Serotonin signaling to regulate energy metabolism: a gut microbiota perspective

Abstract

Serotonin is one of the most potent gastrointestinal, peripheral, and neuronal signaling molecules and plays a key role in regulating energy metabolism. Accumulating evidence has shown the complex interplay between gut microbiota and host energy metabolism. In this review, we summarize recent findings on the role of gut microbiota in serotonin metabolism and discuss the complicated mechanisms by which serotonin, working in conjunction with the gut microbiota, affects total body energy metabolism in the host. Gut microbiota affects serotonin synthesis, storage, release, transport, and catabolism. In addition, serotonin plays an indispensable role in regulating host energy homeostasis through organ crosstalk and microbe–host communication, particularly with a wide array of serotonergic effects mediated by diverse serotonin receptors with unique tissue specificity. This fresh perspective will help broaden the understanding of serotonergic signaling in modulating energy metabolism, thus shedding light on the design of innovative serotonin-targeting strategies to treat metabolic diseases.

Graphical abstract

Keywords

serotonin / gut microbiota / metabolism / gut–brain axis

Introduction

Serotonin, or 5-hydroxytryptamine (5-HT), is a small monoamine molecule that is widely recognized as a central regulator of neuropsychological processes in human central nervous system (CNS). Moreover, serotonin has crucial physiological functions in the periphery, including modulation of cardiac contraction [1], gut motility and fluid secretion [2], vasoconstriction [3–5], bone formation [6], and coagulation [7]. Throughout phylogenetic history, serotonin plays vital roles in the metabolism of various organisms including unicellular organisms, plants, and animals [8]. A range of serotonergic signaling pathways remain to regulate energy metabolism in primitive animals at different stages of evolution [9–12]. These pathways have been conserved in humans and some primate mammals, functioning both in the CNS and peripheral nervous system.

Over the past few years, the key effects of gut microbiota on the regulation of serotonin level and function have garnered increasing attention. The gut microbiota, often referred to as a “forgotten organ”, is now acknowledged as playing a fundamental role in host physiology, including the regulation of the immune response, synthesis of vitamins, development of the gut barrier, and production of bioactive metabolites [13], as well as regulating dietary energy extraction, fat storage, and insulin sensitivity [14]. Notably, the gut microbiota can influence host serotonin synthesis and serotonergic signaling [15]. Gut-derived serotonin not only impacts the local function of the gut, including motility and secretion, but also communicates with distant organs, such as the liver and pancreas [16]. Furthermore, accumulating evidence has indicated that gut serotonin communicates with the serotonergic signaling in the brain via the gut–brain axis, and vice versa [17]. This bidirectional communication highway allows serotonin to play a significant role in host metabolism [18], under the regulatory action of gut microbiota.

In this review, we summarize the present status of the role of gut microbiota in serotonin metabolism, and discuss the various mechanisms by which serotonin, working in conjunction with the gut microbiota, affects total body energy metabolism in the host. Specifically, we explore how the gut microbiota affects serotonin synthesis, release, transportation, and catabolism, and how these factors interact to regulate host energy homeostasis. The fresh perspective will help expand the understanding of serotonin in modulating energy metabolism. We also consider potential serotonin-targeting treatment options based on gut microbiota modulation in managing metabolic diseases.

Serotonin metabolism and the impact of the gut microbiota

Source and synthesis

In mammals, the essential amino acid tryptophan (Trp) serves as the sole source of serotonin. The metabolism of serotonin within various cells and organs is summarized in Fig. 1. Although the majority of absorbed Trp is directed into the kynurenine pathway via indoleamine 2,3-dioxygenase (IDO) in extrahepatic organs, or tryptophan 2,3-dioxygenase in the liver, culminating in NAD⁺ synthesis [19], around 3% of absorbed Trp is converted into serotonin [20]. The rate-limiting step in serotonin synthesis is the conversion of Trp into 5-hydroxytryptophan (5-HTP) by Trp hydroxylase (TPH). Subsequently, 5-HTP is decarboxylated to serotonin by the action of aromatic l-amino acid decarboxylase (AADC) [21] (Fig. 1a).

Two isoforms of TPH exist: TPH1, predominantly found in the pineal gland and peripheral tissues, and TPH2, prevalent in nervous systems (Fig. 1b). TPH1 exhibits a higher efficiency in binding and hydroxylating Trp than TPH2 [22]. TPH1 is primarily expressed in enterochromaffin (EC) cells, a type of enteroendocrine cells. EC cells account for the synthesis of at least 90% of peripheral serotonin [23]. TPH1 is also expressed at other locations to synthesize serotonin for local physiological functions. For example, in response to metabolic stress such as a sudden rise in glucose levels, the pancreatic β cells upregulate TPH1 expression to boost serotonin production, thereby enhancing the capacity to produce insulin [24]. In addition, the pineal gland expresses TPH1 to produce serotonin, as a precursor of melatonin, which is involved in maintaining circadian rhythm [25]. Peripheral serotonin is not capable of crossing the blood–brain barrier [26]. TPH2 is primarily expressed in the raphe nuclei of the brainstem which is the principal source of serotonergic neurons [27] and dominates serotonin synthesis within the CNS. In addition, TPH2 is also expressed in the enteric nervous system (ENS) for the synthesis of serotonin, which is essential for the development of ENS and for regulating gut motility [28].

Release and transportation

Once synthesized in EC cells that exclusively express TPH1, gut serotonin is packed into large dense core vesicles (LDCVs) through the action of vesicular monoamine transporter 1 (VMAT1) (Fig. 1b) [29]. The efficiency of VMAT1 (or VMAT2 in serotonergic neurons) in sequestering serotonin is dependent on a proton gradient, which is driven by the V-type ATPase located on the LDCV membrane [30]. Upon exposure to physical or chemical stimuli, a non-specific Ca²⁺ influx is activated, facilitating the movement of the cytoskeleton and thus assisting in the transport of LDCVs toward the basolateral membrane, resulting in the release of serotonin. Piezo2, recently identified as an EC cell mechanosensor, initiates a prolonged Ca²⁺ current upon stretching [31, 32]. While Del Rosario and colleagues have attempted to elucidate the activation process of Piezo2 through a dual G-protein interaction approach [33], the detailed molecular mechanism by which Piezo2 senses mechanical force and functions remains to be unraveled. The transient receptor potential A1 (TRPA1) ion channel, a broad-spectrum chemosensor located on the EC cell surface [34], triggers serotonin release upon chemical stimulation [35]. Notably, the Ca²⁺ currents derived from these sensor channels elicit the activation of voltage-gated calcium (Ca_v) channels or the endoplasmic reticulum (ER) Ca²⁺ release, causing significant intracellular Ca²⁺ changes to trigger serotonin release [36, 37].

To prevent overstimulation of serotonergic receptors, extracellular serotonin released by EC cells is absorbed by neighboring enterocytes or enters the portal circulation. Enterocytes take up surplus serotonin via the serotonin transporter (SERT) (Fig. 1a and b) [38], and partially degrade serotonin by the mitochondrial enzyme monoamine oxidase A (MAO-A) [39]. Given that serotonin can readily elicit vasoconstriction and coagulation in the circulation [3, 7], a substantial portion of serotonin is sequestered from target sites by SERT-expressing platelets [40]. Although platelets express MAO-B [41], this isoform appears to have a much lower affinity for serotonin compared to MAO-A [42], allowing platelets to purely serve as vehicles for peripheral serotonin without degrading it. Although it has been noticed that under certain scenarios like inflammation and vascular damage, platelets release serotonin [43], it remains uncertain to what extent the platelet-binding serotonin regulates peripheral metabolism. Besides the majority of peripheral serotonin is stored in platelets [44], less than 5% of serotonin also circulates in a free form, which is able to interact with distal organs and regulate their metabolism, a topic that will be explored in detail in the following sections.

Catabolism

The major part of released serotonin in EC cells and serotonergic neurons is deaminated into 5-hydroxyindole aldehyde by MAO-A, which is predominantly expressed in the gut, liver, brain, and ENS (Fig. 1a) [45]. Then, aldehyde dehydrogenase (ALDH) converts 5-hydroxyindole aldehyde into 5-hydroxyindole acetic acid (5-HIAA), the ultimate metabolite of serotonin (Fig. 1a and b). Given its stable chemical properties, Fukui et al. [46] proposed to replace serotonin with 5-HIAA as the primary biomarker when studying the relationship between certain phenotypes and serotonin levels. Recently, 5-HIAA was demonstrated to be a ligand for G-protein-coupled receptor GPR35 to promote the recruitment of neutrophils and play a role in inflammation resolution and bacterial clearance [47]. Besides conversion into 5-HIAA, mammals have two other routes to metabolize serotonin. As an indoleamine derivative, serotonin is a substrate of IDO, which can be converted into N-[2-(3-aminopropanoyl)-4-hydroxyphenyl]formamide [48]. In the pineal gland, arylalkyl amine N-acetyltransferase, together with hydroxyindole O-methyltransferase, transforms serotonin into melatonin [49].

Signaling pathways

Serotonin receptors

Unlike proteins with unique three-dimensional structures, serotonin consists of a limited atomic composition and a relatively simple but clear structure. The wide array of serotonergic effects is mediated by diverse serotonin receptors with unique tissue specificity. To date, 13 G protein-coupled receptors, i.e. 5-HTR_{1A, 1B, 1D, 1E, 1F}, 5-HTR_{2A, 2B, 2C}, 5-HTR₄, 5-HTR_{5A, 5B}, 5-HTR₆, and 5-HTR₇, and a ligand-gated ion channel (5-HTR₃), have been identified in mammals [50, 51]. Members of the subfamily of 5-HTR_1s, sharing 40%−63% sequence identity in humans, are all coupled to G_αi/G_αo proteins to inhibit cyclic adenosine monophosphate (cAMP) formation. Depletion or pharmacological blockade of 5-HTR_1s-mediated signaling have been related to depressive and anxiety disorders [52]. Recent evidence has shown that 5-HTR_1A plays a role in appetite control, particularly alcohol and sucrose consumption [53]. 5-HTR_1B has also been found to play an important role in the anorectic effect induced by antimigraine drug triptan [54]. 5-HTR_2A−2C preferentially couple to G_q/G₁₁ to enhance intracellular inositol phosphate and Ca²⁺ concentration, with longknown roles in regulating CNS activity and muscle contraction [55]. In addition, hepatic 5-HTR_2A and 5-HTR_2B signaling might contribute to hepatic fibroblast growth factor-21 (FGF21) production and the pathophysiological mechanisms of type 2 diabetes (T2D) and metabolic dysfunction-associated fatty liver disease (MAFLD) [56]. 5-HTR_2C is widely expressed in the hypothalamic regions that control feeding behavior and energy expenditure, thus activation of 5-HTR_2C affects energy homeostasis [57]. Mice with a genetic mutation of 5-HTR_2C display hyperphagia prior to hyperinsulinemia, insulin resistance, impaired glucose tolerance, and weight gain [58]. 5-HTR_5s are G_i/G_o coupled receptors and transduce signals via inhibiting adenylate cyclase activity, consequently decreasing cAMP. Activation of 5-HTR_5s exerts an antimigraine effect and improves sleep [50]. On the contrary, 5-HTR₄, 5-HTR₆, and 5-HTR₇ receptors couple with G_s receptors to preferentially trigger a second messenger cascade mediated by protein kinase A to increase cAMP. As an exception, 5-HTR₃ facilitates a fast postsynaptic excitatory response via the non-selective influx of Na⁺ and Ca²⁺, and over-activation of 5-HTR₃ causes vomiting, pain, schizophrenia, and intestinal motility abnormalities [59, 60]. The serotonergic system continually regulates host metabolism through the multiplicity of serotonin receptors (ionotropic and metabotropic), which possess both a fast and precise communication modality and a broader and slower way to regulate metabolic processes. Moreover, the high spatiotemporal variability of their expression is closely associated with the specificity of the serotonin effects [61].

