a light and electron microscope radioautographic study. J Comp Neurol. 1982;207(3):239–54.

    Article  CAS  PubMed  Google Scholar 

  31. Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32(11):1959–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maffei ME. 5-Hydroxytryptophan (5-HTP): natural occurrence, analysis, biosynthesis, Biotechnology, Physiology and Toxicology. Int J Mol Sci. 2020;22(1).

  33. Sharma HS, Dey PK. Role of 5-HT on increased permeability of blood-brain barrier under heat stress. Indian J Physiol Pharmacol. 1984;28(4):259–67.

    CAS  PubMed  Google Scholar 

  34. Sharma HS, Dey PK. Influence of long-term immobilization stress on regional blood-brain barrier permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats. J Neurol Sci. 1986;72(1):61–76.

    Article  CAS  PubMed  Google Scholar 

  35. Sharma HS, Dey PK. Influence of long-term acute heat exposure on regional blood-brain barrier permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats. Brain Res. 1987;424(1):153–62.

    Article  CAS  PubMed  Google Scholar 

  36. Vialli M. Histology of the enterochromaffin cell system. 5-Hydroxytryptamine and related indolealkylamines. 1966:1–65.

  37. Namkung J, Kim H, Park S. Peripheral serotonin: a new player in systemic energy homeostasis. Mol Cells. 2015;38(12):1023–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gershon MD, Ross LL. Location of sites of 5-hydroxytryptamine storage and metabolism by radioautography. J Physiol. 1966;186(2):477–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sjöstedt P, Enander J, Isung J. Serotonin reuptake inhibitors and the gut microbiome: significance of the gut microbiome in relation to mechanism of Action, Treatment Response, Side Effects, and Tachyphylaxis. Front Psychiatry. 2021;12:682868.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sharp T, Barnes NM. Central 5-HT receptors and their function; present and future. Neuropharmacology. 2020;177:108155.

    Article  CAS  PubMed  Google Scholar 

  41. Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav Brain Res. 2008;195(1):198–213.

    Article  CAS  PubMed  Google Scholar 

  42. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, et al. Activation of central melanocortin pathways by fenfluramine. Science. 2002;297(5581):609–11.

    Article  CAS  PubMed  Google Scholar 

  43. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev. 1994;46(2):157–203.

    CAS  PubMed  Google Scholar 

  44. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav. 2002;71(4):533–54.

    Article  CAS  PubMed  Google Scholar 

  45. Thompson AJ, Lummis SC. 5-HT3 receptors. Curr Pharm Des. 2006;12(28):3615–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Breisch ST, Zemlan FP, Hoebel BG. Hyperphagia and obesity following serotonin depletion by intraventricular p-chlorophenylalanine. Science. 1976;192(4237):382–5.

    Article  CAS  PubMed  Google Scholar 

  47. C HL. W, M Y, Y Y, Y H, H L, TPH2 in the dorsal raphe nuclei regulates Energy Balance in a sex-dependent manner. Endocrinology. 2021;162(1).

  48. Karth MD, Baugher BJ, Pellechia SA, Huq SN, Warner AK, Karth MM, et al. Brain serotonin deficiency and fluoxetine lead to sex-specific effects on binge-like food consumption in mice. Psychopharmacology. 2022;239(9):2975–84.

    Article  CAS  PubMed  Google Scholar 

  49. De Fanti BA, Hamilton JS, Horwitz BA. Meal-induced changes in extracellular 5-HT in medial hypothalamus of lean (Fa/Fa) and obese (fa/fa) Zucker rats. Brain Res. 2001;902(2):164–70.

    Article  PubMed  Google Scholar 

  50. Xu Y, Jones JE, Kohno D, Williams KW, Lee CE, Choi MJ, et al. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron. 2008;60(4):582–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. He Y, Cai X, Liu H, Conde KM, Xu P, Li Y et al. 5-HT recruits distinct neurocircuits to inhibit hunger-driven and non-hunger-driven feeding. Mol Psychiatry. 2021.

  52. Blundell JE, Leshem MB. Central action of anorexic agents: effects of amphetamine and fenfluramine in rats with lateral hypothalamic lesions. Eur J Pharmacol. 1974;28(1):81–8.

