A Systems Biology Approach to Investigating the Interaction between Serotonin Synthesis by Tryptophan Hydroxylase and the Metabolic Homeostasis

Abstract

Obesity has become a global public health and economic problem. Obesity is a major risk factor for a number of complications, such as type 2 diabetes, cardiovascular disease, fatty liver disease, and cancer. Serotonin (5-hydroxytryptamine [5-HT]) is a biogenic monoamine that plays various roles in metabolic homeostasis. It is well known that central 5-HT regulates appetite and mood. Several 5-HT receptor agonists and selective serotonin receptor uptake inhibitors (SSRIs) have shown beneficial effects on appetite and mood control in clinics. Although several genetic polymorphisms related to 5-HT synthesis and its receptors are strongly associated with obesity, there is little evidence of the role of peripheral 5-HT in human metabolism. In this study, we performed a systemic analysis of transcriptome data from the Genotype-Tissue Expression (GTEX) database. We investigated the expression of 5-HT and tryptophan hydroxylase (TPH), the rate-limiting enzyme of 5-HT biosynthesis, in the human brain and peripheral tissues. We also performed differential gene expression analysis and predicted changes in metabolites by comparing gene expressions of tissues with high TPH expression to the gene expressions of tissues with low TPH expression. Our analyses provide strong evidence that serotonin plays an important role in the regulation of metabolic homeostasis in humans.

Dietary tryptophan supplementation does not affect growth but increases brain serotonin level and modulates the expression of some liver genes in zebrafish (Danio rerio)

“…Outside the brain, TPH1 is primarily expressed in non-neuronal cells of peripheral organs that are able to synthesize serotonin, such as the gut, kidney, and liver (Chen et al, 2017;Yabut et al, 2019;Yang et al, 2017), among others. In addition, THP2 is also expressed peripherally, especially in neurons of the enteric nervous system (Matthes and Bader, 2018;Yabut et al, 2019); moreover, in rats and humans, its expression was detected in several other organs as well, including the liver, simultaneously with the expression of TPH1 (Chen et al, 2017;Park et al, 2021). In line with this, we detected the isoforms TPH1a, TPH1b, and TPH2 (including variants TPH2a and TPH2b) expressed in zebrafish liver.…”

Melatonin as a Smart Protector of Pregnancy in Dairy Cows

“…This is an insightful response because it infers not only melatonin action within the control systems of the brain, but direct melatonin regulation of tissues such as the uterus. Serotonin, the precursor to melatonin, has a dual control system based on differential expression of two isoforms of tryptophan hydroxylase (TPH1 and TPH2) [ 40 ]. Indeed, TPH1 is highly expressed throughout a plethora of tissues involved in regulation of metabolism (e.g., small intestine, stomach, ovary, uterus, etc.…”

The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine

“…Trp hydroxylase ( TPH ), the specific serotonin-synthesizing gene, exists in two isoforms ( TPH1 and TPH2 ) [ 32 , 33 ]. Both TPH1 and TPH2 show Trp hydroxylating activity.…”