Skip Navigation
Skip to contents

Diabetes Metab J : Diabetes & Metabolism Journal

Search
OPEN ACCESS

Articles

Page Path
HOME > Diabetes Metab J > Volume 40(2); 2016 > Article
Review
Obesity and Metabolic Syndrome Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity
Chang-Myung Oh1, Sangkyu Park2, Hail Kim3orcid
Diabetes & Metabolism Journal 2016;40(2):89-98.
DOI: https://doi.org/10.4093/dmj.2016.40.2.89
Published online: March 27, 2016
  • 6,777 Views
  • 153 Download
  • 68 Web of Science
  • 72 Crossref
  • 78 Scopus

1Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

2Department of Biochemistry, Catholic Kwandong University College of Medicine, Gangneung, Korea.

3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.

Corresponding author: Hail Kim. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea. hailkim@kaist.edu
• Received: November 9, 2015   • Accepted: December 25, 2015

Copyright © 2016 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine that has various functions in both neuronal and non-neuronal systems. In the central nervous system, 5-HT regulates mood and feeding behaviors as a neurotransmitter. Thus, there have been many trials aimed at increasing the activity of 5-HT in the central nervous system, and some of the developed methods are already used in the clinical setting as anti-obesity drugs. Unfortunately, some drugs were withdrawn due to the development of unwanted peripheral side effects, such as valvular heart disease and pulmonary hypertension. Recent studies revealed that peripheral 5-HT plays an important role in metabolic regulation in peripheral tissues, where it suppresses adaptive thermogenesis in brown adipose tissue. Inhibition of 5-HT synthesis reduced the weight gain and improved the metabolic dysfunction in a diet-induced obesity mouse model. Genome-wide association studies also revealed genetic associations between the serotonergic system and obesity. Several genetic polymorphisms in tryptophan hydroxylase and 5-HT receptors were shown to have strong associations with obesity. These results support the clinical significance of the peripheral serotonergic system as a therapeutic target for obesity and diabetes.
Serotonin (5-hydroxytryptamine [5-HT]) has diverse functions in neuronal and non-neuronal systems. It acts as a hormone and a mitogen, as well as a neurotransmitter. At the time of its discovery (1918), 5-HT was thought to be a vasoconstrictor stored in platelets, so it was named serotonin after the Latin word serum and the Greek word tonic [12]. In 1937, 5-HT was found in the enterochromaffin (EC) cells of the gastrointestinal tract and named enteramine because it was thought to cause smooth muscle contraction in the gut [3]. It was not until 1952 that scientists reported 5-HT's role as a neurotransmitter [4]. It has since been discovered that 5-HT is a neurotransmitter associated with mood, behavior, sleep cycles, and appetite [2].
The synthesis of 5-HT is initiated with the hydroxylation of tryptophan by tryptophan hydroxylase (TPH), which is the rate-limiting enzyme for 5-HT synthesis. Thus, 5-HT production is regulated by the activity of TPH and the availability of tryptophan. The biological actions of 5-HT are mediated through the membrane-bound 5-HT receptors and terminated by its uptake into cells through a 5-HT transporter (SERT, Slc6a4) [5]. There are two isoforms of TPH. TPH1 is predominantly expressed in the peripheral tissues including the pineal gland, whereas TPH2 is exclusively expressed in the brain and the enteric nervous system [67]. Because 5-HT cannot cross the blood-brain barrier, the peripheral 5-HT system is functionally separate from the central 5-HT system.
Within the central and enteric nervous systems, 5-HT is synthesized and stored in the presynaptic neurons. Most 5-HT in the periphery is synthesized in EC cells [8] and platelets are the major storage site for circulating 5-HT. Several studies recently reported that 5-HT can be synthesized in other peripheral tissues (e.g., the heart, pancreas, and adipose tissue) and plays a role in a cell-autonomous manner [91011].
In this review, we will discuss the recent findings on the roles of central/peripheral 5-HT in metabolism and its clinical implications for the treatment of obesity.
5-HT regulates various physiological and pathological processes, which are mediated through numerous 5-HT receptors. The 5-HT receptors are phylogenetically ancient and present in the lowest invertebrates as well as the higher mammals [12]. More than fourteen 5-HT receptors in seven families are known to mediate the diverse effects of 5-HT (Table 1) [1314]. All 5-HT receptors are G-protein-coupled receptors except for the 5-HT3 receptor, which is a ligand-gated cation channel [1215].
The 5-HT1 receptor family consists of five receptors: the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptors. All these receptors are Gαi/o protein-coupled receptors that inhibit adenyl cyclase and reduce the cyclic adenosine monophosphate levels. The 5-HT2 receptor family consists of the 5-HT2A, 5-HT2B, and 5-HT2C receptors. These receptors are Gαq/11 protein-coupled receptors that mediate excitatory neurotransmission. The 5-HT2A and 5-HT2C receptors are mainly expressed in the central nervous system (CNS). The 5-HT2B receptor is expressed in peripheral tissues including the liver, kidney, heart, and stomach. It is associated with cardiac function, valvular heart disease, and heart morphogenesis. The 5-HT3 receptor is a member of the Cys-loop ligand-gated ion channel family. This channel is formed by a homopentamer of 5-HT3A subunits or heteropentamer of 5-HT3A subunits with 5-HT3B-E subunits. Opening of the channel in response to 5-HT activates an inward current and depolarizes the membrane.
Appetite is regulated by hypothalamic feeding circuits. Briefly, anorexigenic proopiomelanocortin (POMC) neurons release α-melanocyte-stimulating hormone, the endogenous ligand for the melanocortin 4 receptor (MC4R), to reduce appetite and food intake. Orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons increase appetite and food intake by releasing the endogenous MC4R antagonist, AgRP, and they suppress POMC neurons by releasing γ-aminobutyric acid (GABA).
It has long been known that 5-HT in the hypothalamus plays an important role in the control of appetite and energy balance. Central 5-HT has suppressive effects on food intake and body weight. Fenfluramine, which enhances 5-HT release, is a prototypical agent that leads to serotonergic suppression of feeding [16]. 5-HT reuptake inhibitors and monoamine oxidase inhibitors, which can increase the central serotonergic activity, also reduce food intake [1718]. In contrast, inhibition of central 5-HT synthesis by intraventricular injection of a TPH inhibitor induced hyperphagia and obesity in rats [19].
Studies using receptor-specific knock-out (KO) mice have provided more precise insight into the roles of 5-HT in appetite regulation. The involvement of central 5-HT1B and 5-HT2C receptors in the regulation of appetite was initially suggested by the anorectic effects of a central serotonergic agonist (m-chlorophenylpiperazine [mCPP]) [20]. A major contribution of 5-HT2C receptor to feeding control was confirmed by a study using Htr2c KO mice [21]. Htr2c KO mice are hyperphagic and obese, and the anorectic effects of mCPP do not occur in Htr2c KO mice [22]. Furthermore, studying the effects of 5-HT on the hypothalamic feeding circuit revealed that 5-HT activates POMC neurons through the 5-HT2C receptor and inhibits NPY/AgRP neurons through the 5-HT1B receptor [23]. Thus, central 5-HT inhibits food intake by modulating the hypothalamic feeding circuits. Many drugs targeting 5-HT2C receptor have been produced and some are currently being used in the clinical setting. However, others were discontinued because of severe complications such as pulmonary hypertension and valvular heart disease (Table 2) [2425]. Recently, a selective 5-HT2C receptor agonist (Belviq, lorcaserin hydrochloride; Arena, Zofingen, Switzerland) was officially approved for use in the treatment of obesity [26].
Given that TPH2 is exclusively expressed in the brain, Tph2 KO mice were expected to be hyperphagic and obese. However, Tph2 KO mice do not show an obese phenotype although their central 5-HT level is decreased [2728]. In addition, Htr1b KO mice do not become obese although they are hyperphagic [29]. There have also been reports supporting that central 5-HT increases the sympathetic tone and activates brown adipose tissue (BAT) [3031]. Taken together with the known adverse effects of anti-obesity drugs with regard to their increasing the 5-HT activity in the brain, these controversial data indicate that increasing the 5-HT activity in the brain may not be a good strategy for anti-obesity treatment.
Although TPH1 is widely expressed in the peripheral tissues, over 90% of the total body 5-HT is produced in the gut [32]. The majority of the peripheral 5-HT is stored in platelets and controls the hemodynamics upon the activation of platelets. 5-HT is also present in other peripheral tissues and acts autonomously on many cells in the cardiovascular, gastrointestinal, hematopoietic, and immune systems, as well as in the bone, liver, and placenta [33].
Gut
EC cells are dispersed throughout the intestinal mucosa and are the main source of 5-HT in the gut. The major targets of the gut-derived 5-HT (GDS) are the mucosal projections of primary afferent neurons. These include extrinsic nerves and afferent neurons. The extrinsic nerves transmit sensations of nausea and discomfort to the CNS. There are two types of intrinsic primary afferent neurons (IPANs). The submucosal IPAN regulate the peristaltic and secretory reflexes, whereas myenteric IPAN regulate giant migrating contractions. The 5-HT secreted from myenteric neurons mediates fast and slow excitatory neurotransmission and regulates gastrointestinal motility.
Many 5-HT receptor agonists/antagonists are already used to regulate gut motility in the clinical setting (Table 3). Pressure, acid, and/or cancer therapeutic agents are known to release 5-HT from EC cells, which provokes abdominal discomfort and nausea [3435]. 5-HT3 receptor antagonists, such as ondansetron (Zofran; GSK, London, UK), granisetron (Kytril; Roche Laboratories, Basel, Switzerland), or alosetron (Lotronex; GSK, London, UK), alleviate the 5-HT-induced discomfort that extrinsic sensory nerves convey to the CNS. Irritable bowel syndrome (IBS) is a disease linked to the serotonergic system. The persistent visceral hypersensitivity of the bowel in IBS patients can be blunted by the administration of a 5-HT4 receptor agonist (Tegaserod; Novartis, Basel, Switzerland) [36]. Thus, drugs that inhibit the 5-HT3 receptor or enhance the 5-HT4 receptor have been used to treat IBS.
