Serotonin

Via the 5-HT1B receptor, 5-HT stimulates the release of ?-melanocyte-stimulating hormone in the proopiomelanocortin (POMC) neuron and suppresses the secretion of agouti-related protein (AgRP) in the orexigenic neuropeptide Y (NPY)/AgRP neuron [15], with a resultant decrease in appetite. The 5-HT2C receptor agonist lorcaserin (Belviq, Eisai Inc., Tokyo, Japan), which showed significant bodyweight reduction via appetite suppression, was approved in 2012 for the treatment of obesity by the Food and Drug Administration (FDA) [16] and saw widespread use as an anti-obesity medication until the FDA requested its withdrawal in 2020 due to an increased risk of cancer
Central 5-HT signaling increases energy expenditure via the induction of thermogenic activity in brown adipose tissue (BAT) [14]. TPH2-positive neurons are a component of the neural circuitry between the brain and BAT [18]. The rostral raphé pallius, which regulates sympathetically mediated metabolism and the thermogenic activity of BAT, contains 5-HT neurons [19]. Microinjections of the 5-HT receptor antagonist, methysergide, into the intermediolateral cell column of the rat spinal cord suppressed cold-induced thermogenic activity in the BAT [19]. Central 5-HT deficiency resulted in the loss of thermoregulation and decreased the uncoupling protein 1 (UCP1) content in both BAT and inguinal white adipose tissue (WAT) [20]. Furthermore, through changes in the autonomic nervous system (ANS) and hormonal secretions, central 5-HT regulates peripheral glucose and lipid homeostasis [13], and POMC and AgRP neurons regulate glucose and lipid metabolism [13]. Thus, 5-HT2C receptor agonists regulate energy and glucose homeostasis and appetite via POMC neurons [21], and the AgRP neurons regulate hepatic glucose production [22].
The majority (>95%) of 5-HT is synthesized by TPH1 in enterochromaffin cells of gut and stored in platelets [7]. The major peripheral organs, such as the heart, adipose tissue, pancreatic islets, and skeletal muscle, contain TPH1 and can synthesize 5-HT [23–26]. Furthermore, the ENS can produce 5-HT from TPH2 [27]. Thus, 5-HT can regulate the metabolic function of peripheral organs through autocrine/paracrine pathways.
Through 5-HT receptor transduction in the ENS, 5-HT regulates gut motility through the modulation of muscular peristaltic activity via motor and sensory functions. Submucosal and myenteric neurons that are involved in intestinal peristalsis, secretion, and sensation are regulated by 5-HT3 and 5-HT4 [28]. Ondansetron, a 5-HT3 receptor antagonist that is widely used to prevent nausea and vomiting, can induce side effects such as constipation and ileus. The 5-HT4 receptor accelerates propulsive motility and reduces visceral pain in the large intestine [29]. In vitro, a 5-HT4 receptor agonist can increase enteric neuronal development and survival [30].
Recent studies have suggested a possible relationship between gut microbiota and 5-HT signaling in the gastrointestinal tract. Compared to WT mice, Tph1-KO mice had different gut microbiota composition, which conferred a protective effect that resulted in a lower susceptibility to colitis [31], and which suggested that 5-HT regulates gut microbiota composition. In contrast, gut microbiota alters 5-HT levels in the colon and blood by directly regulating gastrointestinal tryptophan metabolism [32].
Pancreatic islets are important for glycemic control because they comprise ?- and ß-cells that secrete glucagon and insulin, respectively. During pregnancy, pancreatic ß-cells synthesize 5-HT, which increases ß-cell mass and glucose-stimulated insulin secretion via 5-HT2B and 5-HT3 receptor signaling, respectively [26,33]. In addition, 5-HT regulates insulin secretion in a diet-induced insulin resistance state [34] and controls adult ß-cell mass by stimulating perinatal ß-cell proliferation [35]. Furthermore, 5-HT regulates energy metabolism in adipose tissue. During fasting conditions, both lipolysis in adipose tissue and gluconeogenesis in the liver are increased. Sumara et al. [36] discovered that fasting increased the level of gut-derived 5-HT (GDS), which promoted lipolysis in WAT via 5-HT2b receptor signaling.
Tph1 and Tph2 double-KO mice, as well as Tph1-KO mice, have lower body weight [37,38]. In contrast, the body weights of gut-specific Tph1-KO mice are comparable to those of WT control mice [36]. Intriguingly, on a high-fat diet (HFD), adipose tissue-specific Tph1-KO mice had less weight gain than WT mice [24]. The HFD increased 5-HT levels in WAT with upregulated Tph1 expression, and 5-HT subsequently upregulated lipid accumulation in WAT via 5-HT2A receptor-induced lipogenesis [24,39]. These findings imply that 5-HT, in addition to GDS, possibly plays a role in the regulation of energy homeostasis, especially in WAT.
Furthermore, recent studies suggest possible roles of 5-HT in BAT. On an HFD, Tph1-KO mice showed increased energy expenditure when a peripheral TPH inhibitor (LP-533401) was used to confirm the obesogenic actions of peripheral 5-HT [24,40]. In adipocyte-specific Tph1-KO mice, 5-HT depletion induced Ucp1 and Dio2 expression in the BAT and subcutaneous WAT [24]. In brown fat, the 5-HT3 receptor is important for diet-induced thermogenesis, which significantly increased in Htr3a-KO (whole-body KO) mice fed an HFD [31]. Therefore, this lean phenotype could be attributed to either central or peripheral 5-HT effects. Future research is required to identify the primary 5-HT receptor that regulates BAT thermogenesis.