Intracellular post-translational modification

Within the cytoplasm, serotonin takes part in post-translational modification of proteins, i.e. “serotonylation”, to impact molecular signaling by these proteins. Serotonylation of intracellular proteins regulates various physiological processes depending on the location within the body, such as platelet aggregation, insulin release, muscle contraction, and neuron differentiation. Many proteins, including small guanosine triphosphatases (GTPases) (Rab3a, Rab27a, Rab4, Ras homology family member A [RhoA], Ras-related C3 botulinum toxin substrate 1 [Rac1], and cell division cycle 42 [Cdc42]), cytoskeletal proteins (myosin heavy chain, α-actin, β-actin, γ-actin, and actin-binding protein filamin A), extracellular matrix protein fibronectin, and histones have been described as substrates for serotonylation [62]. Intracellular serotonin regulates insulin secretion from pancreatic β cells through serotonylation of GTPases (Rab3a and Rab27a), and mice selectively deficient in serotonin develop diabetes [63]. Serotonylation has first been shown in platelets, with serotonylation of GTPases by transglutaminases increasing the release of coagulation effectors that induce platelet aggregation [64]. An analogous mechanism has sequentially been identified in β cells of the pancreas, where serotonylation of GTPases promotes insulin secretion [63]. In addition, serotonylation of the small GTPase Rab4 in skeletal muscle cells enhances glucose transporter type 4 (GLUT4) translocation to the cell membrane and increases glucose uptake into the cell, thus improving glucose homeostasis [65].

Not only GTPases but also histones can be serotonylated. Histone serotonylation, the first identified endogenous monoamination modification of histone, is described as a novel epigenetic regulatory mechanism [66]. Farrelly et al. found that serotonylation of glutamine at position five on histone H3 (H3Q5ser) promotes its interplay with the transcription factor TFIID (TATA-box-binding protein [TBP] and TBP-associated factors [TAFs]) in collaboration with adjacent histone H3 lysine 4 (H3K4) trimethylation. The dual modification facilitates locus-specific gene expression during neuron differentiation and, consequently, the development of the CNS [67]. WD repeat-containing protein 5 (WDR5) was later described as a specific “reader” for H3Q5ser, which deciphers epigenetic signals to activate neurodevelopment-related genetic programs. Mechanically, WDR5 colocalizes with H3Q5ser in the promoter regions of oncogenes in neuroblastoma cells and facilitates gene transcription to induce cell differentiation and promote tumorigenesis [68].

Furthermore, abnormal serotonylation is associated with several metabolic diseases. Because intracellular serotonin regulates insulin secretion from pancreatic β cells through serotonylation of Rab3a and Rab27a, mice selectively deficient in serotonin develop diabetes [63]. In addition, elevated fibronectin serotonylation is observed in pulmonary artery smooth muscle cells of experimental animal models of hypertension and patients with pulmonary hypertension, indicating that fibronectin serotonylation may serve as a biomarker for pulmonary hypertension [69].

In conclusion, serotonin is more than a neurotransmitter. The widely expressed and diverse serotonin receptors, as well as the recently discovered role of serotonin in protein serotonylation, contribute to revealing unknown cellular mechanisms controlled by serotonin.

Interaction between gut microbiota and serotonin

The gut microbiota, an integral consortium of organisms that maintains a symbiotic relationship within the host's gut, exerts various essential biological functions themselves and through their metabolites. Gut-derived serotonin plays a crucial role in bridging the interaction between the host and microorganisms, providing an effective approach to understanding the impact of gut microbiota on host physiology.

The impact of gut microbiota on serotonin synthesis and release

By using gnotobiotic mouse models, mechanistic insight has been gained into how gut microbiota regulates serotonin levels in the gut. As given in Table 1, gut microbiota influences serotonin synthesis within the gut lumen through at least four distinct mechanisms. Firstly, certain bacterial species, including Corynebacterium [70], Streptococcus [71], and Escherichia coli (E. coli) [72], are capable of synthesizing Trp due to their inherent expression of Trp synthase [85], which provides an auxiliary source for EC cells to synthesize serotonin. Secondly, the expression of serotonin-synthesizing genes in EC cells can be upregulated by several species, such as Akkermansia muciniphila, Clostridium ramosum (C. ramosum), Bifidobacterium, Ruminococcus gnavus, and E. coli [73–78]. Thirdly, some bacterial species can metabolize Trp to kynurenine or indole derivatives, thereby reducing Trp in the gut lumen as the substrate for serotonin synthesis [80–82, 86, 87]. Finally, Enterococcus faecalis per se is reported to express AADC, adding to serotonin production within the gut lumen [79].

Little is known about which aspects of serotonin releases could be regulated by gut microbiota except for TRPA1. Trp metabolites produced by Edwardsiella tarda stimulate TRPA1 on enteroendocrine cells, resulting in the secretion of serotonin to increase intestinal motility and stimulate both vagal sensory ganglia and cholinergic enteric neurons [82].

The impact of gut microbiota on serotonin transportation

As for serotonin transportation from interstitial space into intestinal epithelial cells, gut microbiota plays an indispensable modulating role through multiple mechanisms. Firstly, certain gut microbes, such as Akkermansia muciniphila, can directly modulate SERT expression on intestinal epithelia cells via secretion of specific proteins. For instance, the outer membrane protein Amuc_1100, released by Akkermansia muciniphila, can activate Toll-like receptor 2 in the Caco-2 intestinal epithelial cell model, leading to the downregulation of SERT expression and an increase in extracellular serotonin levels [73]. In contrast, the supernatant of Saccharomyces boulardii has been found to upregulate SERT expression by enhancing the release of heparin-binding epidermal growth factor and activating the epidermal growth factor receptor [83], as a consequence inhibiting gut motility, thereby providing a potential therapeutic strategy for disorders like irritable bowel syndrome (IBS). Secondly, gut microbiota can indirectly affect SERT expression by interacting with the intestinal immune system. For instance, lipopolysaccharide could stimulate mast cells to release prostaglandin E2, which subsequently inhibits SERT expression, leading to increased intestinal serotonin levels and exacerbating the inflammatory response [38].

Moreover, certain gut bacteria have been found to harbor proteins similar to the SERT, enabling them to interact with host serotonin metabolism directly. Turicibacter sanguinis (T. sanguinis) synthesizes a protein related to the neurotransmitter sodium symporter family, sharing similarities in structure and sequence with mammalian SERT [84]. This protein allows T. sanguinis to transport intracellular serotonin, thereby immediately increasing serotonin levels in the intestinal lumen. Interestingly, this transport process in T. sanguinis can be halted by fluoxetine, a drug known for its inhibitory effect on serotonin reuptake. There is no evidence yet that gut microbiota plays a solid role in serotonin catabolism.

Serotonin modulates gut microbiota community

As evident from the previous section, gut microbiota thus plays a crucial role in regulating serotonin metabolism in the gut. Meanwhile, gut microbiota is also subject to be modulated by serotonin signaling. Increasing intestinal luminal serotonin enriches the relative abundance of spore-forming bacteria [84]. Moreover, serotonin levels in the gut are also associated with virulent phenotypes of specific opportunistic pathogens [88, 89]. These findings suggest the existence of serotonin pathways within gut bacteria involved in regulating bacterial growth and function.

Like serotonin exerting effects on the host through a plethora of 5-HTRs, serotonin plays equally complex roles in the microbial milieu of the gut. Aman et al. have reported a bacterial-specific serotonin receptor CpxA, which is a membrane-bound histidine sensor kinase [90]. Serotonin triggers the dephosphorylation of CpxA, inhibiting the activation of virulence genes overseen by the transcription factor CpxR. It especially affects those genes that pose a threat to the structural integrity of the host intestine. Although bacteria do possess a neurotransmitter sodium symporter-related protein with sequence and structural homology to host mammalian SERT [84], suggesting the possibility of serotonylation within bacteria, protein serotonylation in bacteria has not been described yet. These exciting discoveries reveal that serotonin has an important but still poorly understood role in modulating the gut microbiota community, and further research is necessary to provide insights into the underlying modulation pathways of serotonin on gut microbiota.

Serotonin regulates energy metabolism as modulated by gut microbiota

Serotonin exerts metabolic effects in both the CNS and peripheral tissues through distinct serotonin receptors. Figure 2 briefly portrays the regulation of host energy metabolism by serotonin in multiple tissues, the impact of gut microbiota, and the involvement of the gut–brain axis, which will be detailed in this section.

CNS

Serotonin within the CNS has been proven to orchestrate total body energy metabolism (Fig. 2). In animal models of obesity, baseline serotonin release from the hypothalamus was found to be lower [91]. People carrying loss-of-function variants in 5-HTR_2C, which is primarily expressed on hypothalamic proopiomelanocortin (POMC) neurons, have hyperphagia and weight gain in childhood, leading to severe obesity [92]. A clinical trial supported that high-fat high-sugar snacking might decrease extracellular serotonin through a decreased SERT in the hypothalamic region, resulting in abnormal appetite and a higher risk of obesity [93]. Given the mounting evidence for serotonin as a key neurotransmitter in regulating energy metabolism, attempts to target serotonin signal regulation in specific brain nucleus have emerged to attenuate obesity and related comorbidities [94–98].

Decades of studies together have led to a promising proposal that central serotonin reduces food intake via two independent patterns, i.e. the energy-balancing pattern and the reward-restricting pattern [91]. Both patterns originate from serotonergic neurons in the brainstem raphe nuclei [99]. The energy-balancing pathway is activated when energy intake surpasses the body's needs, inhibiting cerebral aspects governing food consumption. This pathway interacts primarily with metabolic state-sensing neurons such as POMC-expressing neurons and those expressing agouti-related peptide (AgRP) and neuropeptide Y (NPY) [100], which mainly produce anorexigenic effects through stimulation of 5-HTR_2C [101] and 5-HTR_1B [54], respectively. A recent study showed a serotonin 1B receptor circuit (5-HTR_1B^AgRP→paraventricular nucleus circuit) for appetite suppression in mice, which suggested that 5-HTR_1B is a potential new target in 5-HT-based weight-loss therapies. 5-HTR_1B and 5-HTR_2C act on different neural pathways for appetite suppression in mice and can be targeted for obesity treatment independently [54]. In addition, serotonin activates preproglucagon neurons in the brainstem to synthesize glucagon-like peptide 1 (GLP-1) [102], further suppressing food intake. Meanwhile, the reward-restricting pathway limits hedonic eating behavior involving the pleasure-responsible mesolimbic system, particularly dopaminergic neurons equipped with 5-HTR_2C [103]. Activation of 5-HTR_2C in these neurons diminishes binge eating and motivational food intake [104]. Serotonin-innervated gamma-aminobutyric acid (GABAergic) neurons also reduce motivational eating behavior upon 5-HTR_2C triggering [105]. Thus, there have been some supporting theories for the idea that overactivity of the appetite-inhibiting pathway can lead to a deficit of pleasure reward. However, obesity and depression usually exhibit high comorbidity [106], indicating the complex roles of serotonergic neurons in the modulation of motivational eating behavior.