    Article  CAS  PubMed  Google Scholar 

  53. McGlashon JM, Gorecki MC, Kozlowski AE, Thirnbeck CK, Markan KR, Leslie KL, et al. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis. Cell Metab. 2015;21(5):692–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Y X, RM YL, LR C, C M. Z, X H, Identification of a neurocircuit underlying regulation of feeding by stress-related emotional responses. Nat Commun. 2019;10(1).

  55. LR M, RM YLYX. C, Y X, BR A, A neural basis for antagonistic control of feeding and compulsive behaviors. Nat Commun. 2018;9(1).

  56. Steiger H. Eating disorders and the serotonin connection: state, trait and developmental effects. J Psychiatry Neurosci. 2004;29(1):20–9.

    PubMed  PubMed Central  Google Scholar 

  57. Nonogaki K, Strack AM, Dallman MF, Tecott LE. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT 2 C receptor gene. Nat Med. 1998;4:1152–6.

    Article  CAS  PubMed  Google Scholar 

  58. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature. 1995;374(6522):542–6.

    Article  CAS  PubMed  Google Scholar 

  59. Lord CC, Wyler SC, Wan R, Castorena CM, Ahmed N, Mathew D, et al. The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2 C. J Clin Invest. 2017;127(9):3402–6.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Karth MM, Baugher BJ, Daly N, Karth MD, Gironda SC, Sachs BD. Brain 5-HT Deficiency prevents antidepressant-like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3β phosphorylation in the Hippocampus. Front Mol Neurosci. 2019;12:298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Friedman M. Analysis, Nutrition, and Health benefits of Tryptophan. Int J Tryptophan Res. 2018;11:1178646918802282.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Saller CF, Stricker EM. Hyperphagia and increased growth in rats after intraventricular injection of 5,7-dihydroxytryptamine. Science. 1976;192(4237):385–7.

    Article  CAS  PubMed  Google Scholar 

  63. Watanabe H, Nakano T, Saito R, Akasaka D, Saito K, Ogasawara H, et al. Serotonin improves high Fat Diet Induced obesity in mice. PLoS ONE. 2016;11(1):e0147143.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Fetissov SO, Meguid MM. Serotonin delivery into the ventromedial nucleus of the hypothalamus affects differently feeding pattern and body weight in obese and lean Zucker rats. Appetite. 2010;54(2):346–53.

    Article  CAS  PubMed  Google Scholar 

  65. Ohliger-Frerking P, Horwitz BA, Horowitz JM. Serotonergic dorsal raphe neurons from obese zucker rats are hyperexcitable. Neuroscience. 2003;120(3):627–34.

    Article  CAS  PubMed  Google Scholar 

  66. Park S, Harrold JA, Widdowson PS, Williams G. Increased binding at 5-HT(1A), 5-HT(1B), and 5-HT(2A) receptors and 5-HT transporters in diet-induced obese rats. Brain Res. 1999;847(1):90–7.

    Article  CAS  PubMed  Google Scholar 

  67. Georgescu T, Lyons D, Heisler LK. Role of serotonin in body weight, insulin secretion and glycaemic control. J Neuroendocrinol. 2021;33(4):e12960.

    Article  CAS  PubMed  Google Scholar 

  68. Burke LK, Ogunnowo-Bada E, Georgescu T, Cristiano C, de Morentin PBM, Valencia Torres L, et al. Lorcaserin improves glycemic control via a melanocortin neurocircuit. Mol Metab. 2017;6(10):1092–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mawe GM, Hoffman JM. Serotonin signalling in the gut–functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2013;10(8):473–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yao Z, Scott K. Serotonergic neurons translate taste detection into internal nutrient regulation. Neuron. 2022;110(6):1036–50e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fornal CA, Metzler CW, Marrosu F, Ribiero-do-Valle LE, Jacobs BL. A subgroup of dorsal raphe serotonergic neurons in the cat is strongly activated during oral-buccal movements. Brain Res. 1996;716(1–2):123–33.

    Article  CAS  PubMed  Google Scholar 

  72. Chieffi S, Carotenuto M, Monda V, Valenzano A, Villano I, Precenzano F, et al. Orexin System: the Key for a healthy life. Front Physiol. 2017;8:357.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K. Distribution of orexin neurons in the adult rat brain. Brain Res. 1999;827(1–2):243–60.

