Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule

Julian M Yabut, Justin D Crane, Alexander E Green, Damien J Keating, Waliul I Khan, Gregory R Steinberg, Julian M Yabut, Justin D Crane, Alexander E Green, Damien J Keating, Waliul I Khan, Gregory R Steinberg

Abstract

Serotonin is a phylogenetically ancient biogenic amine that has played an integral role in maintaining energy homeostasis for billions of years. In mammals, serotonin produced within the central nervous system regulates behavior, suppresses appetite, and promotes energy expenditure by increasing sympathetic drive to brown adipose tissue. In addition to these central circuits, emerging evidence also suggests an important role for peripheral serotonin as a factor that enhances nutrient absorption and storage. Specifically, glucose and fatty acids stimulate the release of serotonin from the duodenum, promoting gut peristalsis and nutrient absorption. Serotonin also enters the bloodstream and interacts with multiple organs, priming the body for energy storage by promoting insulin secretion and de novo lipogenesis in the liver and white adipose tissue, while reducing lipolysis and the metabolic activity of brown and beige adipose tissue. Collectively, peripheral serotonin acts as an endocrine factor to promote the efficient storage of energy by upregulating lipid anabolism. Pharmacological inhibition of serotonin synthesis or signaling in key metabolic tissues are potential drug targets for obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD).

Copyright © 2019 Endocrine Society.

Figures

Figure 1.
Figure 1.
Key enzymes regulating tryptophan metabolism. Left panel: Tryptophan is metabolized by Tph to 5-HTP and subsequently metabolized to serotonin by amino acid decarboxylase (AADC). Serotonin can be metabolized into either 5-HIAA by MAO or N-acetyl-serotonin by arylalkylamine N-acetyltransferase (AAAT). N-acetyl-serotonin is subsequently metabolized into melatonin by hydroxyindole-O-methyl transferase (HIMT). Right panel: Tryptophan is also a substrate for TDO to produce N-formyl kynurenine, which can be made into kynurenine by formamidase (FA). IDO can also metabolize tryptophan into N-formyl-kynurenine alongside any other molecules that contain an indole moiety. Kynurenine aminotransferase (KAT) and kynurenine 3-monooxygenase (KMO) form kynurenic acid and 3-hydroxykynurenine, respectively, from kynurenine. Kynurenine is broken down by kynureninase and 3-hydroxyanthranilic acid dioxygenase (3-HAO) to form quinolinic acid, which can be further metabolized by quinolinic acid phosphoribosyltransferase (QPRT) to form precursors for NAD+. Atoms in red are the structural changes of the previous enzymatic reaction. MarvinSketch (from ChemAxon) was used for drawing and displaying chemical structures in this figure.
Figure 2.
Figure 2.
Tissue-specific regulation of tryptophan, serotonin, and kynurenine metabolism. Left panel: EC cell Tph1 activity is regulated by microbiota-derived short-chain fatty acids (SCFAs), glucose, and secretory products of CD4+ T cells in the gut lumen. Middle panel: Tryptophan (white circle) is converted into 5-HTP in the CNS or in EC cells by Tph2 and Tph1, respectively, and is then quickly metabolized to serotonin (5-HT) by amino acid decarboxylase (AADC). Central (orange circle) and peripheral (blue circle) pools of serotonin are distinct, as they cannot pass the blood–brain barrier (BBB). Centrally synthesized serotonin can affect various areas of the brain such as POMC neurons, ventral tegmental area (VTA), and nucleus of the solitary tract (NST). Serotonin synthesis in the ENS is dependent on Tph2 and innervates neurons in the submucosal plexus (Smp) and myenteric plexus (MyP) to induce motility. Serotonin produced by Tph1 in EC cells is imported into enterocytes by SERT (orange transporter) and subsequently degraded by enterocyte MAO into 5-HIAA (gray circle). Tryptophan is also metabolized into kynurenine (Kyn; green circle) in the liver by TDO. Serotonin, 5-HIAA, and Kyn can be excreted into the circulation. Serotonin is sequestered by SERT of blood platelets, transported to the circulation, and effects systemic metabolism upon release into the plasma (double arrow).
Figure 3.
Figure 3.
Serotonin receptor expression and signaling pathways. The seven distinct serotonin receptors (HTRx) families have unique tissue-specific distributions and can be grouped into four distinct downstream signaling pathways. The HTR2 pathway employs the G-protein αq/11 subunit (Gq/G11), which induces phospholipase C (PLC), leading to the upregulation of inositol triphosphate (IP3), calcium, and diacylglycerol (DAG), which activates protein kinase C (PKC). HTR1/HTR5 use the G-protein αi subunit (Gi/Go) that inhibits adenylate cyclase (AC), thereby reducing the production of cAMP from ATP. HTR4/HTR6/HTR7 use the G-protein αs subunit (Gs) that activates AC, which increases cAMP and induces the phosphorylation of protein kinase A (PKA). HTR3 is a serotonin-gated ion channel that increases intracellular concentrations of cations, which can cause cell depolarization.
Figure 4.
Figure 4.
Metabolic functions of serotonin in different tissues. Central serotonin suppresses appetite, reducing nutrient intake. In the periphery, serotonin promotes nutrient storage by increasing gut motility to facilitate absorption after feeding. Serotonin enhances insulin secretion from pancreatic islets, which enhances nutrient storage in different tissues. The effects of insulin to promote nutrient storage are further enhanced through direct actions of serotonin to promote de novo lipogenesis in WAT and liver and to stimulate glucose uptake in skeletal muscle while at the same time inhibiting futile cycling/thermogenesis within BAT and beige adipose tissue.
Figure 5.
Figure 5.
Multifaceted effects of peripheral serotonin to promote obesity and NAFLD. Peripheral serotonin promotes obesity and NAFLD by promoting insulin secretion, inhibiting the thermogenesis in beige adipose tissue and BAT, and increasing de novo lipogenesis in both WAT and liver. Collectively, these actions may promote the development of obesity and NAFLD.

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