Apart from central inhibition of appetite, there has been a rising interest in the relationship between central serotonin and the regulation of peripheral thermogenic adipose tissue [107]. Intriguingly, eliminating serotonergic neurons by diphtheria toxin impairs thermogenesis within brown adipose tissue (BAT) and beige adipose tissue, implying a vital role of central serotonin in energy expenditure [108]. 5-HTR-expressing steroidogenic factor 1 neurons in the ventral medial nucleus are proposed to be required for the modulation of thermogenesis, especially in high-fat diet (HFD) conditions [109]. In addition, pharmacological activation of central GLP-1 receptor (GLP-1R) signaling expressed by serotonergic neurons [110–112] augments the activity of thermogenic adipose tissue and enhances the utilization of circulating glucose and triglycerides [113, 114]. However, total body GLP-1R knockout (KO) mice maintain brown fat thermogenesis [114], indicating the presence of a sub-population of neurons regulating energy expenditure, and further research should focus on those extraordinary serotonergic neurons involved in appetite and thermogenesis.

The gut microbiota plays a crucial role in influencing CNS physiological homeostasis, such as mood, appetite, pain perception, and stress responses [115, 116], probably with serotonin as one of the underlying bridges [117]. Emerging evidence suggests a relationship between gut microbiota and central serotonin alterations that might impact appetite regulation [118], which is potentially attributed to changes in circulating Trp levels [119, 120]. In addition, gut-derived serotonin can stimulate 5-HTR₃-expressing neurons in the gastro-intestinal tract, which send signals to the CNS via the vagus nerve [121]. Whether gut-derived 5-HTR₃ signals could influence appetite and energy expenditure remains unclear. Moreover, gut-derived serotonin can affect the secretion of other gut-derived hormones such as GLP-1 [122], which can cross the blood–brain barrier to exert metabolism-regulating effects in the CNS or stimulate the activity of vagal afferents similarly to serotonin [102]. This intricate interplay between gut hormones, gut microbiota, and CNS serotonin signaling provides a novel perspective on energy regulation and metabolic health, underlining the complexity of the gut–brain axis in health and disease management.

Gut

Numerous studies suggest that peripheral serotonin also plays an indispensable role in regulating nutrient absorption and storage [123]. Gut motility is closely regulated by local serotonin, irrespective of its origin from EC cells or ENS [124, 125] (Fig. 2). Increased nutritional signaling in the lumen stimulates EC cells to secrete serotonin [126], activating the 5-HTR₃ in afferent neurons of ENS to initiate the gut peristalsis through the gut–brain axis [121]. Meanwhile, activation of 5-HTR₄ on EC cells evokes a more drastic release of serotonin, consolidating the intensity of serotonergic inputs to ENS, thereby maintaining gut motility [127]. TPH1/2-targeting medications have been applied to treat diseases with abnormal gastrointestinal motility [128]. In addition to gut motility, serotonin stimulates gastric emptying, as a shortage of serotonin in the gut was shown to be associated with delayed gastric emptying [129].

Besides, emerging evidence demonstrates that gut-derived serotonin interacts with other gut hormones [130]. GLP-1 is one of the most acknowledged gut hormones that improve metabolism by inducing satiety [131]. In a study using organoids, EC cells have been discovered to express GLP-1R, and GLP-1R agonism increases the secretion of serotonin [132]. Reciprocally, GLP-1-producing L cells also express 5-HTR_3/4 to allow for regulation by serotonin [122, 133]. However, whether activation of 5-HTRs in L cells enhances GLP-1 secretion has not been described yet. Further efforts are required to verify this hypothesis and explore potentially additional interfaces between serotonin and other gut hormones.

Accumulating evidence has shown that gut microbiota fundamentally manipulates the physiology of intestinal peristalsis with serotonin as a commander. The identified microbiome–metabolome signatures for IBS, a group of diseases characterized by gut motility dysfunction, are associated with altered serotonin metabolism and unfavorable stress responses related to gastro-intestinal symptoms, supporting a role of the microbiota–gut–brain circuit in the pathogenesis of IBS [134]. Indeed, depletion of gut microbiota with antibiotics impairs gut motility, which is attributed to decreased colonic serotonin [135]. Furthermore, colonization of germ-free mice with microbiota from conventional mice increases neuronal and mucosal serotonin production accompanied by elevated intestinal transit rates [136]. These studies emphasize the indispensable role of gut microbiota in regulating gut motility. In addition, in a mouse model of autism spectrum disorder, delayed intestinal transit and impaired serotonin production strongly correlated with the abundance of the Blautia genus of the Clostridiales [137]. As mentioned above in the Section “Interaction between gut microbiota and serotonin”, gut microbiota can release metabolites that regulate the expression of host serotonergic genes. For example, Zhai et al. proposed that phenylamine and tryptamine produced by Ruminococcus gnavus accelerate gastrointestinal motility and trigger IBS by increasing TPH1 expression via the stimulation of amine-associated receptor 1 [77]. Accordingly, with the orchestration of gut microbiota, serotonin maintains the homeostasis of gut motility via the gut–brain axis, thereby regulating nutrient absorption and host energy metabolism.

Liver

As a metabolic hub, the liver is responsible for the biosynthesis and biodegradation of major energy substrates for use by peripheral tissues. Recently, serotonin has emerged as an important regulator by which the liver can adapt to environmental changes [138–140] (Fig. 2). In the context of a nutrition crisis, gluconeogenesis and glycogenolysis are triggered in hepatocytes. Under fasting conditions, gut-derived serotonin activates 5-HTR_2B on hepatocytes to enhance the activity of fructose-1,6-bisphosphatase and glucose-6-phosphatase (G6Pase), thus promoting gluconeogenesis, as well as to suppress hepatic glucose uptake via GLUT2, thereby maintaining circulating glucose in a coordinated manner [138]. Conversely, in diet-induced obese mice, knocking out 5-HTR_2C increases hepatic glucose production, indicating how serotonin regulates hepatic gluconeogenesis [139]. Fluoxetine is applied as a first-line antidepressant through increasing extracellular levels of serotonin. However, fluoxetine also induces severe metabolic disorders such as dyslipidemia and hyperglycemia, associated with downregulated hepatic G6Pase expression and enhanced transformation of glucose to lipid, which might be a serotonin-dependent mechanism facilitating hepatic steatosis [140].

Similarly, multiple studies have reported that gut-derived serotonin is closely related to lipid deposition in the liver [141–144], the core pathology of metabolic dysfunction-associated steatotic liver disease (MASLD). Total body Tph1-KO mice fed an HFD showed protection against hepatic steatosis [141]. It has been further shown that eliminating gut-derived serotonin by intestine-specific Tph1-KO markedly ameliorates hepatic steatosis [145], revealing a close relationship between gut-derived serotonin and hepatic lipid metabolism. The 5-HTR_2A signal in the liver has been known as the predominant transduction pathway to regulate genes like sterol regulatory element-binding protein 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma (PPARγ) [145, 146], which play a crucial role in the control of hepatic lipid metabolism. Based on this understanding, gut-derived serotonin exacerbates hepatic steatosis through direct actions on liver, and gut TPH1–liver 5-HTR_2A axis might be a potential drug target for anti-MASLD therapies.

In addition to inducing liver steatosis, serotonin is a key player in the development of steatohepatitis. Within the catabolic pathway, serotonin is oxidized by MAO-A accompanied by generation of many free radicals, exacerbating oxidative stress in the liver [147]. Serotonin also induces the expression of inflammation factors like tumor necrosis factor α and interleukin-6, which can be prevented by the TPH1 inhibitor LP533401. In addition, during the onset of liver damage, serotonin plays a critical role in the characteristic phenotypic remodeling of hepatic stellate cells, crucially involved in collagen production, resulting in the development of hepatic fibrosis [148].

The perturbation of gut microbiota has been increasingly recognized as a causative factor in MASLD, characterized by the increase of serotonin-rising strains like Bifidobacterium, E. coli, and Clostridium [149]. Via the hepatic portal vein system, gut-derived serotonin facilitates the pathogenesis of MASLD [145]. Taken together, the bridging role of serotonin in maintaining liver homeostasis via the gut–liver axis is being unveiled, providing a range of potentially druggable targets.

Pancreas

The pancreas is commonly known as a manager of overall carbohydrate homeostasis, with α cells producing glucagon to increase circulating glucose levels in the fasting or hypoglycemic states and β cells secreting insulin to decrease circulating glucose levels in the fed or hyperglycemic state. Aside from nutrition signals like glucose, the pancreas senses a group of peripheral or local signals in favor of insulin secretion [150]. Serotonin is found to co-exist and be co-released with insulin from β cells [151] (Fig. 2). The origin of this serotonin has been a subject of debate. On one hand, pancreatic β cells are regarded as amine precursor uptake and decarboxylation cells, and as such decarboxylate circulatory residual 5-HTP into serotonin [152, 153]. On the other hand, β-cell-specific elimination of Tph1 significantly blunts serotonin production, indicating de novo synthesis as the primary routine to produce serotonin in the islets of Langerhans [154].

The mechanism by which serotonin regulates the activity of the pancreas is ambiguous. According to predominant evidence, serotonin in the islets exerts an insulin-upregulating effect primarily via intensifying the signaling of insulin production by β cells, promoting the proliferation of β cells, reducing the glucagon excretion by α cells, and attenuating the oxidative stress in the islets [155–159]. Most of these effects above are attributed to stimulating a cluster of 5-HTRs. In addition, upon metabolic need, GTPases are serotonylated to enhance fusion of insulin-containing granules, thereby releasing insulin [63]. To reinforce the hypoglycemic effect, local serotonin in parallel binds to the 5-HTR_1F of α cells to inhibit glucagon secretion [160]. Overall, pancreatic serotonin is beneficial for energy utilization by modulating the hormone secreting pattern of pancreatic cells.

Moreover, serotonin may manipulate pancreatic physiology through the gut–brain axis. Makhmutova et al. reported that serotonin enhances communication between pancreatic β cells and nucleus of the solitary tract in the hypothalamus via 5-HTR₃-expressing vagal sensory axons [161]. Likewise, blockage of 5-HTR₃ in the afferent serotonergic axons of the pancreas decreases insulin secretion. Interestingly, the pancreas excretes elastase to the gut lumen to remodel the gut microbiota into a serotonin-increasing ecosystem [162]. Thus, with the assistance of gut microbiota, serotonin regulates the pancreatic function via the gut–brain axis.