    Article  CAS  PubMed  Google Scholar 

  74. Yamanaka A, Muraki Y, Tsujino N, Goto K, Sakurai T. Regulation of orexin neurons by the monoaminergic and cholinergic systems. Biochem Biophys Res Commun. 2003;303(1):120–9.

    Article  CAS  PubMed  Google Scholar 

  75. Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience. 2001;103(3):777–97.

    Article  CAS  PubMed  Google Scholar 

  76. BÑckberg M, Hervieu G, Wilson S, Meister B. Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. EurJNeurosci. 2002;15:315–28.

    Google Scholar 

  77. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol. 2001;435(1):6–25.

    Article  CAS  PubMed  Google Scholar 

  78. Brown RE, Sergeeva OA, Eriksson KS, Haas HL. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci. 2002;22(20):8850–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liu RJ, van den Pol AN, Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci. 2002;22(21):9453–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Orlando G, Brunetti L, Di Nisio C, Michelotto B, Recinella L, Ciabattoni G, et al. Effects of cocaine- and amphetamine-regulated transcript peptide, leptin and orexins on hypothalamic serotonin release. Eur J Pharmacol. 2001;430(2–3):269–72.

    Article  CAS  PubMed  Google Scholar 

  81. Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature. 2012;492(7429):428–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhao H, Zhang BL, Yang SJ, Rusak B. The role of lateral habenula-dorsal raphe nucleus circuits in higher brain functions and psychiatric illness. Behav Brain Res. 2015;277:89–98.

    Article  PubMed  Google Scholar 

  83. Matsumoto M, Hikosaka O. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci. 2009;12(1):77–84.

    Article  CAS  PubMed  Google Scholar 

  84. Ogawa SK, Cohen JY, Hwang D, Uchida N, Watabe-Uchida M. Organization of monosynaptic inputs to the serotonin and dopamine neuromodulatory systems. Cell Rep. 2014;8(4):1105–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Pollak Dorocic I, Fürth D, Xuan Y, Johansson Y, Pozzi L, Silberberg G, et al. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median Raphe nuclei. Neuron. 2014;83(3):663–78.

    Article  CAS  PubMed  Google Scholar 

  86. Weissbourd B, Ren J, DeLoach Katherine E, Guenthner Casey J, Miyamichi K, Luo L. Presynaptic partners of dorsal Raphe Serotonergic and GABAergic neurons. Neuron. 2014;83(3):645–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491(7423):212–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Swanson LW. Brain architecture: understanding the basic plan. Oxford University Press; 2012.

  89. Wu Z, Kim ER, Sun H, Xu Y, Mangieri LR, Li DP, et al. GABAergic projections from lateral hypothalamus to paraventricular hypothalamic nucleus promote feeding. J Neurosci. 2015;35(8):3312–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Qiu J, Xue C, Bosch MA, Murphy JG, Fan W, Ronnekleiv OK, et al. Serotonin 5-hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons: role in energy homeostasis in females. Mol Pharmacol. 2007;72:885–96.

    Article  CAS  PubMed  Google Scholar 

  91. Roepke TA, Smith AW, Ronnekleiv OK, Kelly MJ. Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons. Am J Physiol Endocrinol Metab. 2012;302(11):E1399–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Burke LK, Heisler LK. 5-hydroxytryptamine medications for the treatment of obesity. J Neuroendocrinol. 2015;27(6):389–98.

    Article  CAS  PubMed  Google Scholar 

  93. Xu Y, O’Brien WG 3rd, Lee CC, Myers MG Jr, Tong Q. Role of GABA release from leptin receptor-expressing neurons in body weight regulation. Endocrinology. 2012;153(5):2223–33.

  94. Xu P, He Y, Cao X, Valencia-Torres L, Yan X, Saito K, et al. Activation of serotonin 2 C receptors in dopamine neurons inhibits binge-like eating in mice. Biol Psychiatry. 2017;81(9):737–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu Z, Lin R, Luo M. Reward contributions to serotonergic functions. Annu Rev Neurosci. 2020;43:141–62.

