Mol. Cells 2015; 38(12): 1023-1028
Published online December 1, 2015
https://doi.org/10.14348/molcells.2015.0258
© The Korean Society for Molecular and Cellular Biology
Correspondence to : *Correspondence: 49park@cku.ac.kr (SP); hailkim@kaist.edu (HK)
Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment.
Keywords adipose tissue, energy homeostasis, obesity, tryptophan hydroxylase, serotonin
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that is synthesized from the essential amino acid tryptophan by the sequential actions of tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase. Once serotonin is released, it exerts its biological action by binding to serotonin receptor (HTR). Its action is then terminated by uptake into cells through the serotonin transporter (SERT, Slc6a4) (
The hydroxylation of tryptophan is the rate-limiting step in serotonin synthesis. Serotonin production is regulated by the activity of TPH and the availability of tryptophan. There are two isoforms of TPH; TPH1 is primarily expressed in peripheral tissues, whereas TPH2 is expressed in the central nervous system (CNS) (
Body energy homeostasis is a primitive and fundamental biological function that is regulated through complex physiological processes. As an ancient neurotransmitter that is conserved throughout the animal phyla, serotonin is a good candidate to play a fundamental role in the regulation of energy homeostasis. At least 14 HTRs, grouped into 7 families according to the signaling mechanisms, are widely expressed in mammalian tissues. This diversity of HTRs can provide diverse effects of serotonin on target cells (
Central serotonin has been considered a target for anti-obesity treatment since an inverse relationship between central serotonin level and food intake was established. Fenfluramine, which increases serotonin release, is the prototypical agent for serotonergic suppression of feeding (
Studies using receptor-specific drugs and knock-out (KO) mice have provided insight into the role of specific HTRs in regulating appetite. The involvement of HTR2C and HTR1B was initially suggested by the anorectic effect of m-chlorophenylpiperazine (mCPP) (
Appetite is regulated by the hypothalamic feeding circuits (
Since TPH2 is responsible for the serotonin production in the brain,
In contrast to the anorectic effect of central serotonin, several lines of evidences suggest different functions of serotonin in the periphery.
Peripheral serotonin is produced in the gut and stored in platelets. There is also a small amount of free serotonin in plasma. The level of serotonin in the blood is determined by the production of serotonin from enterochromaffin cells in the gut. Several studies have reported increased serotonin production and blood serotonin levels in various animal models of obesity and diabetes.
Since the 1960s, the biological functions of peripheral serotonin in the regulation of energy homeostasis have been extensively studied using chemical agonists and antagonists. However, most of data are controversial because of off-target effects. Recently, tissue-specific gene KO technology has allowed us to dissect the complex functions of HTRs in different tissues. In conjunction with recent studies using tissue-specific gene KO of serotonergic systems, reinterpreting the data that have been published over the last several decades provides better understanding on the functions of peripheral serotonin in the regulation of energy metabolism.
In the liver, hepatocytes do not produce serotonin. It is released from platelets upon activation and induces hepatic regeneration through HTR2B (
Although
HTR2A and HTR3 have been identified as receptors mediating the obesogenic effects of serotonin in adipose tissues. Diet-induced thermogenesis was robustly increased in the BAT of
Based on the newly identified roles of peripheral serotonin in energy homeostasis, serotonin can be considered as an energy-saving hormone. Modulating the peripheral serotonergic system may be a good strategy for anti-obesity treatment because it can decrease obesity and increase insulin sensitivity. In general, receptor-specific activation or inhibition is thought to be a better strategy for drug development. However, serotonin plays different roles in different tissues by acting through different receptors. Thus, inhibition of serotonin synthesis in adipose tissue is a potentially beneficial strategy for anti-obesity treatment. This strategy increases insulin sensitivity by simultaneously decreasing lipogenesis and increasing adaptive thermogenesis.
There are still several questions remained to be solved. Mitochondrial biogenesis was enhanced in BAT by
The evidences in support of serotonin as a metabolic regulator in the development of obesity are increasing. Nonetheless, the majority of the data are derived from animal studies, and the clinical relevance of serotonin in humans remains undetermined. More accurate information regarding blood serotonin levels in different clinical settings also needs to be obtained.
Mol. Cells 2015; 38(12): 1023-1028
Published online December 31, 2015 https://doi.org/10.14348/molcells.2015.0258
Copyright © The Korean Society for Molecular and Cellular Biology.