Adipose tissue

Adipose tissue is broadly categorized into white adipose tissue (WAT) and BAT, contributing to energy storage and energy expenditure, respectively [163]. Under specific conditions, WAT can undergo a reversible transformation into a BAT-like phenotype, namely “beige” adipose tissue. This intermediate form between WAT and BAT also exhibits energy-burning capabilities akin to BAT [164]. The discovery of a comprehensive set of serotonergic genes in adipose tissue by Stunes et al. marked the initiation of studies into the potential link between serotonin and adipose tissue function [165]. Crane et al. reported that total body Tph1-KO protects HFD-fed mice from diet-induced weight gain, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) [141]. More importantly, lacking this serotonin-producing key enzyme enhances β-adrenergic receptor/cyclic adenosine monophosphate/protein kinase A signaling and consequently increases the expression of uncoupling protein 1 (UCP-1) [141], the thermogenic marker of BAT or beige adipose tissue, implying an essential role of peripheral serotonin in the regulation of thermogenic fat activity (Fig. 2). In mice with inducible Tph1-KO in adipose tissue, serotonin could attenuate energy storage in WAT via 5-HTR_2A and enhance energy expenditure in BAT via 5-HTR₃, respectively, underscoring the regulation of energy metabolism in different adipose tissues in a serotonin-dependent manner [166]. The similar phenotypes shown between total and adipose-tissue-specific Tph1-KO probably indicates the synthesis of serotonin by TPH1 in adipose tissue in situ, which plays an indispensable role in host metabolism (Fig. 1b). In addition, serotonin impairs browning of adipocytes in vitro [167], an effect that may be regulated by 5-HTR_3A signaling [166]. Although subcutaneous injection of the SERT inhibitor fluoxetine activated thermogenic adipose tissue activity and prevented weight gain in overfed rats [168], most studies support that enhanced central serotonergic signaling upon peripheral administration of fluoxetine increases energy expenditure [107–109, 113, 114].

Lipolysis and lipogenesis, two classical lipid metabolic processes within adipose tissue, are both regulated by serotonin. Fluoxetine administration inhibits the expression of adipose triglyceride lipase and PPAR-γ in visceral adipose tissue, accompanied with the protection from HFD-induced metabolic dysfunction [169]. While one study showed that 5-HTR_2A signaling suppresses lipolysis in WAT [170], another study reported that 5-HTR_2A signaling rather facilitates de novo lipogenesis in WAT [171] (Fig. 2). It seems that different subtypes of 5-HTRs exert distinct effects on lipolysis. For example, in obese mice, 5-HTR_2B is upregulated and found to be responsible for increasing the lipolysis in the visceral adipose tissue, which subsequently worsens insulin resistance through excess free fatty acids [172].

Moreover, gut microbiota plays a pivotal role in regulating adipose tissue function, with gut-derived serotonin being a key factor. With serotonin as an intermediate, gut microbiota can target immune cells within adipose tissue and local inflammation to improve insulin sensitivity. For instance, the prebiotic B-GOS® has been associated with the upregulation of Bifidobacterium spp., a demonstrated TPH1-upregulating strain, coinciding with reduced inflammation within adipose tissues [173]. Similarly, integration of dietary components like docosahexaenoic acid influences the abundance of Lachnospiraceae with increased circulating serotonin levels, which may subsequently improve adipose tissue inflammation and insulin sensitivity [174].

Skeletal muscle

Serotonin also influences the metabolism of skeletal muscles (Fig. 2). Early research indicated that through the stimulation of the key glycolytic regulator phosphofructokinase (PFK), serotonin enhances glucose utilization in skeletal muscle via tyrosine phosphorylation and subsequent intracellular repositioning of PFK [175]. Analogously, a systemic review informs that long-term administration of selective serotonin reuptake inhibitors (SSRIs) raises glycogen synthase activity, a representative marker of insulin sensitivity, in human skeletal muscles [176], which is attributed to an increasing protein kinase B Ser phosphorylation. The mechanism underlying the crosstalk between serotonin and insulin-related signals might be the 5-HTR_2A-initiating Janus kinase/signal transducer and activator of transcription pathway [177]. In addition, serotonylated GTPases promote the translocation of GLUT4 to the membrane of myocytes [65], reinforcing glucose utilization by skeletal muscles.

Dysfunction of insulin sensitivity and glucose metabolism can be caused by sarcopenia, a degenerative disorder characterized by reduced muscle mass [178]. Van Long et al. enumerated a cluster of circulatory biomarkers to diagnose sarcopenia in C57BL/6J mice, with decreased serotonin as a sarcopenia indicator [179]. Compared with healthy individuals, patients with sarcopenia have an abnormal gut microbiome profile characterized by the alteration of certain gut microbes correlated with host serotonin metabolism [180]. A metagenomics analysis from the Xiangya Sarcopenia Study demonstrated that the abundance of Clostridium, an enhancer of the expression of TPH1 in EC cells of the gut, is increased in the sarcopenia group [181]. On the other hand, transplantation of Bifidobacterium, another reported TPH1 expression enhancer, isolated from a weightlifting athlete to rodents improved the function of skeletal muscle including grip strength and endurance without toxicity, accompanied by normal serum lactate, urea nitrogen, and creatine kinase [182]. These seemingly contradictory results indicate the complexity of how gut microbiota regulates the metabolism of skeletal muscle, and warrant further elucidation of the exact role of gut-derived serotonin in skeletal muscle metabolism.

Clinical application of serotonin in metabolic disorders

Beyond regulating a wide range of physiological processes, serotonin is also implicated in various neuropsychiatric disorders (e.g. depression, anxiety, schizophrenia, obsessive-compulsive disorders, addiction, attention-deficit hyperactivity disorders, and Alzheimer's disease) [183]. In addition, it plays an important role in diseases that affect peripheral organs, including gastro-intestinal disorders (e.g. IBS and inflammatory bowel disease) [184] and cardiovascular diseases (e.g. arrhythmias, hypertension, and pulmonary hypertension) [185]. A variety of drugs targeting serotonin are currently used for diverse clinical purposes. Remarkably, in recent decades, the understanding of serotonin's role in metabolic diseases has greatly increased. A growing body of evidence shows associations of genetic variants of TPH1/2, SERT, and 5-HTRs with metabolic diseases such as obesity, T2D, and MAFLD [186–192]. In addition, increased circulating serotonin and its metabolites are associated with obesity [46], and are speculated as biomarkers for diagnosis of metabolic disorders [193]. These collective findings imply that targeting serotonin could be a potential therapeutic approach for treating metabolic diseases. Indeed, a cluster of molecules related to the serotonergic system has been reported to influence serotonin levels and host metabolism (Table 2).

Considering serotonin's peripheral effects on inhibiting thermogenesis in BAT and promoting lipid accumulation in WAT and liver, reducing peripheral serotonin levels could be an attractive attempt to ameliorate metabolic disorders. Inhibition of TPH, the rate-limiting enzyme for serotonin biosynthesis, in EC cells of the gut and the brain effectively decreases serotonin levels. The first-generation TPH inhibitors are phenylalanine analogues. Among these, p-chlorophenyl alanine (Fenclonine, PCPA) was once reported in a clinical trial to treat mental dysfunctions [212], but ended because of its side effects caused by unwanted flow into other amino acid channels [213]. PCPA inhibits serotonin synthesis by occupying Trp-binding site of TPH [214]. Oh et al. found that intraperitoneal administration of PCPA mitigates body weight gain by promoting adipose tissue thermogenesis in mice [166]. Nonetheless, PCPA can cross the blood–brain barrier and increase food intake [166]. The second-generation TPH inhibitors exclusively act on peripheral tissues [215]. LP-533401 has ameliorated adipose tissue weight and improved glucose metabolism in rodents regardless of oral [166] or intraperitoneal [141] administration. In addition, Chajadine et al. showed that inhibition of gut-derived serotonin production by LP-533401 could alleviate inflammation and atherosclerosis development in mice [216]. Interestingly, a clinical TPH inhibitor Telotristat etiprate (LX-1032 and LX-1606) has been approved to treat carcinoid syndrome diarrhea [217] and reduce intestinal inflammation [218], but has not been evaluated in metabolic disorders yet.

Inhibitors for SERT and MAO-A are to prevent serotonin from degradation and enlarge its bio-effects. Medications that reduce serotonin absorption by SERT are known as SSRIs, which are commonly used as antidepressant drugs. The first globally marketed SSRI was fluoxetine in the 1990s. Since then, the effects of fluoxetine on appetite and body weight have been observed. Heisler et al. found that fluoxetine reduces caloric intake and body weight in a dose- and time-dependent manner in rats [94]. In line, Chiu et al. demonstrated that fluoxetine decreases fat accumulation, probably attributed to decreased food intake [169]. Some small short-term clinical trials [194, 196, 197, 201] showed that not only fluoxetine but also some other new class of SSRIs like citalopram and escitalopram ameliorate binge eating behavior and induce body weight loss [219]. Despite these short-term benefits, increasing clinical research [198, 220–223] has demonstrated that long-term SSRI use is associated with metabolic risks. Notably, Gafoor et al. analyzed a cohort for over 10 years and found that long-term use of SSRIs has a high risk of weight gain [198]. Short-term SSRI use induces weight loss seemingly due to temporary appetite suppression and gastrointestinal serotonergic effects. However, with prolonged use, neuroendocrine adaptations and alterations in serotonergic regulation of appetite may lead to weight gain, as homeostatic mechanisms gradually adjust metabolic adaption over time. Another side effect of SSRIs is the retention of redundant serotonin in the liver and adipose tissue, leading to glucose intolerance and fat accumulation [195, 204]. Given the complex results of SSRIs on metabolism, issues remain to be solved before applying SSRIs to treat metabolic disorders.

MAO inhibitors, known as antidepressants, were developed in 1950s. Phenelzine, pargyline, mebanazine, and harmine were all reported to exert glucose-lowering effects via increasing insulin secretion in β cells [205, 224, 225]. Moreover, phenelzine, pargyline, and selegiline were shown to markedly alleviate fat deposition in rodents fed a high-caloric diet [226–229]. However, food intake was barely documented in these studies, leaving the effects of MAO inhibitors on appetite unknown. Because MAO inhibitors target not only serotonin but also other monoamines like catecholamine hormones [230], one should be cautious to apply them to treat metabolic disorders.