Many studies suggest that 5-HT plays a role in the pathogenesis of gastrointestinal diseases by affecting the production of pro-inflammatory mediators and the immune system [37]. 5-HT receptors have been identified on various immune cells such as lymphocytes, monocytes, macrophages, and dendritic cells [3839]. The T lymphocyte-derived 5-HT may act as an autocrine factor and has demonstrated a fundamental role as an intrinsic cofactor in T-cell activation and function through the 5-HT7 receptor [40].
Liver
5-HT is known to regulate liver regeneration. Partial hepatectomy has been widely used as an experimental model to understand the role of 5-HT in liver regeneration. The number of platelets (filled with 5-HT) strongly correlates with the hepatocyte proliferative capacity [41]. In contrast, several studies using SERT-deficient rats reported that the regenerative process is not influenced when the platelet 5-HT level is reduced [42]. Thus, the mechanism underlying liver regeneration is more complex than has previously been thought, and more studies are needed to elucidate the main source of 5-HT to regulate liver regeneration. To directly examine the function of 5-HT in liver regeneration, partial hepatectomy was performed on Tph1 KO and wild type (WT) control mice. All markers of hepatocyte proliferation were reduced in Tph1 KO mice, suggesting that 5-HT is involved in the induction of hepatocyte proliferation after a major loss of hepatic tissue [43]. It has also been demonstrated that 5-HT can promote liver regeneration after liver injury through the 5-HT2 receptor or 5-HT7 receptor [4445].
Crane et al. [46] reported a role of peripheral 5-HT in the liver after exposure to a high fat diet (HFD). When fed a HFD, WT mice become obese and develop fatty liver disease. In contrast, Tph1 KO mice do not develop a fatty liver after exposure to a HFD and have reduced fat accumulation in the liver. 5-HT increases hepatic glucose uptake and fat content in liver [4748]. The duodenal 5-HT content increases in ob/ob mice and treatment with a 5-HT3 receptor antagonist caused the reduction of the elevated 5-HT levels and an increase in SERT in the duodenum. In these mice, the 5-HT3 receptor antagonist also reduced the fat content, inflammation, and necrosis of the liver [48].
With regard to insulin resistance, Sumara et al. [8] reported that inhibition of GDS improves the glucose tolerance in mice fed a HFD. In hepatocytes, GDS signaling through the 5-HT2B receptor promotes gluconeogenesis. In addition, GDS prevents glucose uptake into hepatocytes in a glucose transporter 2-dependent manner. Therefore, gut-specific Tph1 KO mice and liver-specific Htr2b KO mice showed improved glucose tolerance compared to WT mice [8].
Pancreatic β-cells and the impact of 5-HT on diabetes mellitus
It has long been known that 5-HT is present in the same vesicle with insulin in pancreatic β-cell after preloading of 5-hydroxytryptophan, a precursor of 5-HT, and 5-HT has been associated with the regulation of the blood glucose concentration [4950]. Recently, 5-HT has been identified as a downstream molecule of placental lactogen that mediates the adaptation of β-cells to pregnancy [10]. In response to the lactogens produced during pregnancy, the expression of Tph1 rises sharply in pancreatic β-cells, resulting in massive production of 5-HT in β-cells [10]. Islet 5-HT acts in an autocrine/paracrine manner through the 5-HT3 receptor to increase the glucose responsiveness of β-cells and thereby increases the overall islet glucose-stimulated insulin secretion (GSIS) [5152]. In addition, the expression of the 5-HT2B receptor increases during mid-gestation to stimulate β-cell proliferation and increase the β-cell mass, whereas 5-HT1D receptor expression increases at the end of gestation to reduce the β-cell mass [10].
5-HT also regulates insulin secretion in a diet-induced insulin-resistant state. The β-cell-specific Tph1 KO mice and Htr3a KO mice developed glucose intolerance compared to WT mice after exposure to an HFD. The GSIS was impaired in islets isolated from HFD-fed Htr3a KO and β-cell-specific Tph1 KO mice, and 5-HT treatment improved the insulin secretion from the islets of β-cell-specific Tph1 KO mice, but not from the Htr3a KO islets [51]. In addition, 5-HT production has been observed in the embryonic pancreas. In particular, TPH1 expression is upregulated in newborn β-cells during the perinatal period while β-cells are actively proliferating [53]. Given that β-cells produce 5-HT under two physiological conditions of β-cell proliferation, the perinatal period and pregnancy, 5-HT is thought to be an important regulator of β-cell proliferation as well as insulin secretion [10515254].
Adipose tissues
The biological functions of peripheral 5-HT in the regulation of energy homeostasis have been extensively studied using chemical agonists and antagonists since the 1960s. By taking advantage of mouse genetic studies, it has become possible to better understand the precise roles of 5-HT in energy metabolism. SERT KO mice exhibit an obese phenotype although they are expected to be slim due to the anorexigenic effects of central 5-HT [55]. Body weight is reduced in Tph1 and Tph2 double KO mice, as well as Tph1 KO mice [2728]. However, the body weights of gut-specific Tph1 KO mice are comparable to those of WT control mice [8]. These data suggest that 5-HT, other than GDS, may play a role in regulating systemic energy homeostasis. Recently, two independent studies have highlighted the role of adipocyte-derived 5-HT in energy storage in the white adipose tissue (WAT) and energy expenditure in the BAT [1146]. In a diet-induced mouse model of obesity, the Tph1 expression and tissue 5-HT concentrations were elevated in adipose tissues [1146]. Tph1 KO mice were protected from obesity and the related metabolic dysfunctions [46]. Tph1 KO mice gained significantly less weight and had lower adiposity when fed an HFD. The glycemic control is also improved in Tph1 KO mice, although the glucose uptake was similar in the muscle, liver and heart, indicating that the BAT make a major contribution to the increase in the basal metabolic rate [46]. Indeed, energy expenditure was enhanced in Tph1 KO mice when they were fed an HFD. The BAT activity increased in a Ucp1-dependent manner in Tph1 KO mice. The obesogenic actions of peripheral 5-HT were also confirmed using a peripheral TPH inhibitor (LP-533401) [1146]. Furthermore, a cell autonomous effect of 5-HT in adipose tissue has been shown in adipocyte-specific Tph1 KO mice [11]. The adipocyte-specific Tph1 KO induced Ucp1 and Dio2 expression in the BAT and subcutaneous WAT [11].
Regarding brown fat thermogenesis, the 5-HT3 receptor plays a major role in diet-induced thermogenesis [11]. Diet-induced thermogenesis was robustly increased in the BAT of Htr3a KO mice fed a HFD [11]. In addition to the role of 5-HT in the BAT, in vitro experiments using 3T3-L1 adipocytes provided a hint about the role of 5-HT in adipogenesis [1156]. It was known that 5-HT can increase the lipid accumulation in human and mouse fat cells [57]. It was also known that 5-HT2A receptor expression is increased in the hypertrophied 3T3L1 adipocytes and WAT of db/db mice, and the activation of the 5-HT2A receptor reduces adiponectin expression in hypertrophied 3T3L1 adipocytes [58]. Treatment with a 5-HT2A receptor antagonist increased the lipid accumulation and circulating adiponectin levels [1159]. An antagonist for the 5-HT2A receptor inhibited adipogenesis [56]. Thus, 5-HT increases energy storage in the WAT through 5-HT2A receptor and inhibits energy expenditure in the BAT through 5-HT3 receptor. Taken together, these recent findings suggest that 5-HT negatively regulates the sensitivity of BAT to β-adrenergic stimulation.
To understand the genetic basis of obesity, many genome-wide association studies (GWAS) have been conducted. Several GWAS revealed genetic associations between the serotonergic system and obesity. The first association between TPH1 and obesity was identified through a GWAS in Koreans [60]. A genetic variant of TPH1 (rs623580) was associated with the body mass index in a GWAS comprising 8,842 subjects (P=0.0047), and single nucleotide polymorphisms (SNPs) of TPH1 were significantly associated with weight gain during pregnancy in women with gestational diabetes mellitus. Several GWAS revealed associations between SNPs of the 5-HT receptors and obesity (Table 4) [6061626364656667]. SNPs of HTR2A had strong associations with obesity in both European and Asian ethnic groups [61626367]. SNPs in the promoter (rs6311, -1438 [G/A]) and intron (rs2070040, 2416 [C/T]) were associated with metabolic syndrome in a study of 934 European subjects. Central obesity (a high waist circumference) showed a significant association with the -1438 GG genotype (odds ratio [OR], 1.57; P=0.003), and the -1438 GG and 2416 TT genotypes were associated with an increased risk of metabolic syndrome (OR, 1.71; P=0.016) [62]. In 478 healthy Chinese subjects, 12 SNPs in seven genes (MAOB, SLC18A1, HTR2A, HTR2C, HTR3B, HTR4, and HTR7) were significantly associated with the body mass index [67]. These genetic studies indicate that the identification of serotonergic system defects can be used for risk prediction and to develop individualized treatments for obesity and metabolic syndrome.
The human body has two separate serotonergic systems: the central 5-HT and peripheral 5-HT systems (Fig. 1). With regard to the central 5-HT system, increasing the 5-HT signaling has been utilized therapeutically to reduce body weight by reducing appetite. In 2010, the U.S. Food and Drug Administration approved a new selective 5-HT2C receptor agonist (Belviq, lorcaserin hydrochloride) for use in the treatment of obesity [26]. This drug was also approved by the Ministry of Food and Drug Substances in Korea. In peripheral tissues, suppressing 5-HT signaling might represent a new target for anti-obesity treatment by increasing energy expenditure and improving insulin resistance [1146]. Systemic TPH1 inhibitors and a peripheral TPH1 inhibitor (LP-533401) have already been patented for treating diabetes and obesity [6869]. However, there have not yet been any clinical trials using these drugs to treat obesity. Recent GWAS results support the clinical importance of serotonergic regulation in human metabolism, but most of these studies have small sample sizes and have not been validated. Therefore, to enhance our understanding of the role of 5-HT in metabolism and to provide effective therapeutic applications of 5-HT, more clinical studies are needed on drugs that can regulate the serotonergic system, and genetic studies are needed to investigate the associations between 5-HT and metabolic diseases.
Acknowledgements
This work was supported by a grant from the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014M3A9D8034464, NRF-2014M3A9D5A0173546 to H.K.).

CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

  • 1. Janeway TC, Richardson HB, Park EA. Experiments on the vasoconstrictor action of blood serum. Arch Intern Med 1918;21:565-603.Article
  • 2. Zucker MB. A study of the substances in blood serum and platelets which stimulate smooth muscle. Am J Physiol 1944;142:12-26.Article
  • 3. Erspamer V, Asero B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 1952;169:800-801. ArticlePDF
  • 4. Brodie BB, Shore PA. A concept for a role of serotonin and norepinephrine as chemical mediators in the brain. Ann N Y Acad Sci 1957;66:631-642. ArticlePubMed
  • 5. Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD, Gershon MD. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci 1996;16:2352-2364. ArticlePubMedPMC
  • 6. Malek ZS, Dardente H, Pevet P, Raison S. Tissue-specific expression of tryptophan hydroxylase mRNAs in the rat midbrain: anatomical evidence and daily profiles. Eur J Neurosci 2005;22:895-901. ArticlePubMed
  • 7. Li Z, Chalazonitis A, Huang YY, Mann JJ, Margolis KG, Yang QM, Kim DO, Cote F, Mallet J, Gershon MD. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J Neurosci 2011;31:8998-9009. ArticlePubMedPMC
  • 8. Sumara G, Sumara O, Kim JK, Karsenty G. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab 2012;16:588-600. ArticlePubMedPMC
  • 9. Ponicke K, Gergs U, Buchwalow IB, Hauptmann S, Neumann J. On the presence of serotonin in mammalian cardiomyocytes. Mol Cell Biochem 2012;365:301-312. ArticlePubMedPDF
  • 10. Kim H, Toyofuku Y, Lynn FC, Chak E, Uchida T, Mizukami H, Fujitani Y, Kawamori R, Miyatsuka T, Kosaka Y, Yang K, Honig G, van der Hart M, Kishimoto N, Wang J, Yagihashi S, Tecott LH, Watada H, German MS. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med 2010;16:804-808. ArticlePubMedPMCPDF
  • 11. Oh CM, Namkung J, Go Y, Shong KE, Kim K, Kim H, Park BY, Lee HW, Jeon YH, Song J, Shong M, Yadav VK, Karsenty G, Kajimura S, Lee IK, Park S, Kim H. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat Commun 2015;6:6794ArticlePubMedPMCPDF
  • 12. Peroutka SJ, Howell TA. The molecular evolution of G protein-coupled receptors: focus on 5-hydroxytryptamine receptors. Neuropharmacology 1994;33:319-324. ArticlePubMed
  • 13. Mohammad-Zadeh LF, Moses L, Gwaltney-Brant SM. Serotonin: a review. J Vet Pharmacol Ther 2008;31:187-199. ArticlePubMed
  • 14. Barnes NM, Neumaier JF. Neuronal 5-HT receptors and SERT. Tocris Biosci Sci Rev Ser 2011;34:1-16.
  • 15. Reeves DC, Lummis SC. The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel (review). Mol Membr Biol 2002;19:11-26. ArticlePubMed
  • 16. Lam DD, Heisler LK. Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes. Expert Rev Mol Med 2007;9:1-24. Article
  • 17. Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord 1998;22(Suppl 1):S18-S28. PubMed
  • 18. Heisler LK, Kanarek RB, Gerstein A. Fluoxetine decreases fat and protein intakes but not carbohydrate intake in male rats. Pharmacol Biochem Behav 1997;58:767-773. ArticlePubMed
  • 19. Breisch ST, Zemlan FP, Hoebel BG. Hyperphagia and obesity following serotonin depletion by intraventricular p-chlorophenylalanine. Science 1976;192:382-385. ArticlePubMed
  • 20. Kennett GA, Curzon G. Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors: hypophagia induced by RU 24969 only requires 5-HT1B receptors. Psychopharmacology (Berl) 1988;96:93-100. ArticlePubMedPDF
  • 21. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 1995;374:542-546. ArticlePubMedPDF
  • 22. Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 1998;4:1152-1156. ArticlePubMedPDF
  • 23. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H, Lee CE, Cone RD, Elmquist JK. Activation of central melanocortin pathways by fenfluramine. Science 2002;297:609-611. ArticlePubMed
  • 24. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR. Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363:245-256. ArticlePubMed
  • 25. CinicalTrials.gov: A service of the U.S. National Insititutes of Health cited 2016 Jan 11. Available from: https://www.clinicaltrials.gov.
  • 26. U.S. Food and Drug Administration. FDA approves Belviq to treat some overweight or obese adults. Home Healthc Nurse 2012;30:443-444. PubMed
  • 27. Savelieva KV, Zhao S, Pogorelov VM, Rajan I, Yang Q, Cullinan E, Lanthorn TH. Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS One 2008;3:e3301ArticlePubMedPMC
  • 28. Gutknecht L, Araragi N, Merker S, Waider J, Sommerlandt FM, Mlinar B, Baccini G, Mayer U, Proft F, Hamon M, Schmitt AG, Corradetti R, Lanfumey L, Lesch KP. Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification. PLoS One 2012;7:e43157ArticlePubMedPMC
  • 29. Bouwknecht JA, van der Gugten J, Hijzen TH, Maes RA, Hen R, Olivier B. Male and female 5-HT(1B) receptor knockout mice have higher body weights than wildtypes. Physiol Behav 2001;74:507-516. ArticlePubMed
  • 30. Le Feuvre RA, Aisenthal L, Rothwell NJ. Involvement of corticotrophin releasing factor (CRF) in the thermogenic and anorexic actions of serotonin (5-HT) and related compounds. Brain Res 1991;555:245-250. ArticlePubMed
  • 31. Sakaguchi T, Bray GA. Effect of norepinephrine, serotonin and tryptophan on the firing rate of sympathetic nerves. Brain Res 1989;492:271-280. ArticlePubMed
  • 32. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med 2009;60:355-366. ArticlePubMedPMC
  • 33. Amireault P, Sibon D, Cote F. Life without peripheral serotonin: insights from tryptophan hydroxylase 1 knockout mice reveal the existence of paracrine/autocrine serotonergic networks. ACS Chem Neurosci 2013;4:64-71. ArticlePubMed
  • 34. Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J Clin Gastroenterol 2005;39(5 Suppl 3):S184-S193. PubMed
  • 35. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs 1998;55:173-189. ArticlePubMed
  • 36. Liang LX, Zhang Q, Qian W, Hou XH. Antinociceptive property of tegaserod in a rat model of chronic visceral hypersensitivity. Chin J Dig Dis 2005;6:21-25. ArticlePubMed
  • 37. Manocha M, Khan WI. Serotonin and GI disorders: an update on clinical and experimental studies. Clin Transl Gastroenterol 2012;3:e13ArticlePubMedPMCPDF
  • 38. O'Connell PJ, Wang X, Leon-Ponte M, Griffiths C, Pingle SC, Ahern GP. A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells. Blood 2006;107:1010-1017. ArticlePubMedPMCPDF
  • 39. Ahern GP. 5-HT and the immune system. Curr Opin Pharmacol 2011;11:29-33. ArticlePubMedPMC
  • 40. Leon-Ponte M, Ahern GP, O'Connell PJ. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood 2007;109:3139-3146. ArticlePubMedPMCPDF
  • 41. Murata S, Ohkohchi N, Matsuo R, Ikeda O, Myronovych A, Hoshi R. Platelets promote liver regeneration in early period after hepatectomy in mice. World J Surg 2007;31:808-816. ArticlePubMedPDF
