Associations Among Obesity, Inflammation, and Tryptophan Catabolism in Pregnancy

Abstract

Objective: To evaluate relationships among obesity in pregnancy and plasma levels of tryptophan (TRP) and kynurenine (KYN), inflammatory markers, and depressed mood.

Methods: Pregnant women ( N = 374) were enrolled, and data were collected at a mean gestation of 20 weeks in this cross-sectional study. Plasma was analyzed for TRP, KYN, neopterin, and nitrite levels. Women completed demographic and mood scales.

Results: There was a statistically significant inverse correlation between body mass index (BMI) and TRP and positive correlations between BMI and KYN and the kynurenine/tryptophan (KYN/TRP) ratio. Neopterin was correlated with KYN/TRP, suggesting that the indoleamine 2,3-dioxygenase-1 (IDO-1) enzyme was activated. The correlations of neopterin and nitrite with BMI were too small to be clinically meaningful but may provide mechanistic insight. There was a correlation between depressed mood and nitrite levels. Depressed mood was also associated with lower TRP levels. When the sample was divided into pregnant women with or without obesity, TRP was significantly lower and the KYN/TRP ratio was significantly higher in the women with obesity.

Conclusion: The pro-inflammatory state of obesity in pregnancy may drive activation of IDO-1, resulting in diversion of TRP away from serotonin and melatonin production and toward KYN metabolites. This alteration could contribute to depression, impaired sleep, increased production of excitotoxic neurotransmitters, and reinforcement of a pro-inflammatory state in pregnancy.

Keywords: BMI; inflammation; kynurenine; pregnancy; tryptophan.

Figure 1.

Inflammation affects multiple pathways. Serotonin can be enzymatically activated by tryptophan hydroxylase to form 5-hydroxytryptophan,N-methyl-D-aspartate which is then converted into serotonin BH4, a cofactor for this and other amino acid hydoxylases (phenylalanine, tyrosine), has GTP as its source through the GTP cyclohydrolase enzymatic reaction. These amino acids are substrates for the formation of dopamine, melatonin, and other catecholamines. In the other pathway, tryptophan is enzymatically catabolized to kynurenine, which forms kynurenic acid and then QA. QA is able to bind to the receptors, thus acquiring neurotransmitter properties. The enzymes TDO and IDO catalyze this reaction, but TDO is largely active only in the liver, while IDO reactivity is immune cell bound. These reactions occur in macrophages and other immune cells, so this interaction of amino acid substrates and immune cells is of note. Of particular importance is the role of the inflammatory cytokines IFN-γ and TNF-α, which stimulate BH4 production and IDO activation. +++ = pathways affected by inflammation; BH4 = tetrahydrobiopterin; GTP = guanosine triphosphate; GTPCH = guanosine triphosphate cyclohydrolase; IDO = indoleamine 2,3-dioxygenase; IFN-γ = interferon-γ; PHA = phenylalanine hydrolase; ThH = tyrosine hydrolase; TNF-α = tumor necrosis factor-α; TPH = tryptophan hydrolase; QA = quinolinic acid.