    Article  PubMed  Google Scholar 

  96. D’Agostino G, Lyons D, Cristiano C, Lettieri M, Olarte-Sanchez C, Burke LK, et al. Nucleus of the Solitary Tract serotonin 5-HT(2 C) receptors modulate Food Intake. Cell Metab. 2018;28(4):619–30e5.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Aklan I, Sayar-Atasoy N, Deng F, Kim H, Yavuz Y, Rysted J, et al. Dorsal raphe serotonergic neurons suppress feeding through redundant forebrain circuits. Mol Metab. 2023;69:101676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Paquelet GE, Carrion K, Lacefield CO, Zhou P, Hen R, Miller BR. Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors. Neuron. 2022;110(16):2664–79e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ren J, Friedmann D, Xiong J, Liu CD, Ferguson BR, Weerakkody T, et al. Anatomically defined and functionally distinct dorsal Raphe serotonin sub-systems. Cell. 2018;175(2):472–87e20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Baruni J, Luo L. Illuminating complexity in serotonin neurons of the dorsal raphe nucleus. Neuron. 2022;110(16):2519–21.

    Article  CAS  PubMed  Google Scholar 

  101. Ren J, Isakova A, Friedmann D, Zeng J, Grutzner SM, Pun A et al. Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei. Elife. 2019;8.

  102. Halford JC, Harrold JA, Lawton CL, Blundell JE. Serotonin (5-HT) drugs: effects on appetite expression and use for the treatment of obesity. Curr Drug Targets. 2005;6(2):201–13.

    Article  CAS  PubMed  Google Scholar 

  103. Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE. Serotonergic drugs: effects on appetite expression and use for the treatment of obesity. Drugs. 2007;67(1):27–55.

    Article  CAS  PubMed  Google Scholar 

  104. Halford JC, Boyland EJ, Lawton CL, Blundell JE, Harrold JA. Serotonergic anti-obesity agents: past experience and future prospects. Drugs. 2011;71(17):2247–55.

    Article  CAS  PubMed  Google Scholar 

  105. Feldman JM. Effect of the monoamine oxidase inhibitors clorgyline and pargyline on the hyperphagia of obese mice. Behav Brain Res. 1988;29(1–2):147–58.

    Article  CAS  PubMed  Google Scholar 

  106. Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord. 1998;22(Suppl 1):18–28. discussion S9.

    Google Scholar 

  107. Heisler LK, Kanarek RB, Gerstein A. Fluoxetine decreases fat and protein intakes but not carbohydrate intake in male rats. Pharmacol Biochem Behav. 1997;58(3):767–73.

    Article  CAS  PubMed  Google Scholar 

  108. Heisler LK, Cowley MA, Kishi T, Tecott LH, Fan W, Low MJ, et al. Central serotonin and melanocortin pathways regulating energy homeostasis. Ann N Y Acad Sci. 2003;994:169–74.

    Article  CAS  PubMed  Google Scholar 

  109. Costa E, Groppetti A, Revuelta A. Action of fenfluramine on monoamine stores of rat tissues. Br J Pharmacol. 1971;41(1):57–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Götestam KG, Andersson BE. Self-administration of amphetamine analogues in rats. Pharmacol Biochem Behav. 1975;3(2):229–33.

    Article  PubMed  Google Scholar 

  111. Ghosh MN, Parvathy S. Tolerance pattern of the anorexigenic action of amphetamines, fenfluramine, phenmetrazine and diethylpropion in rats. Br J Pharmacol. 1976;57(4):479–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Garattini S, Mennini T, Samanin R. From fenfluramine racemate to d-fenfluramine. Specificity and potency of the effects on the serotoninergic system and food intake. Ann N Y Acad Sci. 1987;499:156–66.

    Article  CAS  PubMed  Google Scholar 

  113. Mennini T, Bizzi A, Caccia S, Codegoni A, Fracasso C, Frittoli E, et al. Comparative studies on the anorectic activity of d -fenfluramine in mice, rats and guinea pigs. Naunyn-Schmiedeberg’s ArchPharmacol. 1991;343:483–90.

    CAS  Google Scholar 

  114. Boschmann M, Frenz U, Murphy CM, Noack R. Changes in energy metabolism and metabolite patterns of obese rats after application of dexfenfluramine. Pharmacol Biochem Behav. 1996;53(3):549–58.

    Article  CAS  PubMed  Google Scholar 

  115. Xu Y, Jones JE, Lauzon DA, Anderson JG, Balthasar N, Heisler LK, et al. A serotonin and melanocortin circuit mediates D-fenfluramine anorexia. J Neurosci. 2010;30(44):14630–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Vickers SP, Clifton PG, Dourish CT, Tecott LH. Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2 C) receptor mutant mice. Psychopharmacology. 1999;143(3):309–14.