  • 42. Matondo RB, Punt C, Homberg J, Toussaint MJ, Kisjes R, Korporaal SJ, Akkerman JW, Cuppen E, de Bruin A. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration. Am J Physiol Gastrointest Liver Physiol 2009;296:G963-G968. ArticlePubMed
  • 43. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104-107. ArticlePubMed
  • 44. Papadimas GK, Tzirogiannis KN, Panoutsopoulos GI, Demonakou MD, Skaltsas SD, Hereti RI, Papadopoulou-Daifoti Z, Mykoniatis MG. Effect of serotonin receptor 2 blockage on liver regeneration after partial hepatectomy in the rat liver. Liver Int 2006;26:352-361. ArticlePubMed
  • 45. Tzirogiannis KN, Kourentzi KT, Zyga S, Papalimneou V, Tsironi M, Grypioti AD, Protopsaltis I, Panidis D, Panoutsopoulos GI. Effect of 5-HT7 receptor blockade on liver regeneration after 60-70% partial hepatectomy. BMC Gastroenterol 2014;14:201ArticlePubMedPMCPDF
  • 46. Crane JD, Palanivel R, Mottillo EP, Bujak AL, Wang H, Ford RJ, Collins A, Blumer RM, Fullerton MD, Yabut JM, Kim JJ, Ghia JE, Hamza SM, Morrison KM, Schertzer JD, Dyck JR, Khan WI, Steinberg GR. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat Med 2015;21:166-172. ArticlePubMedPDF
  • 47. Moore MC, DiCostanzo CA, Dardevet D, Lautz M, Farmer B, Neal DW, Cherrington AD. Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs. Am J Physiol Endocrinol Metab 2004;287:E1057-E1063. ArticlePubMed
  • 48. Haub S, Ritze Y, Ladel I, Saum K, Hubert A, Spruss A, Trautwein C, Bischoff SC. Serotonin receptor type 3 antagonists improve obesity-associated fatty liver disease in mice. J Pharmacol Exp Ther 2011;339:790-798. ArticlePubMed
  • 49. Gershon MD, Ross LL. Location of sites of 5-hydroxytryptamine storage and metabolism by radioautography. J Physiol 1966;186:477-492. ArticlePubMedPMC
  • 50. Ekholm R, Ericson LE, Lundquist I. Monoamines in the pancreatic islets of the mouse. Subcellular localization of 5-hydroxytryptamine by electron microscopic autoradiography. Diabetologia 1971;7:339-348. ArticlePubMedPDF
  • 51. Kim K, Oh CM, Ohara-Imaizumi M, Park S, Namkung J, Yadav VK, Tamarina NA, Roe MW, Philipson LH, Karsenty G, Nagamatsu S, German MS, Kim H. Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology 2015;156:444-452. ArticlePubMedPDF
  • 52. Ohara-Imaizumi M, Kim H, Yoshida M, Fujiwara T, Aoyagi K, Toyofuku Y, Nakamichi Y, Nishiwaki C, Okamura T, Uchida T, Fujitani Y, Akagawa K, Kakei M, Watada H, German MS, Nagamatsu S. Serotonin regulates glucose-stimulated insulin secretion from pancreatic beta cells during pregnancy. Proc Natl Acad Sci U S A 2013;110:19420-19425. PubMedPMC
  • 53. Ohta Y, Kosaka Y, Kishimoto N, Wang J, Smith SB, Honig G, Kim H, Gasa RM, Neubauer N, Liou A, Tecott LH, Deneris ES, German MS. Convergence of the insulin and serotonin programs in the pancreatic beta-cell. Diabetes 2011;60:3208-3216. PubMedPMC
  • 54. Berger M, Scheel DW, Macias H, Miyatsuka T, Kim H, Hoang P, Ku GM, Honig G, Liou A, Tang Y, Regard JB, Sharifnia P, Yu L, Wang J, Coughlin SR, Conklin BR, Deneris ES, Tecott LH, German MS. Galphai/o-coupled receptor signaling restricts pancreatic beta-cell expansion. Proc Natl Acad Sci U S A 2015;112:2888-2893. PubMedPMC
  • 55. Murphy DL, Lesch KP. Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci 2008;9:85-96. ArticlePubMedPDF
  • 56. Kinoshita M, Ono K, Horie T, Nagao K, Nishi H, Kuwabara Y, Takanabe-Mori R, Hasegawa K, Kita T, Kimura T. Regulation of adipocyte differentiation by activation of serotonin (5-HT) receptors 5-HT2AR and 5-HT2CR and involvement of microRNA-448-mediated repression of KLF5. Mol Endocrinol 2010;24:1978-1987. ArticlePubMedPMC
  • 57. Gres S, Canteiro S, Mercader J, Carpene C. Oxidation of high doses of serotonin favors lipid accumulation in mouse and human fat cells. Mol Nutr Food Res 2013;57:1089-1099. ArticlePubMed
  • 58. Uchida-Kitajima S, Yamauchi T, Takashina Y, Okada-Iwabu M, Iwabu M, Ueki K, Kadowaki T. 5-Hydroxytryptamine 2A receptor signaling cascade modulates adiponectin and plasminogen activator inhibitor 1 expression in adipose tissue. FEBS Lett 2008;582:3037-3044. ArticlePubMed
  • 59. Nomura S, Shouzu A, Omoto S, Nishikawa M, Iwasaka T. 5-HT2A receptor antagonist increases circulating adiponectin in patients with type 2 diabetes. Blood Coagul Fibrinolysis 2005;16:423-428. ArticlePubMed
  • 60. Kwak SH, Park BL, Kim H, German MS, Go MJ, Jung HS, Koo BK, Cho YM, Choi SH, Cho YS, Shin HD, Jang HC, Park KS. Association of variations in TPH1 and HTR2B with gestational weight gain and measures of obesity. Obesity (Silver Spring) 2012;20:233-238. ArticlePubMedPDF
  • 61. Rosmond R, Bouchard C, Bjorntorp P. Increased abdominal obesity in subjects with a mutation in the 5-HT(2A) receptor gene promoter. Ann N Y Acad Sci 2002;967:571-575. ArticlePubMed
  • 62. Halder I, Muldoon MF, Ferrell RE, Manuck SB. Serotonin receptor 2A (HTR2A) gene polymorphisms are associated with blood pressure, central adiposity, and the metabolic syndrome. Metab Syndr Relat Disord 2007;5:323-330. ArticlePubMedPMC
  • 63. Li P, Tiwari HK, Lin WY, Allison DB, Chung WK, Leibel RL, Yi N, Liu N. Genetic association analysis of 30 genes related to obesity in a European American population. Int J Obes (Lond) 2014;38:724-729. ArticlePubMedPDF
  • 64. Opgen-Rhein C, Brandl EJ, Muller DJ, Neuhaus AH, Tiwari AK, Sander T, Dettling M. Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics 2010;11:773-780. ArticlePubMed
  • 65. Suviolahti E, Oksanen LJ, Ohman M, Cantor RM, Ridderstrale M, Tuomi T, Kaprio J, Rissanen A, Mustajoki P, Jousilahti P, Vartiainen E, Silander K, Kilpikari R, Salomaa V, Groop L, Kontula K, Peltonen L, Pajukanta P. The SLC6A14 gene shows evidence of association with obesity. J Clin Invest 2003;112:1762-1772. ArticlePubMedPMC
  • 66. Corpeleijn E, Petersen L, Holst C, Saris WH, Astrup A, Langin D, MacDonald I, Martinez JA, Oppert JM, Polak J, Pedersen O, Froguel P, Arner P, Sorensen TI, Blaak EE. Obesity-related polymorphisms and their associations with the ability to regulate fat oxidation in obese Europeans: the NUGENOB study. Obesity (Silver Spring) 2010;18:1369-1377. ArticlePubMedPDF
  • 67. Chen C, Chen W, Chen C, Moyzis R, He Q, Lei X, Li J, Wang Y, Liu B, Xiu D, Zhu B, Dong Q. Genetic variations in the serotoninergic system contribute to body-mass index in Chinese adolescents. PLoS One 2013;8:e58717ArticlePubMedPMC
  • 68. Karsenty G, Sumara G, Sumara O. The Trustees of Columbia University in the City of New York, assignee. Methods of preventing and treating diabetes by inhibiting serotonin synthesis. United States patent US 9,150,521. 2013;8 8.
  • 69. Khan W, Steinberg G, Palanivel R. Mcmaster University, assignee. A method of treating obesity. Canada patent CA 2900413A1. 2014;8 21.
Fig. 1