Receptor subtype Agonist Antagonist Effect5-HT1A BuspironeR-137696 NAN-190PindobindSDZ21-009 Slower gastric, accommodation, central nervous system depressant5-HT1B CGS12066ACGS-12066BCP93129 GR127935MethiothepinSB216641SB224289SDZ21-009 Alters release of serotonin in the brain, mitochondrial function induced endoplasmic reticular stressReducing oxidative phosphorylationReduced cocaine induced locomotionReduced the mitogenic activity and by preventing the decrease of cyclic AMP generation elicited5-HT1D Sumatriptan GR127935Metergoline Enhanced gastric emptying5-HT1E BRL-544435-HT1F Lasmiditan Cardiovascular parameters5-HT2A DOI KetanserinMesulergineMetergolineRitanserin Induced vasoconstriction and plateletAggregation are inhibitionStimulate lactationNegative symptoms of schizophrenia5-HT2B ?-ME-HTP LY272015MetergolineSB204741SB2283571 Terguride Anti-hypertensive effectsPulmonary artery banding affects right heart function and structureAntidepressant/anxiolytic effectsSkin fibrosis5-HT2C Tegaserod MesulergineMetergolineRitanserinSB228357Terguride Pulmonary artery banding affects right heart function and structureAntidepressant/anxiolytic effectsSkin fibrosis5-HT3 MKC-733 Y25130 Slower emptying of liquidsFaster small bowel transit, stimulation of interdigestive phase35-HT4 CisaprideTegaserodRenzapride RS-23597-190 Enhanced intestinal secretionFaster gastric emptyingFaster bowel and colon transit5-HT5A OlanzapineValerenic acid ASP-5736AS-203068 No significant effect5-HT6 E-6801EMDT Increased recognition memory and corrected scopolamine-induced memory impairments, short- and long-term memory formation5-HT7 8-OH-DPAT Methysergide Potently reversed catalepsyhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743581/