Since the 1990s, multiple agonists and antagonists for each serotonin receptor have been developed. However, very few are with high specificity. In the CNS, 5-HTR_2C takes command of negative appetite regulation [92], assisted by 5-HTR_1A [231]. Most 5-HTR_2C (ant) agonists share affinity with 5-HTR_2A and 5-HTR_2B because of the structure similarity among these three subtypes [232]. Lorcaserin, a high-selective 5-HTR_2C agonist that inhibits appetite [233], could alleviate obesity and diabetes in humans [209] with cardiovascular safety [97]. However, it has been withdrawn because of increasing the risk of cancer [234]. No other 5-HT_2C agonists have been evaluated in humans for treating metabolic disorders yet. Recently, Beecher et al. demonstrated that a selective 5-HTR_1A heteroreceptor agonist NLX-101 (a.k.a. F15599; 3-chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin- 1-yl]methanone) reduces sucrose consumption in mice fed a high-sugar diet [53], suggesting that targeting 5-HTR_1A autoreceptors might represent a promising therapeutic strategy to combat obesity. In addition to those receptors that are predominantly present in the CNS, targeting peripheral 5-HTRs is also a valuable strategy for treating metabolic diseases. Given the fact that adipocyte-specific knockdown of 5-HTR_2A decreased lipogenesis, and adipocyte-specific knockdown of 5-HTR_2B decreased lipolysis, respectively [171, 172], 5-HTR_2A and 5-HTR_2B counteract each other to maintain lipid hemostasis in adipose tissues. Correspondingly, administration of a selective 5-HTR_2A agonist 4-bromo-3, 6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2) suppresses lipolysis in primary adipocytes [170], and a selective 5-HTR_2B antagonist SB-204741 reverses the phosphorylation of hormone-sensitive lipase in vitro, suggesting decreased lipolysis. In addition, SB-204741 prevents glucose-stimulated insulin secretion in pancreatic β-cell line MIN6 [208]. Ondansetron, a selective 5-HTR₃ antagonist, could increase the thermogenic activity in immortalized brown adipocytes, while this effect is mitigated by the 5-HTR₃ agonist meta-chlorophenylbiguanide (m-CPBG) [166]. Notably, it was shown that injecting m-CPBG into rats increases body temperature and reduces appetite [211], suggesting the complex effects of 5-HTR₃ signaling on whole-body metabolism. Because 5-HTR₃ is highly expressed in vagal-nerve-dominating organs such as the pancreas and intestine, it allows this ligand-gated cation channel to transmit signals to the CNS [161, 235].

Of particular importance is the gut microbiota's interaction with medicines that target the serotonergic system to regulate host energy metabolism. For instance, one of the SSRIs, fluoxetine, was shown to increase fecal serotonin level, accompanied by an alteration in gut microbiota composition [236]. For other SSRIs, Wang et al. illustrated treating depressed patients with SSRI escitalopram shifted gut microbiota to produce more indole-3-propionic acid (I3PA) [200], while excess I3PA could lead to obesity and hepatic fibrosis [202, 203]. Plant-derived harmine can be fermented by gut microbes and display selective MAO-A inhibiting effects [206]. In parallel with the metabolic benefits of several selective MAO-A inhibitors, Zhu et al. [207] reported that harmine is negatively associated with body weight, fat mass weight, and plasma triglycerides. Song et al. [210] found that the metabolic benefits of the selective 5-HTR_2C agonist lorcaserin are accompanied by an increase in the Firmicutes/Bacteroidetes ratio. Taken together, gut microbiota plays crucial roles not only in host metabolism but also in regulating serotonergic system and impacting the efficiency of medicines to treat metabolic diseases.

Conclusion and perspective

As one of the oldest neurotransmitters in evolutionary terms, serotonin has a simple chemical structure and a wide range of physiological functions. Emerging evidence suggests that serotonin has a profound and distinguished influence on appetite, energy expenditure, lipid and glucose metabolism, and overall metabolic health simultaneously, apart from its classical role in maintaining mental health. Strikingly, the effects of serotonin on metabolism homeostasis rely on the complexity of the serotonergic system, which encompasses synthesis, storage, release, transport, catabolism, and receptor signaling. More importantly, the gut microbiota strongly influences the serotonergic system and complex web of interactions among serotonin and multiple organs. Although the detailed molecular mechanisms by which serotonin contributes to or ameliorates metabolic diseases are still rather obscure, this review provides a new perspective to understand, discover, and elucidate the function of serotonergic system in a spectrum of physiological and pathological conditions. By combining serotonin modulating strategies and intervention to manipulate gut microbiota, innovative treatment tools for precision medicine of metabolic disorders can be developed. In conclusion, future research should focus on dissecting mechanisms underlying the effects of serotonin on metabolism directly (locally) and indirectly (systemically) and searching for new targets related with the serotonergic system, to lead to a new era in metabolic health management.

References

[1] Côté F, Thévenot E, Fligny C et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci USA 2003; 100: 13525-30.

[2] Shajib MS, Baranov A, Khan WI. Diverse effects of gut-derived serotonin in intestinal inflammation. ACS Chem Neurosci 2017; 8: 920-31.

[3] Rapport MM, Green AA, Page IH. Serum vasoconstrictor (serotonin): IV. Isolation and characterization. J Biol Chem 1948; 176: 1243-51.

[4] Erspamer V, Asero B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 1952; 169: 800-1.

[5] Rapport MM, Green AA, Page IH. Crystalline serotonin. Science 1948; 108: 329-30.

[6] Yadav VK, Ryu JH, Suda N et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008; 135: 825-37.

[7] Jindal S, Leyton C, Cohen F et al. Indeterminate serotonin release assays are associated with a high mortality rate. Res Pract Thromb Haemost 2022; 6: e12667.

[8] Azmitia EC. Serotonin and brain: evolution, neuroplasticity, and homeostasis. Int Rev Neurobiol 2007; 77: 31-56.

[9] Vargas MA, Luo N, Yamaguchi A et al. A role for S6 kinase and serotonin in postmating dietary switch and balance of nutrients in D. melanogaster. Curr Biol 2010; 20: 1006-11.

[10] French AS, Simcock KL, Rolke D et al. The role of serotonin in feeding and gut contractions in the honeybee. J Insect Physiol 2014; 61: 8-15.

[11] Srinivasan S, Sadegh L, Elle IC et al. Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms. Cell Metab 2008; 7: 533-44.

[12] Sze JY, Victor M, Loer C et al. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 2000; 403: 560-4.

[13] Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J 2017; 474: 1823-36.

[14] Van Hul M, Cani PD. The gut microbiota in obesity and weight management: microbes as friends or foe? Nat Rev Endocrinol 2023; 19: 258-71.

[15] Stasi C, Sadalla S, Milani S. The relationship between the serotonin metabolism, gut-microbiota and the gut-brain axis. Curr Drug Metab 2019; 20: 646-55.

[16] Spohn SN, Mawe GM. Non-conventional features of peripheral serotonin signalling—the gut and beyond. Nat Rev Gastroenterol Hepatol 2017; 14: 412-20.

[17] Ridaura V, Belkaid Y. Gut microbiota: the link to your second brain. Cell 2015; 161: 193-4.

[18] Wachsmuth HR, Weninger SN, Duca FA. Role of the gut–brain axis in energy and glucose metabolism. Exp Mol Med 2022; 54: 377-92.

[19] Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: tryptophan's metabolites in exercise, inflammation, and mental health. Science 2017; 357: eaaf9794.

[20] Stone TW, Darlington LG. The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br J Pharmacol 2013; 169: 1211-27.

[21] Ng J, Papandreou A, Heales SJ et al. Monoamine neurotransmitter disorders—clinical advances and future perspectives. Nat Rev Neurol 2015; 11: 567-84.

[22] Nakamura K, Sugawara Y, Sawabe K et al. Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels. J Neurosci 2006; 26: 530-4.

[23] Bertaccini G. Tissue 5-hydroxytryptamine and urinary 5-hydroxyindoleacetic acid after partial or total removal of the gastro-intestinal tract in the rat. J Physiol 1960; 153: 239-49.

[24] Zhang Y, Deng R, Yang X et al. Glucose potentiates β-cell function by inducing Tphl expression in rat islets. FASEB J 2017; 31: 5342-55.

[25] Huang Z, Liu T, Chattoraj A et al. Posttranslational regulation of TPH1 is responsible for the nightly surge of 5-HT output in the rat pineal gland. J Pineal Res 2008; 45: 506-14.

[26] Lexchin J, Cude-Simpson K, Stancer H. Brain and blood indole metabolites after peripheral administration of ¹⁴C-5-HT in rat. Neurochem Res 1977; 2: 39-50.

[27] Waider J, Araragi N, Gutknecht L et al. Tryptophan hydroxylase-2 (TPH2) in disorders of cognitive control and emotion regulation: a perspective. Psychoneuroendocrinology 2011; 36: 393-405.

[28] Li Z, Chalazonitis A, Huang YY et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J Neurosci 2011; 31: 8998-9009.

[29] Weihe E, Eiden LE. Chemical neuroanatomy of the vesicular amine transporters. FASEB J. 2000; 14: 2435-49.

[30] Lawal HO, Krantz DE. SLC18: vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med 2013; 34: 360-72.

[31] Wang F, Knutson K, Alcaino C et al. Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces. J Physiol 2017; 595: 79-91.

[32] Alcaino C, Knutson KR, Treichel AJ et al. A population of gut epithelial enterochromaffin cells is mechanosensitive and requires Piezo2 to convert force into serotonin release. Proc Natl Acad Sci USA 2018; 115: E7632-41.

[33] Del Rosario JS, Yudin Y, Su S et al. Gi-coupled receptor activation potentiates Piezo2 currents via Gβγ. EMBO Rep 2020; 21: e49124.

[34] Bautista DM, Jordt SE, Nikai T et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 2006; 124: 1269-82.

[35] Nozawa K, Kawabata-Shoda E, Doihara H et al. TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proc Natl Acad Sci USA 2009; 106: 3408-13.

[36] Bellono NW, Bayrer JR, Leitch DB et al. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 2017; 170: 185-98.e6.

[37] Knutson KR, Whiteman ST, Alcaino C et al. Intestinal enteroendocrine cells rely on ryanodine and IP₃ calcium store receptors for mechanotransduction. J Physiol 2023; 601: 287-305.

[38] Gao J, Xiong T, Grabauskas G et al. Mucosal serotonin reuptake transporter (SERT) expression in irritable bowel syndrome is modulated by gut microbiota via mast cell–prostaglandin E2. Gastroenterology 2022; 162: 1962-74.e6.

[39] Xie Y, Wang C, Zhao D et al. Dietary proteins regulate serotonin biosynthesis and catabolism by specific gut microbes. J Agric Food Chem 2020; 68: 5880-90.

[40] Brenner B, Harney JT, Ahmed BA et al. Plasma serotonin levels and the platelet serotonin transporter. J Neurochem 2007; 102: 206-15.

[41] Sandler M, Reveley M, Glover V. Human platelet monoamine oxidase activity in health and disease: a review. J Clin Pathol 1981; 34: 292-302.

[42] Shih J, Chen K, Ridd M. Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 1999; 22: 197-217.

[43] Magro A, Osswald W, Reis D, Vanhoutte P, editors. Central and Peripheral Mechanisms of Cardiovascular Regulation. New York, NY: Springer; 1986.

[44] Choi W, Moon JH, Kim H. Serotonergic regulation of energy metabolism in peripheral tissues. J Endocrinol 2020; 245: R1-10.

[45] Kaludercic N, Mialet-Perez J, Paolocci N et al. Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 2014; 73: 34-42.

[46] Fukui M, Tanaka M, Toda H et al. High plasma 5-hydroxyindole-3-acetic acid concentrations in subjects with metabolic syndrome. Diabetes Care 2012; 35: 163-7.