Roles of 5-hydroxytryptamine (5-HT) on metabolic organs. Central 5-HT regulates appetite and controls metabolic organs through sympathetic/parasympathetic nervous system. Peripheral 5-HT regulates glucose metabolism, insulin resistance and energy expenditure in an autocrine/paracrine or endocrine manner. TPH, tryptophan hydroxylase; HTR, 5-HT receptor; β-AR β-adrenergic receptor; BAT, brown adipose tissue; WAT, white adipose tissue.

dmj-40-89-g001.jpg
Table 1

The 5-HT receptors, their functions and the specific receptor agonists/antagonists

dmj-40-89-i001.jpg
Receptor subtype Structure Transduction system
5-HT1A GPCR ↓cAMP
G-protein coupled- K+ current
5-HT1B GPCR ↓cAMP
5-HT1D GPCR ↓cAMP
5-HT1E GPCR ↓cAMP
5-HT1F GPCR ↓cAMP
5-HT2A GPCR ↑PCR
5-HT2B GPCR ↑PCR
5-HT2C GPCR ↑PCR
5-HT3 LGIC Ion conductance (K+, Na+, Ca2+)
5-HT4 GPCR ↑cAMP
5-HT5A GPCR ↓cAMP
Ca2+ mobilization
K+ current
5-HT5B GPCR Not known
5-HT6 GPCR ↑cAMP
5-HT7 GPCR ↑cAMP

5-HT, 5-hydroxytryptamine; GPCR, G protein coupled receptor; cAMP, cyclic adenosine monophosphate; PCR, phosphocreatine; LGIC, ligand-gated ion channel.

Table 2

Anti-obesity drugs that work by regulating the central serotonergic system

dmj-40-89-i002.jpg
Name or code Company Action Current status
Lorcaserin Arena Pharma 5-HT2C receptor agonist FDA approved.
ATHX-105 Athersys 5-HT2C receptor agonist Withdrawn
BVT.74316 Biovitrum 5-HT6 receptor antagonist Withdrawn
PRX-07034 EPIX Pharma 5-HT6 receptor antagonist Phase lI
Tesofensine NeuroSearch 5-HT/DA/NA reuptake inhibitor Phase III
Dov-21,947 Dov Pharmaceuticals 5-HT/DA/NA reuptake blocker Phase ll
Sibutramine 5-HT/NA reuptake inhibitor FDA approved (1997)
Withdrawn due to cardiovascular complication (2010)
Fenfluramine/phentermine 5-HT releasing agent/NA stimulant FDA approved (1973)
Withdrawn due to cardiovascular complication (1997)

Adapted from ClinicalTrials.gov [25].

5-HT, 5-hydroxytryptamine; FDA, Food and Drug Administration; DA, dopamine; NA, noradrenaline.

Table 3

Effects of 5-HT receptor agonists/antagonists in the gut

dmj-40-89-i003.jpg
Class Compound Effect
5-HT3 receptor antagonist Ondansetron Slower small bowel transit
Granisetron Decreased intestinal secretion
Alosetron Inhibition of colonic response to feeding
Cilansetron Slower colonic transit
5-HT3 receptor agonist MKC-733 Slower emptying of liquids
Faster small bowel transit
Stimulation of interdigestive phase 3
5-HT4 receptor agonist Tegaserod Faster gastric emptying
Prucalopride Enhanced gastric accommodation
Renzapride Faster small bowel and colonic transit
Cisapride Enhanced intestinal secretion
5-HT1 receptor agonist Sumatriptan Enhanced gastric accommodation
Buspirone Slower gastric emptying
R-137696 Stimulation of interdigestive phase 3

5-HT, 5-hydroxytryptamine.

Table 4

The results of genome-wide association studies on the serotonergic system and obesity

dmj-40-89-i004.jpg
Study Ethnicity Sample size, n SNP ID Gene Chromosome Allele Association
Kwak et al. (2012) [60] Korean 8,842 rs623580 TPH1 11 A/T BMI and WC
Rosmond et al.(2002) [61] Swedish 284 rs6311 HTR2A 13 C/T BMI, WHR
Halder et al. (2007) [62] European 934 rs6311 HTR2A 13 C/T Central obesity, metabolic syndrome
rs2070040 HTR2A 13 A/G
Li et al. (2014) [63] European 1,982 rs912127 HTR2A 13 A/G BMI
American rs1745837 HTR2A 13 C/T
Opgen-Rhein et al. (2010) [64] German 128 rs498207 HTR2C X C/T Weight gain
Suviolahti et al. (2003) [65] Finnish, 2,104 rs2011162 SLC6A14 X C/G BMI
Swedish rs2071877 SLC6A14 X C/T
Corpeleijn et al. (2010) [66] European 722 rs2011162 SLC6A14 X C/G BMI, fat oxidation in women
Chen et al. (2013) [67] Chinese 478 rs1018079 SLC18A1 8 A/G BMI
rs11214769 HTR3B 11 A/G
rs2224721 HTR2A 13 A/C
rs4911871 HTR2C X A/G

SNP, single nucleotide polymorphism; BMI, body mass index; WC, waist circumference; WHR, waist to hip ratio.