Receptory

5-HT Receptors, Structure, Transduction System, and Tissue Expression
Receptor subtype Structure Distribution Effects Transduction system5-HT1A GPCR Raphe nuclei Regulates sleep ˇcAMPHippocampus Feeling and anxiety G-protein coupled- K+ current5-HT1B GPCR Substantia nigra, globus pallidus Neuronal inhibition, behavioral changes ˇcAMP5-HT1D GPCR Brain Vasoconstriction ˇcAMP5-HT1E GPCR Cortex, hippocampus Memory ˇcAMP5-HT1F GPCR Globus pallidus, putamen Anxiety ˇcAMP5-HT2A GPCR Platelets, cerebral cortex Cellular excitation ^GPCR5-HT2B GPCR Stomach Appetite ^GPCR5-HT2C GPCR Hippocampus, substantia nigra Anxiety ^GPCR5-HT3 LGIC Area postrema, enteric nerves Vomiting Ion conductance (K+, Na+, Ca2+)5-HT4 GPCR Cortex, smooth muscle Gut motility ^cAMP5-HT5A GPCR Brain CNS ˇcAMPBrain Sleep Ca2+ mobilizationBrain Locomotion K+ current5-HT5B GPCR Brain Sleep Not known5-HT6 GPCR Brain Cognition, learning ^cAMP5-HT7 GPCR CNS Blood vessel ^cAMP

Serotonin (5-hydroxytryptamine [5-HT])

• Biogenic amine
• Central and peripheral systems.
• 5-HT functions as a neurotransmitter in the brain
• Hormone in peripheral tissues
• Regulate systemic energy homeostasis
• Various roles of 5-HT in hepatic metabolism and inflammation
• 5-HT signaling as a potential therapeutic target in NAFLD.

• TPH1
• Mainly expressed in peripheral tissues and, centrally
• Mainly expressed in the pineal gland
• Extremely low levels in the rest of the central nervous system (CNS)
• TPH2
• Neuronal 5-HT synthesis in the CNS
• Enteric nervous system (ENS)
• 5-HT does not cross the blood–brain barrier
• Changes in activities of TPH1 and TPH1 alters 5-HT levels in peripheral tissues and CNS

• From tryptophan, TPH generates 5-hydroxytryptophan (5-HTP)
• Converted to 5-HT by aromatic acid decarboxylase (AADC)
• 5-HT transporter (serotonin transporter [SERT])
• Facilitates 5-HT reuptake
• Monoamine oxidase (MAO)-A
• Catalyzes the oxidative deamination of 5-HT
• SERT and MAO-A activities
• Important factors to determine 5-HT levels in the target organs
• 5-HT can be converted to N-acetyl-serotonin
• By arylalkylamine N-acetyltransferase
• Subsequently, to melatonin by hydroxyindole O-methyltransferase in the pineal gland and retina
• Indoleamine 2,3-dioxygenase (IDO)
• Metabolizes tryptophan
• Allowing it to enter the kynurenine pathway,
• Approximately 95% of dietary tryptophan degradation

• 5-HT modulates various physiological and pathological processes
• Most of the 5-HT-related biological processes
• More than fourteen 5-HT receptors into seven families
• Six are G-protein-coupled receptors
• One is a ligand-gated cation channel (serotonin receptor 3 [HTR3])
• www.ncbi.nlm.nih.gov/pmc/articles/PMC8743581/

Serotonin is synthesized by two distinct tryptophan hydroxylases, one in the brain and one in the periphery. The latter is known to be unable to cross the blood-brain barrier. These two serotonin systems have apparently independent functions, although the functions of peripheral serotonin have yet to be fully elucidated. In this study, we have investigated the physiological effect of peripheral serotonin on the concentrations of metabolites in the circulation and in the liver. After fasting, mice were ip injected with 1 mg serotonin. The plasma glucose concentration was significantly elevated between 60 and 270 min after the injection. In contrast, plasma triglyceride, cholesterol, and nonesterified fatty acid concentrations were decreased. The hepatic glycogen synthesis and concentrations were significantly higher at 240 min. At the same time, the hepatic triglyceride content was significantly lower than the basal levels noted before the serotonin injection, whereas the hepatic cholesterol content was significantly higher by 60 min after the injection. Furthermore, serotonin stimulated the contraction of the gallbladder and the excretion of bile. After the serotonin injection, there was a significant induction of apical sodium-dependent bile acid transporter expression, resulting in a decrease in the concentration of bile acids in the feces. Additionally, data are presented to show that the functions of serotonin are mediated through diverse serotonin receptor subtypes. These data indicate that peripheral serotonin accelerates the metabolism of lipid by increasing the concentration of bile acids in circulation.
https://pubmed.ncbi.nlm.nih.gov/20685881/