[47] De Giovanni M, Tam H, Valet C et al. GPR35 promotes neutrophil recruitment in response to serotonin metabolite 5-HIAA. Cell 2022; 185: 815-30.e19.

[48] Yamazaki F, Kuroiwa T, Takikawa O et al. Human indolylamine 2, 3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme. Biochem J 1985; 230: 635-8.

[49] Chamberlain RS, Herman BH. A novel biochemical model linking dysfunctions in brain melatonin, proopiomelanocortin peptides, and serotonin in autism. Biol Psychiatry 1990; 28: 773-93.

[50] Conde K, Fang S, Xu Y. Unraveling the serotonin saga: from discovery to weight regulation and beyond - a comprehensive scientific review. Cell Biosci 2023; 13: 143.

[51] Wang H, Gu Y, Khalid R et al. Herbal medicines for insomnia through regulating 5-hydroxytryptamine receptors: a systematic review. Chin J Nat Med 2023; 21: 483-98.

[52] Sałaciak K, Pytka K. Biased agonism in drug discovery: is there a future for biased 5-HT1A receptor agonists in the treatment of neuropsychiatric diseases? Pharmacol Ther 2021; 227: 107872.

[53] Beecher K, Wang J, Chehrehasa F et al. Dissecting the contribution of 5-HT1A auto- and heteroreceptors in sucrose overconsumption in mice. Biomed Pharmacother 2022; 148: 112699.

[54] Li, L, Wyler SC, León-Mercado LA et al. Delineating a serotonin 1B receptor circuit for appetite suppression in mice. J Exp Med 2022; 219: e20212307.

[55] Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav Brain Res 2008; 195: 198-213.

[56] Nonogaki K. The regulatory role of the central and peripheral serotonin network on feeding signals in metabolic diseases. Int J Mol Sci 2022; 23: 1600.

[57] Przegalinski E, Witek K, Wydra K et al. 5-HT_2C receptor stimulation in obesity treatment: orthosteric agonists vs. allosteric modulators. Nutrients 2023; 15: 1449.

[58] Nonogaki K, Strack AM, Dallman MF et al. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT_2C receptor gene. Nat Med 1998; 4: 1152-6.

[59] Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002; 71: 533-54.

[60] Thompson AJ, Lummis SC. 5-HT₃ receptors. Curr Pharm Des 2006; 12: 3615-30.

[61] Gianni G, Pasqualetti M. Wiring and volume transmission: an overview of the dual modality for serotonin neurotransmission. ACS Chem Neurosci 2023; 14: 4093-104.

[62] Jiang SH, Wang YH, Hu LP et al. The physiology, pathology and potential therapeutic application of serotonylation. J Cell Sci 2021; 134: jcs257337.

[63] Paulmann N, Grohmann M, Voigt JP et al. Intracellular serotonin modulates insulin secretion from pancreatic β-cells by protein serotonylation. PLoS Biol 2009; 7: e1000229.

[64] Walther DJ, Peter JU, Winter S et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet α-granule release. Cell 2003; 115: 851-62.

[65] Al-Zoairy R, Pedrini MT, Khan MI et al. Serotonin improves glucose metabolism by serotonylation of the small GTPase Rab4 in L6 skeletal muscle cells. Diabetol. Metab. Syndr 2017; 9: 1.

[66] Fu L, Zhang L. Serotonylation: a novel histone H3 marker. Signal Transduct Target Ther 2019; 4: 15.

[67] Farrelly LA, Thompson RE, Zhao S et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 2019; 567: 535-9.

[68] Zhao J, Chen W, Pan Y et al. Structural insights into the recognition of histone H3Q5 serotonylation by WDR5. Sci Adv 2021; 7: eabf4291.

[69] Wei L, Warburton RR, Preston IR et al. Serotonylated fibronectin is elevated in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2012; 302: L1273-9.

[70] Ferrer L, Elsaraf M, Mindt M et al. L-serine biosensor-controlled fermentative production of L-tryptophan derivatives by Corynebacterium glutamicum. Biol 2022; 11: 744.

[71] Michalska K, Kowiel M, Bigelow L et al. 3D domain swapping in the TIM barrel of the α subunit of Streptococcus pneumoniae tryptophan synthase. Acta Crystallogr Section D 2020; 76: 166-75.

[72] Xiong B, Zhu Y, Tian D et al. Flux redistribution of central carbon metabolism for efficient production of l-tryptophan in Escherichia coli. Biotechnol Bioeng 2021; 118: 1393-404.

[73] Wang J, Xu W, Wang R et al. The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling. Food Funct 2021; 12: 3597-610.

[74] Yano JM, Yu K, Donaldson GP et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015; 161: 264-76.

[75] Tian P, Chen Y, Zhu H et al. Bifidobacterium breve CCFM1025 attenuates major depression disorder via regulating gut microbiome and tryptophan metabolism: a randomized clinical trial. Brain Behav Immun 2022; 100: 233-41.

[76] Engevik MA, Luck B, Visuthranukul C et al. Human-derived Bifidobacterium dentium modulates the mammalian serotonergic system and gut–brain axis. Cell Mol Gastroenterol Hepatol 2021; 11: 221-48.

[77] Zhai L, Huang C, Ning Z et al. Ruminococcus gnavus plays a pathogenic role in diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis. Cell Host Microbe 2023; 31: 33-44.e5.

[78] Nzakizwanayo J, Dedi C, Standen G et al. Escherichia coli Nissle 1917 enhances bioavailability of serotonin in gut tissues through modulation of synthesis and clearance. Sci Rep 2015; 5: 17324.

[79] Sugiyama Y, Mori Y, Nara M et al. Gut bacterial aromatic amine production: aromatic amino acid decarboxylase and its effects on peripheral serotonin production. Gut Microbes 2022; 14: 2128605.

[80] Wlodarska M, Luo C, Kolde R et al. Indoleacrylic acid produced by commensal peptostreptococcus species suppresses inflammation. Cell Host Microbe 2017; 22: 25-37.e6.

[81] Lamas B, Richard ML, Leducq V et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 2016; 22: 598-605.

[82] Ye L, Bae M, Cassilly CD et al. Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways. Cell Host Microbe 2021; 29: 179-96.e9.

[83] Gu Y, Wang C, Qin X et al. Saccharomyces boulardii, a yeast probiotic, inhibits gut motility through upregulating intestinal serotonin transporter and modulating gut microbiota. Pharmacol Res 2022; 181: 106291.

[84] Fung TC, Vuong HE, Luna CDG et al. Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut. Nat Microbiol 2019; 4: 2064-73.

[85] Raboni S, Bettati S, Mozzarelli A. Tryptophan synthase: a mine for enzymologists. Cell Mol Life Sci 2009; 66: 2391-403.

[86] Zhao L-P, Wu J, Zhao W-J et al. DSS-induced colitis activates the kynurenine pathway in serum and brain by affecting IDO-1 and gut microbiota. Front Immunol 2023; 13: 1089200.

[87] Williams BB, Van Benschoten AH, Cimermancic P et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 2014; 16: 495-503.

[88] Kwon YH, Wang H, Denou E et al. Modulation of gut microbiota composition by serotonin signaling influences intestinal immune response and susceptibility to colitis. Cell Mol Gastroenterol Hepatol 2019; 7: 709-28.

[89] Knecht LD, O'Connor G, Mittal R et al. Serotonin activates bacterial quorum sensing and enhances the virulence of Pseudomonas aeruginosa in the host. EBioMedicine 2016; 9: 161-9.

[90] Kumar A, Russell RM, Pifer R et al. The serotonin neurotransmitter modulates virulence of enteric pathogens. Cell Host Microbe 2020; 28: 41-53.e8.

[91] van Galen KA, Ter Horst KW, Serlie MJ. Serotonin, food intake, and obesity. Obes Rev 2021; 22: e13210.

[92] He Y, Brouwers B, Liu H et al. Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior. Nat Med 2022; 28: 2537-46.

[93] Koopman KE, Booij J, Fliers E et al. Diet-induced changes in the lean brain: hypercaloric high-fat-high-sugar snacking decreases serotonin transporters in the human hypothalamic region. Mol Metab 2013; 2: 417-22.

[94] Heisler LK, Kanarek RB, Gerstein A. Fluoxetine decreases fat and protein intakes but not carbohydrate intake in male rats. Pharmacol Biochem Behav 1997; 58: 767-73.

[95] Heisler LK, Kanarek RB, Homoleski B. Reduction of fat and protein intakes but not carbohydrate intake following acute and chronic fluoxetine in female rats. Pharmacol Biochem Behav 1999; 63: 377-85.

[96] Burke LK, Heisler L. 5-hydroxytryptamine medications for the treatment of obesity. J Neuroendocrinol 2015; 27: 389-98.

[97] Bohula EA, Wiviott SD, McGuire DK et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med 2018; 379: 1107-17.

[98] Voigt JP, Fink H. Serotonin controlling feeding and satiety. Behav Brain Res 2015; 277: 14-31.

[99] Dahlstrom A, Fuxe K. Evidencefor the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 1964; 60: 293-4.

[100] He Z, Gao Y, Alhadeff AL et al. Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol Metab 2018; 18: 107-19.

[101] Xu Y, Jones JE, Kohno D et al. 5-HT_2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 2008; 60: 582-9.

[102] Brierley DI, Holt MK, Singh A et al. Central and peripheral GLP-1 systems independently suppress eating. Nat Metab 2021; 3: 258-73.

[103] Bubar M, Cunningham K. Distribution of serotonin 5-HT_2C receptors in the ventral tegmental area. Neuroscience 2007; 146: 286-97.

[104] Xu P, He Y, Cao X et al. Activation of serotonin 2C receptors in dopamine neurons inhibits binge-like eating in mice. Biol Psychiatry 2017; 81: 737-47.

[105] Valencia-Torres L, Olarte-Sánchez CM, Lyons DJ et al. Activation of ventral tegmental area 5-HT_2C receptors reduces incentive motivation. Neuropsychopharmacology 2017; 42: 1511-21.

[106] Xia G, Han Y, Meng F et al. Reciprocal control of obesity and anxiety–depressive disorder via a GABA and serotonin neural circuit. Mol Psychiatry 2021; 26: 2837-53.

[107] Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 2014; 19: 741-56.

[108] McGlashon JM, Gorecki MC, Kozlowski AE et al. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis. Cell Metab 2015; 21: 692-705.

[109] Choi Y-H, Fujikawa T, Lee J et al. Revisiting the ventral medial nucleus of the hypothalamus: the roles of SF-1 neurons in energy homeostasis. Front Neurosci 2013; 7: 71.

[110] Leon RM, Borner T, Reiner DJ et al. Hypophagia induced by hindbrain serotonin is mediated through central GLP-1 signaling and involves 5-HT_2C and 5-HT₃ receptor activation. Neuropsychopharmacology 2019; 44: 1742-51.

[111] Wagner S, Brierley DI, Leeson-Payne A 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.

[112] Holt MK, Llewellyn-Smith IJ, Reimann F et al. Serotonergic modulation of the activity of GLP-1 producing neurons in the nucleus of the solitary tract in mouse. Mol Metab 2017; 6: 909-21.

[113] Kooijman S, Wang Y, Parlevliet ET et al. Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice. Diabetologia 2015; 58: 2637-46.