Figure & Data

References

    Citations

    Citations to this article as recorded by  
    • Methylation of serotonin regulating genes in cord blood cells: association with maternal metabolic parameters and correlation with methylation in peripheral blood cells during childhood and adolescence
      Ivona Bečeheli, Marina Horvatiček, Maja Perić, Barbara Nikolić, Cyrielle Holuka, Marija Klasić, Marina Ivanišević, Mirta Starčević, Gernot Desoye, Dubravka Hranilović, Jonathan D. Turner, Jasminka Štefulj
      Clinical Epigenetics.2024;[Epub]     CrossRef
    • Agomelatine improves streptozotocin-induced diabetic nephropathy through melatonin receptors/SIRT1 signaling pathway
      Nevertyty M. Mahmoud, Shimaa M. Elshazly, Arwa A. Hassan, Eman Soliman
      International Immunopharmacology.2023; 115: 109646.     CrossRef
    • Branched Chain Amino Acids, New Target of Germinated Brown Rice against Type 2 Diabetes Mellitus: A Randomized Controlled Trial
      Wenting Wan, Xianchen Jiang, Ruifang Zhao, Fenfen Cai, Fan Wu, Yunqi Hu, Xiaoqin Zhou, Zhipeng Liu, Yujuan Shan
      Molecular Nutrition & Food Research.2023;[Epub]     CrossRef
    • Metabolic and Molecular Response to High-Fat Diet Differs between Rats with Constitutionally High and Low Serotonin Tone
      Petra Baković, Maja Kesić, Darko Kolarić, Jasminka Štefulj, Lipa Čičin-Šain
      International Journal of Molecular Sciences.2023; 24(3): 2169.     CrossRef
    • Consumo de Frutose Altera Aminas Biogênicas Associadas a Fatores de Risco Cardiovasculares
      Fabiane Valentini Francisqueti-Ferron, Matheus Antônio Filiol Belin, Thiago Luiz Novaga Palacio, Artur Junio Togneri Ferron, Jéssica Leite Garcia, Juliana Silva Siqueira, Erika Tiemi Nakandakare-Maia, Taynara Aparecida Vieira, Hugo Tadashi Kano, Fernando
      Arquivos Brasileiros de Cardiologia.2023;[Epub]     CrossRef
    • Constitutive Serotonin Tone as a Modulator of Brown Adipose Tissue Thermogenesis: A Rat Study
      Maja Kesić, Petra Baković, Vladimir Farkaš, Robert Bagarić, Darko Kolarić, Jasminka Štefulj, Lipa Čičin-Šain
      Life.2023; 13(7): 1436.     CrossRef
    • Serotonergic regulation of appetite and sodium appetite
      Yurim Shin, Seungjik Kim, Jong‐Woo Sohn
      Journal of Neuroendocrinology.2023;[Epub]     CrossRef
    • Epstein–Barr virus-acquired immunodeficiency in myalgic encephalomyelitis—Is it present in long COVID?
      Manuel Ruiz-Pablos, Bruno Paiva, Aintzane Zabaleta
      Journal of Translational Medicine.2023;[Epub]     CrossRef
    • Targeting the Gut in Obesity: Signals from the Inner Surface
      Natalia Petersen, Thomas U. Greiner, Lola Torz, Angie Bookout, Marina Kjærgaard Gerstenberg, Carlos M. Castorena, Rune Ehrenreich Kuhre
      Metabolites.2022; 12(1): 39.     CrossRef
    • Intersections between Copper, β-Arrestin-1, Calcium, FBXW7, CD17, Insulin Resistance and Atherogenicity Mediate Depression and Anxiety Due to Type 2 Diabetes Mellitus: A Nomothetic Network Approach
      Hussein Kadhem Al-Hakeim, Hadi Hasan Hadi, Ghoufran Akeel Jawad, Michael Maes
      Journal of Personalized Medicine.2022; 12(1): 23.     CrossRef
    • Tryptophan Metabolism in Atherosclerosis and Diabetes
      Emina Sudar-Milovanovic, Zoran Gluvic, Milan Obradovic, Bozidarka Zaric, Esma R. Isenovic
      Current Medicinal Chemistry.2022; 29(1): 99.     CrossRef
    • The Temporal Profile of Circulating miRNAs during Gestation in Overweight and Obese Women with or without Gestational Diabetes Mellitus
      Anja Elaine Sørensen, Mireille N. M. van Poppel, Gernot Desoye, David Simmons, Peter Damm, Dorte Møller Jensen, Louise Torp Dalgaard
      Biomedicines.2022; 10(2): 482.     CrossRef
    • Comparative effectiveness of Hypericum perforatum, acupuncture, and lifestyle modification in the management of obesity: A randomized clinical trial
      Monirsadat Sahebkar-Khorasani, Mohammad Safarian, Lida Jarahi, Mahdi Yousefi, Roshanak Salari, Mojtaba Meshkat, Mohammad Hossein Ayati, Hamidreza Bahrami-Taghanaki, Raheleh Kargozar, Hoda Azizi
      European Journal of Integrative Medicine.2022; 52: 102119.     CrossRef
    • Research Progresses for 5-Hydroxytryptamine in Lipid Metabolism
      钰婷 吴
      Bioprocess.2022; 12(01): 1.     CrossRef
    • Fast and Sensitive Quantification of AccQ-Tag Derivatized Amino Acids and Biogenic Amines by UHPLC-UV Analysis from Complex Biological Samples
      Andrea Guba, Orsolya Bába, József Tőzsér, Éva Csősz, Gergő Kalló
      Metabolites.2022; 12(3): 272.     CrossRef
    • Chronic Treatment With Psilocybin Decreases Changes in Body Weight in a Rodent Model of Obesity
      Joyce Huang, Michelle Pham, William J. Panenka, William G. Honer, Alasdair M. Barr
      Frontiers in Psychiatry.2022;[Epub]     CrossRef
    • Antidepressants for depressed patients with type 2 diabetes mellitus: A systematic review and network meta-analysis of short-term randomized controlled trials
      Manit Srisurapanont, Sirijit Suttajit, Natapong Kosachunhanun, Surinporn Likhitsathian, Chawisa Suradom, Benchalak Maneeton
      Neuroscience & Biobehavioral Reviews.2022; 139: 104731.     CrossRef
    • Synthesis and biological evaluation of tyrosine derivatives as peripheral 5HT2A receptor antagonists for nonalcoholic fatty liver disease
      Minhee Kim, Wonil Choi, Jihyeon Yoon, Byung-kwan Jeong, Suvarna H. Pagire, Haushabhau S. Pagire, Jungsun Park, Jung Eun Nam, Chang Joo Oh, Jae-Han Jeon, Seong Soon Kim, Byung Hoi Lee, Jin Sook Song, Myung Ae Bae, In-Kyu Lee, Hail Kim, Jin Hee Ahn
      European Journal of Medicinal Chemistry.2022; 239: 114517.     CrossRef
    • The serotonergic system dysfunction in diabetes mellitus
      Yan Cai, Xiaolong Li, Hongli Zhou, Jiyin Zhou
      Frontiers in Cellular Neuroscience.2022;[Epub]     CrossRef
    • A Comprehensive Review on Anti-obesity Potential of Medicinal Plants and their Bioactive Compounds
      Piyush Verma, Bhuwan Chandra Joshi, Partha Sarathi Bairy
      Current Traditional Medicine.2022;[Epub]     CrossRef
    • Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease
      Eun Jung Bae, Won Gun Choi, Haushabhau S. Pagire, Suvarna H. Pagire, Saravanan Parameswaran, Jun-Ho Choi, Jihyeon Yoon, Won-il Choi, Ji Hun Lee, Jin Sook Song, Myung Ae Bae, Mijin Kim, Jae-Han Jeon, In-Kyu Lee, Hail Kim, Jin Hee Ahn
      Journal of Medicinal Chemistry.2021; 64(2): 1037.     CrossRef
    • Serotonin level as a potent diabetes biomarker based on electrochemical sensing: a new approach in a zebra fish model
      Kamyar Khoshnevisan, Hadi Baharifar, Farzad Torabi, Mahsa Sadeghi Afjeh, Hassan Maleki, Elham Honarvarfard, Hassan Mohammadi, Sayed Mahmoud Sajjadi-Jazi, Sadegh Mahmoudi-Kohan, Farnoush Faridbod, Bagher Larijani, Farshid Saadat, Reza Faridi Majidi, Mohamm
      Analytical and Bioanalytical Chemistry.2021; 413(6): 1615.     CrossRef
    • Serotonin, food intake, and obesity
      Katy A. van Galen, Kasper W. ter Horst, Mireille J. Serlie