    Article  CAS  PubMed  Google Scholar 

  117. Rowland NE, Robertson K, Green DJ. Effect of repeated administration of dexfenfluramine on feeding and brain Fos in mice. Physiol Behav. 2003;78(2):295–301.

    Article  CAS  PubMed  Google Scholar 

  118. Rowland NE. Long-term administration of dexfenfluramine to genetically obese (ob/ob) and lean mice: body weight and brain serotonin changes. Pharmacol Biochem Behav. 1994;49(2):287–94.

    Article  CAS  PubMed  Google Scholar 

  119. Rowland NE, Rokadia S, Green DJ, Robertson K. Relationship between anorexia and loss of serotonin uptake sites in brain of mice and rats receiving d-norfenfluramine or d-fenfluramine. Pharmacol Biochem Behav. 2004;77(3):541–6.

    Article  CAS  PubMed  Google Scholar 

  120. Foltin RW, Moran TH. Food intake in baboons: effects of a long-acting cholecystokinin analog. Appetite. 1989;12(2):145–52.

    Article  CAS  PubMed  Google Scholar 

  121. Rogers PJ, Blundell JE. Effect of anorexic drugs on food intake and the micro-structure of eating in human subjects. Psychopharmacology. 1979;66(2):159–65.

    Article  CAS  PubMed  Google Scholar 

  122. McGuirk J, Goodall E, Silverstone T, Willner P. Differential effects of d-fenfluramine, l-fenfluramine and d-amphetamine on the microstructure of human eating behaviour. Behav Pharmacol. 1991;2(2):113–9.

    Article  PubMed  Google Scholar 

  123. Vivero LE, Anderson PO, Clark RF. A close look at fenfluramine and dexfenfluramine. J Emerg Med. 1998;16(2):197–205.

    Article  CAS  PubMed  Google Scholar 

  124. Rothman RB, Baumann MH. Serotonin releasing agents. Neurochemical, therapeutic and adverse effects. Pharmacol Biochem Behav. 2002;71(4):825–36.

    Article  CAS  PubMed  Google Scholar 

  125. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581–8.

    Article  CAS  PubMed  Google Scholar 

  126. Nelson DL, Gehlert DR. Central nervous system biogenic amine targets for control of appetite and energy expenditure. Endocrine. 2006;29(1):49–60.

    Article  CAS  PubMed  Google Scholar 

  127. Rowley HL, Butler SA, Prow MR, Dykes SG, Aspley S, Kilpatrick IC, et al. Comparison of the effects of sibutramine and other weight-modifying drugs on extracellular dopamine in the nucleus accumbens of freely moving rats. Synapse. 2000;38(2):167–76.

    Article  CAS  PubMed  Google Scholar 

  128. Wortley KE, Heal DJ, Stanford SC. Modulation of sibutramine-induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by alpha2-adrenoceptors. Br J Pharmacol. 1999;128(3):659–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. McNeely W, Goa KL. Sibutramine. A review of its contribution to the management of obesity. Drugs. 1998;56(6):1093–124.

    Article  CAS  PubMed  Google Scholar 

  130. Hauner H, Meier M, Wendland G, Kurscheid T, Lauterbach K. Weight reduction by sibutramine in obese subjects in primary care medicine: the SAT Study. Exp Clin Endocrinol Diabetes. 2004;112(4):201–7.

    Article  CAS  PubMed  Google Scholar 

  131. Smith IG, Goulder MA. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract. 2001;50(6):505–12.

    CAS  PubMed  Google Scholar 

  132. Wooltorton E. Obesity drug sibutramine (Meridia): hypertension and cardiac arrhythmias. CMAJ. 2002;166(10):1307–8.

    PubMed  PubMed Central  Google Scholar 

  133. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363(10):905–17.

    Article  CAS  PubMed  Google Scholar 

  134. Lam DD, Przydzial MJ, Ridley SH, Yeo GS, Rochford JJ, O’Rahilly S, et al. Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology. 2008;149(3):1323–8.

    Article  CAS  PubMed  Google Scholar 

  135. Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, et al. Serotonin 2 C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 2007;6(5):398–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wagner S, Brierley DI, Leeson-Payne A, Jiang W, Chianese R, Lam BYH, et al. Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression. Mol Metab. 2023;68:101665.

