The Interactions Between Kynurenine, Folate, Methionine and Pteridine Pathways in Obesity

Abstract

Obesity activates both innate and adaptive immune responses in adipose tissue. Elevated levels of eosinophils with depression of monocyte and neutrophil indicate the deficiencies in the immune system of morbidly obese individuals. Actually, adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-gamma)-producing CD4+ T cells in adipose tissue of obese subjects. Eventually, diet-induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in visceral adipose tissue. Activity of inducible indoleamine 2,3-dioxygenase-1 (IDO-1) plays a major role under pro-inflammatory, IFN-gamma dominated settings. One of the two rate-limiting enzymes which can metabolize tryptophan to kynurenine is IDO-1. Tumor necrosis factor-alpha (TNF-alpha) correlates with IDO-1 in adipose compartments. Actually, IDO-1-mediated tryptophan catabolism due to chronic immune activation is the cause of reduced tryptophan plasma levels and be considered as the driving force for food intake in morbidly obese patients. Thus, decrease in plasma tryptophan levels and subsequent reduction in serotonin (5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. However, after bariatric surgery, weight reduction does not lead to normalization of IDO-1 activity. Furthermore, there is a connection between arginine and tryptophan metabolic pathways in the generation of reactive nitrogen intermediates. Hence, abdominal obesity is associated with vascular endothelial dysfunction and reduced nitric oxide (NO) availability. IFN-gamma-induced activation of the inducible nitric oxide synthase (iNOS) and dissociation of endothelial adenosine monophosphate activated protein kinase (AMPK)- phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)- endothelial NO synthase (eNOS) pathway enhances oxidative stress production secondary to high-fat diet. Thus, reduced endothelial NO availability correlates with the increase in plasma non-esterified fatty acids and triglycerides levels. Additionally, in obese patients, folate-deficiency leads to hyperhomocysteinemia. Folic acid confers protection against hyperhomocysteinemia-induced oxidative stress.

A Multi-omics Approach to Unraveling the Microbiome-Mediated Effects of Arabinoxylan Oligosaccharides in Overweight Humans

“…Indeed, some obese individuals show folate deficiency, which could lead to hyperhomocysteinemia related to atherosclerosis risk (38). In line with this, administration of folic acid and derivatives seems to confer protection against hyperhomocysteinemia-induced oxidative stress (39). AXOS intervention also increased the capacity of the gut microbiome for aromatic amino acid production (shikimate pathway producing precursors for tryptophan, phenylalanine, and tyrosine biosynthesis), which theoretically could increase the generation of derivative neurotransmitters (e.g., serotonin, dopamine, epinephrine, and norepinephrine).…”

Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits

“…DAP3 has been shown to mediate interferon gamma-induced cell death, 62 which is involved in pro-inflammatory responses related to obesity. 63 Of note, a GWAS in Europeans 43 also identified BMI-associated variants in this chromosomal region, although the European and Japanese GWAS variants exhibited low pairwise LD (r 2 ¼ 0.32 in 1000 Genomes East Asians and r 2 ¼ 0.35 in Finns) and the European signal was not colocalized with any genes (Table S9). While further characterization of the locus may identify additional candidate genes, the shared LD patterns support cross-ancestry conclusions of colocalized GWAS and eQTL signals.…”

Obesity and Cancer: Existing and New Hypotheses for a Causal Connection

“…The increased tryptophan oxidation correlated with abdominal adiposity rather than overall BMI, suggesting that it specifically involved an aspect of fat metabolism – the basis of the metabolic syndrome. The inflammation-induced activation of IDO and its metabolism of tryptophan to kynurenine has been proposed as the major mechanism linking inflammation, depression, type-1 diabetes and obesity ( Engin and Engin, 2017 ; Murfitt et al, 2017 ; Zhong et al, 2017 ), partly attributable to the effects of tryptophan metabolites on food craving ( Dalkner et al, 2017 ).…”