      Obesity Reviews.2021;[Epub]     CrossRef
    • Involvement of serotonergic pathways in gastric dysmotility induced by fat burning nutritional supplements in mice
      Luciano N. de Sousa, Débora S. Paraguassú Sant'ana, Rildo G. Siqueira dos Santos, Anita Eugênia A. dos Santos Ribeiro, Camila F. da Costa, Ana Paula de Oliveira, Jackson Roberto G. da Silva Almeida, Davi M. Jucá, Moisés Tolentino Bento da Silva, Armênio A
      Current Research in Pharmacology and Drug Discovery.2021; 2: 100018.     CrossRef
    • An Insight into the Roles of Dietary Tryptophan and Its Metabolites in Intestinal Inflammation and Inflammatory Bowel Disease
      Xiaolan Li, Zhi‐Hong Zhang, Hossain M. Zabed, Junhua Yun, Guoyan Zhang, Xianghui Qi
      Molecular Nutrition & Food Research.2021;[Epub]     CrossRef
    • A Systems Biology Approach to Investigating the Interaction between Serotonin Synthesis by Tryptophan Hydroxylase and the Metabolic Homeostasis
      Suhyeon Park, Yumin Kim, Jibeom Lee, Jeong Yun Lee, Hail Kim, Sunjae Lee, Chang-Myung Oh
      International Journal of Molecular Sciences.2021; 22(5): 2452.     CrossRef
    • Loss of Znt8 function in diabetes mellitus: risk or benefit?
      Carla P. Barragán-Álvarez, Eduardo Padilla-Camberos, Nestor F. Díaz, Agustín Cota-Coronado, Claudia Hernández-Jiménez, Carlos C. Bravo-Reyna, Nestor E. Díaz-Martínez
      Molecular and Cellular Biochemistry.2021; 476(7): 2703.     CrossRef
    • Consolidation of network and experimental pharmacology to divulge the antidiabetic action of Ficus benghalensis L. bark
      Pukar Khanal, B. M. Patil
      3 Biotech.2021;[Epub]     CrossRef
    • A metabolomics approach to investigate the proceedings of mitochondrial dysfunction in rats from prediabetes to diabetes
      Chun-Feng Huang, Ann Chen, Siao-Yun Lin, Mei-Ling Cheng, Ming-Shi Shiao, Tso-Yen Mao
      Saudi Journal of Biological Sciences.2021; 28(8): 4762.     CrossRef
    • Metabolic Disturbances in Rat Sublines with Constitutionally Altered Serotonin Homeostasis
      Maja Kesić, Petra Baković, Ranko Stojković, Jasminka Štefulj, Lipa Čičin-Šain
      International Journal of Molecular Sciences.2021; 22(10): 5400.     CrossRef
    • The effects of 5-hydroxytryptophan on carrageenan-induced mouse paw oedemas
      Gokçen TELLI, Inci KAZKAYASI, Serdar UMA
      Revista de Nutrição.2021;[Epub]     CrossRef
    • Tapping into 5-HT3 Receptors to Modify Metabolic and Immune Responses
      Helen Irving, Ilona Turek, Christine Kettle, Nor Yaakob
      International Journal of Molecular Sciences.2021; 22(21): 11910.     CrossRef
    • Serotonergic Regulation of Hepatic Energy Metabolism
      Jiwon Park, Wooju Jeong, Chahyeon Yun, Hail Kim, Chang-Myung Oh
      Endocrinology and Metabolism.2021; 36(6): 1151.     CrossRef
    • Design, Synthesis, and Biological Evaluation of New Peripheral 5HT2A Antagonists for Nonalcoholic Fatty Liver Disease
      Minhee Kim, Inseon Hwang, Haushabhau S. Pagire, Suvarna H. Pagire, Wonsuk Choi, Won Gun Choi, Jihyeon Yoon, Won Mi Lee, Jin Sook Song, Eun Kyung Yoo, Seung Mi Lee, Mi-jin Kim, Myung Ae Bae, Dooseop Kim, Heejong Lee, Eun-Young Lee, Jae-Han Jeon, In-Kyu Lee
      Journal of Medicinal Chemistry.2020; 63(8): 4171.     CrossRef
    • Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis
      Maja Kesić, Petra Baković, Marina Horvatiček, Bastien Lucien Jean Proust, Jasminka Štefulj, Lipa Čičin-Šain
      Frontiers in Neuroscience.2020;[Epub]     CrossRef
    • Appetite and weight control by Hypericum perforatum and acupuncture added to lifestyle modification: Study protocol for a randomized clinical trial
      Monirsadat Sahebkar-Khorasani, Mohammad Safarian, Lida Jarahi, Mahdi Yousefi, Roshanak Salari, Hoda Azizi
      Advances in Integrative Medicine.2020; 7(2): 101.     CrossRef
    • Update on the genetic and epigenetic etiology of gestational diabetes mellitus: a review
      Tajudeen O. Yahaya, Titilola Salisu, Yusuf B. Abdulrahman, Abdulrazak K. Umar
      Egyptian Journal of Medical Human Genetics.2020;[Epub]     CrossRef
    • Paraben Exposure Related To Purine Metabolism and Other Pathways Revealed by Mass Spectrometry-Based Metabolomics
      Hongzhi Zhao, Yuanyuan Zheng, Lin Zhu, Li Xiang, Yanqiu Zhou, Jiufeng Li, Jing Fang, Shunqing Xu, Wei Xia, Zongwei Cai
      Environmental Science & Technology.2020; 54(6): 3447.     CrossRef
    • An anxiolytic drug buspirone ameliorates hyperglycemia and endothelial dysfunction in type 2 diabetic rat model
      Tugba Gurpinar Çavuşoğlu, Ertan Darıverenli, Kamil Vural, Nuran Ekerbicer, Cevval Ulman, Ercüment Ölmez, Nazan Uysal
      Turkish Journal of Biochemistry.2020; 45(4): 397.     CrossRef
    • Pomegranate Metabolites Impact Tryptophan Metabolism in Humans and Mice
      Jieping Yang, Yuanqiang Guo, Rupo Lee, Susanne M Henning, Jing Wang, Yajing Pan, Tianyu Qing, Mark Hsu, Alex Nguyen, Siddarth Prabha, Rashi Ojha, Gary W Small, David Heber, Zhaoping Li
      Current Developments in Nutrition.2020; 4(11): nzaa165.     CrossRef
    • Network pharmacology-based assessment to elucidate the molecular mechanism of anti-diabetic action of Tinospora cordifolia
      Pukar Khanal, B. M. Patil, Bijendra K. Mandar, Yadu Nandan Dey, Taaza Duyu
      Clinical Phytoscience.2019;[Epub]     CrossRef
    • The distribution of serotonergic nerve on the hippocampus of the fruit bats (Rousettus amplexicaudatus)
      Vivin Wirawati, Nourrisma D. A. Widiati, Geraldus Gunawan, Golda R. Saragih, Puspa Hening, Hevi Wihadmadyatami
      Veterinary World.2019; 12(9): 1460.     CrossRef
    • How important is tryptophan in human health?
      Joanna Kałużna-Czaplińska, Paulina Gątarek, Salvatore Chirumbolo, Max Stanley Chartrand, Geir Bjørklund
      Critical Reviews in Food Science and Nutrition.2019; 59(1): 72.     CrossRef
    • Deuterium-Depleted Water as Adjuvant Therapeutic Agent for Treatment of Diet-Induced Obesity in Rats
      Tetiana Halenova, Igor Zlatskiy, Anton Syroeshkin, Tatiana Maximova, Tatiana Pleteneva
      Molecules.2019; 25(1): 23.     CrossRef
    • Human biodistribution and radiation dosimetry of the 5-HT2A receptor agonist Cimbi-36 labeled with carbon-11 in two positions
      Annette Johansen, Søren Holm, Bente Dall, Sune Keller, Jesper L. Kristensen, Gitte M. Knudsen, Hanne D. Hansen
      EJNMMI Research.2019;[Epub]     CrossRef
    • Biological activities of water‐soluble polysaccharides fromOpuntia humifusastem in high‐fat‐diet‐fed mice
      Eun‐In Yang, Chang‐Hyun Lee, Denis Nchang Che, Seon‐Il Jang, Young‐Soo Kim
      Journal of Food Biochemistry.2019; 43(4): e12806.     CrossRef
    • Countering the Modern Metabolic Disease Rampage With Ancestral Endocannabinoid System Alignment
      Ian Pepper, Aaron Vinik, Frank Lattanzio, William McPheat, Anca Dobrian
      Frontiers in Endocrinology.2019;[Epub]     CrossRef
    • The regulation of insulin secretion via phosphoinositide-specific phospholipase Cβ signaling