    Article  CAS  PubMed  Google Scholar 

  137. Martin BR, Compton DR, Semus SF, Lin S, Marciniak G, Grzybowska J, et al. Pharmacological evaluation of iodo and nitro analogs of delta 8 -THC and delta 9 -THC. PharmacolBiochemBehav. 1993;46:295–301.

    CAS  Google Scholar 

  138. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96(10):3067–77.

    Article  CAS  PubMed  Google Scholar 

  139. Colman E, Golden J, Roberts M, Egan A, Weaver J, Rosebraugh C. The FDA’s assessment of two drugs for chronic weight management. N Engl J Med. 2012;367(17):1577–9.

    Article  CAS  PubMed  Google Scholar 

  140. de Andrade Mesquita L, Fagundes Piccoli G, Richter da Natividade G, Frison Spiazzi B, Colpani V, Gerchman F. Is lorcaserin really associated with increased risk of cancer? A systematic review and meta-analysis. Obes Rev. 2021;22(3):e13170.

    Article  PubMed  Google Scholar 

  141. He Y, Liu H, Yin N, Yang Y, Wang C, Yu M, et al. Barbadin Potentiates Long-Term Effects of lorcaserin on POMC neurons and weight loss. J Neurosci. 2021;41(26):5734–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. He Y, Brouwers B, Liu H, Lawler K, Mendes de Oliveira E, Lee DK, et al. Human loss-of-function variants in the serotonin 2 C receptor associated with obesity and maladaptive behavior. Nat Med. 2022;28(12):2537–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Gorelik E, Gorelik B, Masarwa R, Perlman A, Hirsh-Raccah B, Matok I. The cardiovascular safety of antiobesity drugs-analysis of signals in the FDA adverse event Report System Database. Int J Obes (Lond). 2020;44(5):1021–7.

    Article  CAS  PubMed  Google Scholar 

  144. Bohula EA, Wiviott SD, McGuire DK, Inzucchi SE, Kuder J, Im K, et al. Cardiovascular Safety of lorcaserin in overweight or obese patients. N Engl J Med. 2018;379(12):1107–17.

    Article  CAS  PubMed  Google Scholar 

  145. FDA. Safety clinical trial shows possible increased risk of cancer with weight-loss medicine Belviq, Belviq XR (lorcaserin., ) 2020 [Available from: https://www.fda.gov/drugs/drug-safety-and-availability/safety-clinical-trial-shows-possible-increased-risk-cancer-weight-loss-medicine-belviq-belviq-xr.

  146. Bialer M, Perucca E. Lorcaserin for Dravet Syndrome: a potential advance over fenfluramine? CNS Drugs. 2022;36(2):113–22.

    Article  CAS  PubMed  Google Scholar 

  147. Doslikova B, Garfield AS, Shaw J, Evans ML, Burdakov D, Billups B, et al. 5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication: an effect mediated via increased proportion of pro-opiomelanocortin neurons activated. J Neurosci. 2013;33(23):9800–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Li L, Wyler SC, León-Mercado LA, Xu B, Oh Y, Swati et al. Delineating a serotonin 1B receptor circuit for appetite suppression in mice. J Exp Med. 2022;219(8).

  149. Negro A, Koverech A, Martelletti P. Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential. J Pain Res. 2018;11:515–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Authors of this manuscript were supported by grants from the USDA/CRIS (51000-064-01 S to YX) and NIH (F32DK134121 to KC).

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Authors and Affiliations

  1. USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, USA

    Kristine Conde & Yong Xu

  2. College of Art and Sciences, Washington University in St. Louis, St. Louis, MO, USA

    Shuzheng Fang

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, USA

    Yong Xu

  4. Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Houston, TX, 77030, USA

    Yong Xu

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  1. Kristine Conde
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  2. Shuzheng Fang
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  3. Yong Xu
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KC and YX contributed to the literature search and writing of the manuscript. SF edited the manuscript and contributed to figure production. All authors read and approved the final manuscript.

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Conde, K., Fang, S. & Xu, Y. Unraveling the serotonin saga: from discovery to weight regulation and beyond - a comprehensive scientific review. Cell Biosci 13, 143 (2023). https://doi.org/10.1186/s13578-023-01091-7

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Keywords

Cell & Bioscience

ISSN: 2045-3701

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