Jun Namkung1, Hail Kim1,*, and Sangkyu Park2,*
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea, 2Department of Biochemistry, College of Medicine, Catholic Kwandong University, Gangwon 25601, Korea
Correspondence to:*Correspondence: 49park@cku.ac.kr (SP); hailkim@kaist.edu (HK)
Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment.
Keywords: adipose tissue, energy homeostasis, obesity, tryptophan hydroxylase, serotonin
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that is synthesized from the essential amino acid tryptophan by the sequential actions of tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase. Once serotonin is released, it exerts its biological action by binding to serotonin receptor (HTR). Its action is then terminated by uptake into cells through the serotonin transporter (SERT, Slc6a4) (
The hydroxylation of tryptophan is the rate-limiting step in serotonin synthesis. Serotonin production is regulated by the activity of TPH and the availability of tryptophan. There are two isoforms of TPH; TPH1 is primarily expressed in peripheral tissues, whereas TPH2 is expressed in the central nervous system (CNS) (
Body energy homeostasis is a primitive and fundamental biological function that is regulated through complex physiological processes. As an ancient neurotransmitter that is conserved throughout the animal phyla, serotonin is a good candidate to play a fundamental role in the regulation of energy homeostasis. At least 14 HTRs, grouped into 7 families according to the signaling mechanisms, are widely expressed in mammalian tissues. This diversity of HTRs can provide diverse effects of serotonin on target cells (
Central serotonin has been considered a target for anti-obesity treatment since an inverse relationship between central serotonin level and food intake was established. Fenfluramine, which increases serotonin release, is the prototypical agent for serotonergic suppression of feeding (
Studies using receptor-specific drugs and knock-out (KO) mice have provided insight into the role of specific HTRs in regulating appetite. The involvement of HTR2C and HTR1B was initially suggested by the anorectic effect of m-chlorophenylpiperazine (mCPP) (
Appetite is regulated by the hypothalamic feeding circuits (
Since TPH2 is responsible for the serotonin production in the brain,
In contrast to the anorectic effect of central serotonin, several lines of evidences suggest different functions of serotonin in the periphery.
Peripheral serotonin is produced in the gut and stored in platelets. There is also a small amount of free serotonin in plasma. The level of serotonin in the blood is determined by the production of serotonin from enterochromaffin cells in the gut. Several studies have reported increased serotonin production and blood serotonin levels in various animal models of obesity and diabetes.
Since the 1960s, the biological functions of peripheral serotonin in the regulation of energy homeostasis have been extensively studied using chemical agonists and antagonists. However, most of data are controversial because of off-target effects. Recently, tissue-specific gene KO technology has allowed us to dissect the complex functions of HTRs in different tissues. In conjunction with recent studies using tissue-specific gene KO of serotonergic systems, reinterpreting the data that have been published over the last several decades provides better understanding on the functions of peripheral serotonin in the regulation of energy metabolism.
In the liver, hepatocytes do not produce serotonin. It is released from platelets upon activation and induces hepatic regeneration through HTR2B (
Although
HTR2A and HTR3 have been identified as receptors mediating the obesogenic effects of serotonin in adipose tissues. Diet-induced thermogenesis was robustly increased in the BAT of
Based on the newly identified roles of peripheral serotonin in energy homeostasis, serotonin can be considered as an energy-saving hormone. Modulating the peripheral serotonergic system may be a good strategy for anti-obesity treatment because it can decrease obesity and increase insulin sensitivity. In general, receptor-specific activation or inhibition is thought to be a better strategy for drug development. However, serotonin plays different roles in different tissues by acting through different receptors. Thus, inhibition of serotonin synthesis in adipose tissue is a potentially beneficial strategy for anti-obesity treatment. This strategy increases insulin sensitivity by simultaneously decreasing lipogenesis and increasing adaptive thermogenesis.
There are still several questions remained to be solved. Mitochondrial biogenesis was enhanced in BAT by
The evidences in support of serotonin as a metabolic regulator in the development of obesity are increasing. Nonetheless, the majority of the data are derived from animal studies, and the clinical relevance of serotonin in humans remains undetermined. More accurate information regarding blood serotonin levels in different clinical settings also needs to be obtained.
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