[114] Lockie SH, Heppner KM, Chaudhary N et al. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 2012; 61: 2753-62.

[115] Jenkins TA, Nguyen JC, Polglaze KE et al. Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutr 2016; 8: 56.

[116] Hu J, Johnson TA, Zhang H et al. The microbiota–gut–brain axis: gut microbiota modulates conspecific aggression in diversely selected laying hens. Microorganisms 2022; 10: 1081.

[117] Liu Z, Dai X, Zhang H et al. Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment. Nat Commun 2020; 11: 855.

[118] Agustí A, Campillo I, Balzano T et al. Bacteroides uniformis CECT 7771 modulates the brain reward response to reduce binge eating and anxiety-like behavior in rat. Mol Neurobiol 2021; 58: 4959-79.

[119] Liaqat H, Parveen A, Kim SY. Neuroprotective natural products' regulatory effects on depression via gut–brain axis targeting tryptophan. Nutr 2022; 14: 3270.

[120] Roth W, Zadeh K, Vekariya R et al. Tryptophan metabolism and gut-brain homeostasis. Int J Mol Sci 2021; 22: 2973.

[121] Browning KN. Role of central vagal 5-HT₃ receptors in gastrointestinal physiology and pathophysiology. Front Neurosci 2015; 9: 413.

[122] Ripken D, van der Wielen N, Wortelboer HM et al. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin. J Nutr Biochem 2016; 32: 142-50.

[123] Yabut JM, Crane JD, Green AE et al. Emerging roles for serotonin in regulating metabolism: new implications for an ancient molecule. Endocr Rev 2019; 40: 1092-107.

[124] Cerminara M, Spirito G, Pisciotta L et al. Case report: whole exome sequencing revealed disease-causing variants in two genes in a patient with autism spectrum disorder, intellectual disability, hyperactivity, sleep and gastrointestinal disturbances. Front Genet 2021; 12: 625564.

[125] Reigstad CS, Salmonson CE, Rainey JF et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J 2015; 29: 1395-403.

[126] Martin AM, Jones LA, Jessup CF et al. Diet differentially regulates enterochromaffin cell serotonin content, density and nutrient sensitivity in the mouse small and large intestine. Neurogastroenterol Motil 2020; 32: e13869.

[127] Hoffman JM, Tyler K, MacEachern SJ et al. Activation of colonic mucosal 5-HT₄ receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 2012; 142: 844-54.e4.

[128] Markham A. Telotristat ethyl: first global approval. Drugs 2017; 77: 793-8.

[129] Wei L, Singh R, Ha SE et al. Serotonin deficiency is associated with delayed gastric emptying. Gastroenterology 2021; 160: 2451-66.e19.

[130] Braun T, Voland P, Kunz L et al. Enterochromaffin cells of the human gut: sensors for spices and odorants. Gastroenterology 2007; 132: 1890-901.

[131] Hansen L, Deacon CF, Ørskov C et al. Glucagon-like peptide-1-(7–36) amide is transformed to glucagon-like peptide-1-(9–36) amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 1999; 140: 5356-63.

[132] Lund ML, Egerod KL, Engelstoft MS et al. Enterochromaffin 5-HT cells–A major target for GLP-1 and gut microbial metabolites. Mol Metab 2018; 11: 70-83.

[133] Lund ML, Sorrentino G, Egerod KL et al. L-cell differentiation is induced by bile acids through GPBAR1 and paracrine GLP-1 and serotonin signaling. Diabetes 2020; 69: 614-23.

[134] Mujagic Z, Kasapi M, Jonkers DM et al. Integrated fecal microbiome–metabolome signatures reflect stress and serotonin metabolism in irritable bowel syndrome. Gut Microbes 2022; 14: 2063016.

[135] Ge X, Ding C, Zhao W et al. Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility. J Transl Med 2017; 15: 13.

[136] De Vadder F, Grasset E, Mannerås Holm L et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Natl Acad Sci USA 2018; 115: 6458-63.

[137] Golubeva AV, Joyce SA, Moloney G et al. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine 2017; 24: 166-78.

[138] Sumara G, Sumara O, Kim JK et al. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab 2012; 16: 588-600.

[139] Xu Y, Berglund ED, Sohn J-W et al. 5-HT_2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nat Neurosci 2010; 13: 1457-9.

[140] Lu S, Ma Z, Gu Y et al. Downregulation of glucose-6-phosphatase expression contributes to fluoxetine-induced hepatic steatosis. J Appl Toxicol 2021; 41: 1232-40.

[141] Crane JD, Palanivel R, Mottillo EP et al. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat Med 2015; 21: 166-72.

[142] Ko M, Kamimura K, Owaki T et al. Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver. Dis Model Mech 2021; 14: dmm048922.

[143] Li HY, Huang SY, Zhou DD et al. Theabrownin inhibits obesity and non-alcoholic fatty liver disease in mice via serotonin-related signaling pathways and gut-liver axis. J Adv Res 2023; 52: 59-72.

[144] Ming X, Chung ACK, Mao D et al. Pancreatic sirtuin 3 deficiency promotes hepatic steatosis by enhancing 5-hydroxytryptamine synthesis in mice with diet-induced obesity. Diabetes 2021; 70: 119-31.

[145] Choi W, Namkung J, Hwang I et al. Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nat Commun 2018; 9: 4824.

[146] Kim M, Hwang I, Pagire HS et al. Design, synthesis, and biological evaluation of new peripheral 5HT_2A antagonists for nonalcoholic fatty liver disease. J Med Chem 2020; 63: 4171-82.

[147] Nocito A, Dahm F, Jochum W et al. Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis. Gastroenterology 2007; 133: 608-18.

[148] Ruddell RG, Oakley F, Hussain Z et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol 2006; 169: 861-76.

[149] Aron-Wisnewsky J, Vigliotti C, Witjes J et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol 2020; 17: 279-97.

[150] Sandoval DA, D'Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev 2015; 95: 513-48.

[151] GYLFE E. Association between 5-hydroxytryptamine release and insulin secretion. J Endocrinol 1978; 78: 239-48.

[152] Di Gialleonardo V, Signore A, Scheerstra EA et al. ¹¹C-hydroxytryptophan uptake and metabolism in endocrine and exocrine pancreas. J Nucl Med 2012; 53: 1755-63.

[153] Andrew A, Kramer B, Rawdon B. Gut and pancreatic amine precursor uptake and decarboxylation cells are not neural crest derivatives. Gastroenterology 1983; 84: 429-31.

[154] Moon JH, Kim YG, Kim K et al. Serotonin regulates adult β-cell mass by stimulating perinatal β-cell proliferation. Diabetes 2020; 69: 205-14.

[155] Kim K, Oh CM, Ohara-Imaizumi M et al. Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology 2015; 156: 444-52.

[156] Castell A-L, Goubault C, Ethier M et al. β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood. JCI Insight 2022; 7: e160854.

[157] Naderi R, Shirpoor A, Samadi M et al. Tropisetron attenuates pancreas apoptosis in the STZ-induced diabetic rats: involvement of SIRT1/NF-κB signaling. Pharmacol Rep 2020; 72: 1657-65.

[158] Naderi R, Shirpoor A, Samadi M et al. Tropisetron improves pancreas function and increases insulin synthesis and secretion in the STZ-induced diabetic rats: involvement of UCP2/ZnT8 pathway. J Pharm Pharmacol 2020; 72: 1082-91.

[159] Nagata M, Yokooji T, Nakai T et al. Blockade of multiple monoamines receptors reduce insulin secretion from pancreatic β-cells. Sci Rep 2019; 9: 16438.

[160] Almaça J, Molina J, Menegaz D et al. Human beta cells produce and release serotonin to inhibit glucagon secretion from alpha cells. Cell Rep 2016; 17: 3281-91.

[161] Makhmutova M, Weitz J, Tamayo A et al. Pancreatic β-cells communicate with vagal sensory neurons. Gastroenterology 2021; 160: 875-88.e11.

[162] Pietzner M, Budde K, Rühlemann M et al. Exocrine pancreatic function modulates plasma metabolites through changes in gut microbiota composition. J Clin Endocrinol Metab 2021; 106: e2290-8.

[163] Shamsi F, Wang CH, Tseng YH. The evolving view of thermogenic adipocytes—ontogeny, niche and function. Nat Rev Endocrinol 2021; 17: 726-44.

[164] Wu J, Boström P, Sparks LM et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366-76.

[165] Stunes A, Reseland J, Hauso O et al. Adipocytes express a functional system for serotonin synthesis, reuptake and receptor activation. Diabetes Obes Metab 2011; 13: 551-8.

[166] Oh C-M, Namkung J, Go Y et al. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat Commun 2015; 6: 6794.

[167] Rozenblit-Susan S, Chapnik N, Froy O. Serotonin prevents differentiation into brown adipocytes and induces transdifferentiation into white adipocytes. Int J Obes (Lond) 2018; 42: 704-10.

[168] Braz GRF, da Silva AI, Silva SCA et al. Chronic serotonin reuptake inhibition uncouples brown fat mitochondria and induces beiging/browning process of white fat in overfed rats. Life Sci 2020; 245: 117307.

[169] Chiu YJ, Tu HH, Kung ML et al. Fluoxetine ameliorates high-fat diet-induced metabolic abnormalities partially via reduced adipose triglyceride lipase-mediated adipocyte lipolysis. Biomed Pharmacother 2021; 141: 111848.

[170] Hansson B, Medina A, Fryklund C et al. Serotonin (5-HT) and 5-HT_2A receptor agonists suppress lipolysis in primary rat adipose cells. Biochem Biophys Res Commun 2016; 474: 357-63.

[171] Shong KE, Oh CM, Namkung J et al. Serotonin regulates de novo lipogenesis in adipose tissues through serotonin receptor 2A. Endocrinol Metab (Seoul) 2020; 35: 470-9.

[172] Choi WG, Choi W, Oh TJ et al. Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance. J Clin Invest 2021; 131: e145331.

[173] Kao AC, Spitzer S, Anthony DC et al. Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota. Transl Psychiatry 2018; 8: 66.

[174] Zhuang P, Zhang Y, Shou Q et al. Eicosapentaenoic and docosahexaenoic acids differentially alter gut microbiome and reverse high-fat diet–induced insulin resistance. Mol Nutr Food Res 2020; 64: e1900946.

[175] Coelho WS, Costa KC, Sola-Penna M. Serotoninstimulates mouse skeletal muscle 6-phosphofructo-1-kinase through tyrosine-phosphorylation of the enzyme altering its intracellular localization. Mol Genet Metab 2007; 92: 364-70.

[176] Visco DB, Manhães-de-Castro R, Chaves WF et al. Selective serotonin reuptake inhibitors affect structure, function and metabolism of skeletal muscle: a systematic review. Pharmacol Res 2018; 136: 194-204.

[177] Guillet-Deniau I, Burnol AF, Girard J. Identification and localization of a skeletal muscle secrotonin 5-HT_2A receptor coupled to the Jak/STAT pathway. J Biol Chem 1997; 272: 14825-9.