      Hyeon-Jeong Hwang, Hyun-Jun Jang, Lucio Cocco, Pann-Ghill Suh
      Advances in Biological Regulation.2019; 71: 10.     CrossRef
    • Clostridium ramosum regulates enterochromaffin cell development and serotonin release
      Ana D. Mandić, Anni Woting, Tina Jaenicke, Anika Sander, Wiebke Sabrowski, Ulrike Rolle-Kampcyk, Martin von Bergen, Michael Blaut
      Scientific Reports.2019;[Epub]     CrossRef
    • Estrogen – serotonin interaction and its implication on insulin resistance
      Zulvikar Syambani Ulhaq
      Alexandria Journal of Medicine.2019; 55(1): 76.     CrossRef
    • Serotonin prevents differentiation into brown adipocytes and induces transdifferentiation into white adipocytes
      S Rozenblit-Susan, N Chapnik, O Froy
      International Journal of Obesity.2018; 42(4): 704.     CrossRef
    • Combined brain Fe, Cu, Zn and neurometabolite analysis – a new methodology for unraveling the efficacy of transcranial direct current stimulation (tDCS) in appetite control
      Agata Ziomber, Artur Dawid Surowka, Lucyna Antkiewicz-Michaluk, Irena Romanska, Pawel Wrobel, Magdalena Szczerbowska-Boruchowska
      Metallomics.2018; 10(3): 397.     CrossRef
    • The Effect of Antidepressants on Mesenchymal Stem Cell Differentiation
      Jeffrey S. Kruk, Sandra Bermeo, Kristen K. Skarratt, Stephen J. Fuller, Gustavo Duque
      Journal of Bone Metabolism.2018; 25(1): 43.     CrossRef
    • Acute anti‐obesity effects of intracerebroventricular 11β‐HSD1 inhibitor administration in diet‐induced obese mice
      M. Seo, S. A. Islam, S.‐S. Moon
      Journal of Neuroendocrinology.2018;[Epub]     CrossRef
    • Calcium channel blockers as drug repurposing candidates for gestational diabetes: Mining large scale genomic and electronic health records data to repurpose medications
      Jeffery A. Goldstein, Lisa A. Bastarache, Joshua C. Denny, Dan M. Roden, Jill M. Pulley, David M. Aronoff
      Pharmacological Research.2018; 130: 44.     CrossRef
    • Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat
      Xiaowen Han, Mengjun Min, Juan Wang, Zejun Bao, Hongbin Fan, Xinyu Li, Temitope Isaac Adelusi, Xueyan Zhou, Xiaoxing Yin
      Journal of Neuroscience Research.2018; 96(1): 138.     CrossRef
    • A randomized controlled trial of lorcaserin and lifestyle counselling for weight loss maintenance: changes in emotion‐ and stress‐related eating, food cravings and appetite
      A. M. Chao, T. A. Wadden, R. L. Pearl, N. Alamuddin, S. M. Leonard, Z. M. Bakizada, E. Pinkasavage, K. A. Gruber, O. A. Walsh, R. I. Berkowitz, N. Alfaris, J. S. Tronieri
      Clinical Obesity.2018; 8(6): 383.     CrossRef
    • Lorcaserin and metabolic disease: weight‐loss dependent and independent effects
      H. Bays, C. Perdomo, E. Nikonova, R. Knoth, M. Malhotra
      Obesity Science & Practice.2018; 4(6): 499.     CrossRef
    • Rol del sistema serotoninérgico en la diabetes mellitus y sus dianas farmacológicas
      Victor Orozco, Camilo Caicedo
      Revista Médica Sanitas.2018; 21(3): 125.     CrossRef
    • Effects of Melatonin Administration in Different Time Modes on Morphofunctional Indices of the Hypothalamic Serotonergic Neurons in Obese Rats
      O. O. Kalmukova, A. V. Yurchenko, V. M. Kyryk, V. M. Nepomnyaschy, O. M. Savchuk, M. E. Dzerzhynsky
      Neurophysiology.2018; 50(6): 398.     CrossRef
    • Role of central and peripheral serotonin in obesity: what to expect in the near pharmacotherapy future?
      Mina T Kelleni
      Advances in Obesity, Weight Management & Control.2018;[Epub]     CrossRef
    • Elevating serotonin pre-partum alters the Holstein dairy cow hepatic adaptation to lactation
      Samantha R. Weaver, Allan S. Prichard, Noah L. Maerz, Austin P. Prichard, Elizabeth L. Endres, Lorenzo E. Hernández-Castellano, Matthew S. Akins, Rupert M. Bruckmaier, Laura L. Hernandez, Juan J. Loor
      PLOS ONE.2017; 12(9): e0184939.     CrossRef
    • Biology of obesity and weight regain
      Mary Madeline Rogge, Bibha Gautam
      Journal of the American Association of Nurse Practitioners.2017; 29(S1): S15.     CrossRef
    • 5-HT 2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress
      Minal Jaggar, Noelia Weisstaub, Jay A. Gingrich, Vidita A. Vaidya
      Neurobiology of Stress.2017; 7: 89.     CrossRef
    • Serotonergic Control of Metabolic Homeostasis
      Steven C. Wyler, Caleb C. Lord, Syann Lee, Joel K. Elmquist, Chen Liu
      Frontiers in Cellular Neuroscience.2017;[Epub]     CrossRef
    • Serotonin and Its Receptor as a New Antioxidant Therapeutic Target for Diabetic Kidney Disease
      Yu Yang, Hui Huang, Zheng Xu, Jun-kai Duan
      Journal of Diabetes Research.2017; 2017: 1.     CrossRef
    • Bivalent role of intra-platelet serotonin in liver regeneration and tumor recurrence in humans
      Robin Padickakudy, David Pereyra, Florian Offensperger, Philipp Jonas, Lukas Oehlberger, Christian Schwarz, Stefanie Haegele, Alice Assinger, Christine Brostjan, Thomas Gruenberger, Patrick Starlinger
      Journal of Hepatology.2017; 67(6): 1243.     CrossRef
    • Factors involved in white‐to‐brown adipose tissue conversion and in thermogenesis: a review
      T. Montanari, N. Pošćić, M. Colitti
      Obesity Reviews.2017; 18(5): 495.     CrossRef
    • Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors
      Qin Fu, Qian Shi, Toni M. West, Yang K. Xiang
      Journal of Cardiovascular Pharmacology.2017; 70(2): 74.     CrossRef
    • P62 plasmid can alleviate diet-induced obesity and metabolic dysfunctions
      Tatiana Halenova, Oleksii Savchuk, Ludmila Ostapchenko, Andrey Chursov, Nathan Fridlyand, Andrey B. Komissarov, Franco Venanzi, Sergey I. Kolesnikov, Albert A. Sufianov, Michael Y. Sherman, Vladimir L. Gabai, Alexander M. Shneider
      Oncotarget.2017; 8(34): 56030.     CrossRef
    • Regulation of Systemic Energy Homeostasis by Peripheral Serotonin
      Jun Namkung, Chang-Myung Oh, Sangkyu Park, Hail Kim
      Journal of mucopolysaccharidosis and rare disease.2016; 2(2): 43.     CrossRef
    • Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells
      Joana Almaça, Judith Molina, Danusa Menegaz, Alexey N. Pronin, Alejandro Tamayo, Vladlen Slepak, Per-Olof Berggren, Alejandro Caicedo
      Cell Reports.2016; 17(12): 3281.     CrossRef

    • PubReader PubReader
    • Cite
      CITE
      export Copy
      Close
      Download Citation
      Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

      Format:
      • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
      • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
      Include:
      • Citation for the content below
      Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity
      Diabetes Metab J. 2016;40(2):89-98.   Published online March 27, 2016
      Close
    • XML DownloadXML Download
    Figure
    Related articles

    Diabetes Metab J : Diabetes & Metabolism Journal