[178] Daily JW, Park S. Sarcopenia is a cause and consequence of metabolic dysregulation in aging humans: effects of gut dysbiosis, glucose dysregulation, diet and lifestyle. Cells 2022; 11: 338.

[179] Van Long N, Chien PN, Tung TX et al. Complementary combination of biomarkers for diagnosis of sarcopenia in C57BL/6J mice. Life Sci 2023; 312: 121213.

[180] Ticinesi A, Nouvenne A, Cerundolo N et al. Gut microbiota, muscle mass and function in aging: a focus on physical frailty and sarcopenia. Nutrients 2019; 11: 1633.

[181] Wang Y, Zhang Y, Lane NE et al. Population-based metagenomics analysis reveals altered gut microbiome in sarcopenia: data from the Xiangya Sarcopenia study. J Cachexia, Sarcopenia Muscle 2022; 13: 2340-51.

[182] Lee MC, Hsu YJ, Chuang HL et al. In vivo ergogenic properties of the Bifidobacterium longum OLP-01 isolated from a weightlifting gold medalist. Nutrients 2019; 11: 2003.

[183] Pourhamzeh M, Moravej FG, Arabi M et al. The roles of serotonin in neuropsychiatric disorders. Cell Mol Neurobiol 2022; 42: 1671-92.

[184] Guzel T, Mirowska-Guzel D. The role of serotonin neurotransmission in gastrointestinal tract and pharmacotherapy. Molecules 2022; 27: 1680.

[185] Neumann J, Hofmann B, Dhein S et al. Cardiac roles of serotonin (5-HT) and 5-HT-receptors in health and disease. Int J Mol Sci 2023; 24: 4765.

[186] Kwak SH, Park BL, Kim H et al. Association of variations in TPH1 and HTR2B with gestational weight gain and measures of obesity. Obesity (Silver Spring) 2012; 20: 233-8.

[187] Li P, Tiwari HK, Lin WY et al. Genetic association analysis of 30 genes related to obesity in a European American population. Int J Obes (Lond) 2014; 38: 724-9.

[188] Chen C, Chen W, Chen C et al. Genetic variations in the serotoninergic system contribute to body-mass index in Chinese adolescents. PLoS One 2013; 8: e58717.

[189] Zhang M, Li Q, Wang KL et al. Lipolysis and gestational diabetes mellitus onset: a case-cohort genome-wide association study in Chinese. J Transl Med 2023; 21: 47.

[190] Kring SI, Werge T, Holst C et al. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes. PLoS One 2009; 4: e6696.

[191] Halder I, Muldoon MF, Ferrell RE et al. Serotonin receptor 2A (HTR2A) gene polymorphisms are associated with blood pressure, central adiposity, and the metabolic syndrome. Metab Syndr Relat Disord 2007; 5: 323-30.

[192] Kwon Y-J, Hong K-W, Park BJ et al. Serotonin receptor 3B polymorphisms are associated with type 2 diabetes: the Korean genome and epidemiology study. Diabetes Res Clin Pract 2019; 153: 76-85.

[193] Gu X, Al Dubayee M, Alshahrani A et al. Distinctive metabolomics patterns associated with insulin resistance and type 2 diabetes mellitus. Front Mol Biosci 2020; 7: 609806.

[194] Ljung T, Ahlberg AC, Holm G et al. Treatment of abdominally obese men with a serotonin reuptake inhibitor: a pilot study. J Intern Med 2001; 250: 219-24.

[195] Zha W, Ho HTB, Hu T et al. Serotonin transporter deficiency drives estrogen-dependent obesity and glucose intolerance. Sci Rep 2017; 7: 1137.

[196] Marcus MD, Wing RR, Ewing L et al. A double-blind, placebo-controlled trial of fluoxetine plus behavior modification in the treatment of obese binge-eaters and non-binge-eaters. Am J Psychiatry 1990; 147: 876-81.

[197] Darga LL, Carroll-Michals L, Botsford SJ et al. Fluoxetine's effect on weight loss in obese subjects. Am J Clin Nutr 1991; 54: 321-5.

[198] Gafoor R, Booth HP, Gulliford MC. Antidepressant utilisation and incidence of weight gain during 10 years' follow-up: population based cohort study. BMJ 2018; 361: k1951.

[199] Ortuño MJ, Schneeberger M, Ilanges A et al. Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure. J Clin Investig 2021; 131: e151976.

[200] Wang Y, Zhou J, Ye J et al. Multi-omics reveal microbial determinants impacting the treatment outcome of antidepressants in major depressive disorder. Microbiome 2023; 11: 195.

[201] Guerdjikova AI, McElroy SL, Kotwal R et al. High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial. Hum Psychopharmacol -Clin Exp 2007; 23: 1-11.

[202] Sehgal R, Ilha M, Vaittinen M et al. Indole-3-propionic acid, a gut-derived tryptophan metabolite, associates with hepatic fibrosis. Nutrients 2021; 13: 3509.

[203] Zhang B, Jiang M, Zhao J et al. The mechanism underlying the influence of indole-3-propionic acid: a relevance to metabolic disorders. Front Endocrinol (Lausanne) 2022; 13: 841703.

[204] Rozenblit-Susan S, Chapnik N, Froy O. Metabolic effect of fluvoxamine in mouse peripheral tissues. Mol Cell Endocrinol 2016; 424: 12-22.

[205] Wang P, Alvarez-Perez JC, Felsenfeld DP et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med 2015; 21: 383-8.

[206] Djamshidian A, Bernschneider-Reif S, Poewe W et al. Banisteriopsis caapi, a forgotten potential therapy for parkinson's disease? Mov Disord Clin Pract 2016; 3: 19-26.

[207] Zhu Z, Huang R, Liu W et al. Whole Agrocybe cylindracea prevented obesity linking with modification of gut microbiota and associated fecal metabolites in high-fat diet-fed mice. Mol Nutr Food Res 2022; 66: e2100897.

[208] Cataldo LR, Mizgier ML, Sagua RB et al. Prolonged activation of the Htr2b serotonin receptor impairs glucose stimulated insulin secretion and mitochondrial function in MIN6 cells. PLoS One 2017; 12: e0170213.

[209] Bohula EA, Scirica BM, Inzucchi SE et al. Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): a randomised, placebo-controlled trial. Lancet (London, England) 2018; 392: 2269-79.

[210] Song EJ, Shin NR, Jeon S et al. Lorcaserin and phentermine exert anti-obesity effects with modulation of the gut microbiota. Front Microbiol 2023; 13: 1109651.

[211] Mazzola-Pomietto P, Aulakh CS, Murphy DL. Temperature, food intake, and locomotor activity effects of a 5-HT₃ receptor agonist and two 5-HT₃ receptor antagonists in rats. Psychopharmacology (Berl) 1995; 121: 488-93.

[212] Cremata VY, Koe BK. Clinical-pharmacological evaluation of p-chlorophenylalanine: a new serotonin-depleting agent. Clin Pharmacol Ther 1966; 7: 768-76.

[213] Lipton MA, Gordon R, Guroff G et al. p-Chlorophenylalanine-induced chemical manifestations of phenylketonuria in rats. Science 1967; 156: 248-50.

[214] Weber LJ. p-Chlorophenylalanine depletion of gastrointestinal 5-hydroxytryptamine. Biochem Pharmacol 1970; 19: 2169-72.

[215] Liu Q, Yang Q, Sun W et al. Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J Pharmacol Exp Ther 2008; 325: 47-55.

[216] Chajadine M, Laurans L, Radecke T et al. Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice. Nat Commun 2024; 15: 6390.

[217] Lyseng-Williamson KA. Telotristat ethyl: a review in carcinoid syndrome diarrhoea. Drugs 2018; 78: 941-50.

[218] Margolis KG, Stevanovic K, Li Z et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut 2014; 63: 928-37.

[219] Grilo CM, Masheb RM, Wilson GT. Efficacy of cognitive behavioral therapy and fluoxetine for the treatment of binge eating disorder: a randomized double-blind placebo-controlled comparison. Biol Psychiatry 2005; 57: 301-9.

[220] Michelson D, Amsterdam JD, Quitkin FM et al. Changes in weight during a 1-year trial of fluoxetine. Am J Psychiatry 1999; 156: 1170-6.

[221] Fava M, Judge R, Hoog SL et al. Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry 2000; 61: 863-7.

[222] Kivimäki M, Hamer M, Batty GD et al. Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care 2010; 33: 2611-6.

[223] Blumenthal SR, Castro VM, Clements CC et al. An electronic health records study of long-term weight gain following antidepressant use. JAMA Psychiatry 2014; 71: 889-96.

[224] Wickstrom L, Pettersson K. Treatment of diabetics with monoamine-oxidase inhibitors. Lancet 1964; 2: 995-7.

[225] Frohman LA. Stimulation of insulin secretion in rats by pargyline and mebanazine. Diabetes 1971; 20: 266-70.

[226] Carpéné C, Iffiú-Soltesz Z, Bour S et al. Reduction of fat deposition by combined inhibition of monoamine oxidases and semicarbazide-sensitive amine oxidases in obese Zucker rats. Pharmacol Res 2007; 56: 522-30.

[227] Carpéné C, Mercader J, Le Gonidec S et al. Body fat reduction without cardiovascular changes in mice after oral treatment with the MAO inhibitor phenelzine. Br J Pharmacol 2018; 175: 2428-40.

[228] Nagy CT, Koncsos G, Varga ZV et al. Selegiline reduces adiposity induced by high-fat, high-sucrose diet in male rats. Br J Pharmacol 2018; 175: 3713-26.

[229] Mercader J, Sabater AG, Le Gonidec S et al. Oral phenelzine treatment mitigates metabolic disturbances in mice fed a high-fat diet. J Pharmacol Exp Ther 2019; 371: 555-66.

[230] Gordon CJ, Duncan WC. Autonomic and behavioral thermoregulation in the golden-hamster during subchronic administration of clorgyline. Pharmacol Biochem Behav 1994; 48: 119-25.

[231] Halford JCG, Harrold JA, Boyland EJ et al. Serotonergic drugs: effects on appetite expression and use for the treatment of obesity. Drugs 2007; 67: 27-55.

[232] Barnes NM, Ahern GP, Becamel C et al.. International union of basic and clinical pharmacology. Classification of receptors for 5-hydroxytryptamine; pharmacology and function. Pharmacol Rev 2021; 73: 310-520.

[233] Halford JCG. Lorcaserin—not a new weapon in the battle with appetite. Nat Rev Endocrinol 2010; 6: 663-4.

[234] Sharretts J, Galescu O, Gomatam S et al. Cancer risk associated with lorcaserin—the FDA's review of the CAMELLIA-TIMI 61 trial. N Engl J Med 2020; 383: 1000-2.

[235] Dockray GJ. Enteroendocrine cell signalling via the vagus nerve. Curr Opin Pharmacol 2013; 13: 954-8.

[236] Zhang W, Qu W, Wang H et al. Antidepressants fluoxetine and amitriptyline induce alterations in intestinal microbiota and gut microbiome function in rats exposed to chronic unpredictable mild stress. Transl Psychiatry 2021; 11: 131.

RIGHTS & PERMISSIONS

The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.