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

  • Ayse Basak EnginEmail author
  • Atilla EnginEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 960)

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.

Keywords

Dihydrofolate reductase (DHFR) Endothelial nitric oxide synthase (eNOS) Folate Glutathione Guanosine triphosphate (GTP)-cyclohydrolase 1 (GTPCH1) Hyperhomocysteinemia Serotonin (5-hydroxytryptamine, 5-HT) Indoleamine 2,3-dioxygenase-1 (IDO-1) Inducible nitric oxide synthase (iNOS) Insulin resistance Nitric oxide (NO) Obesity S-adenosylhomocysteine (SAH) S-adenosylmethionine (SAM) Tetrahydrobiopterine (BH4) Tetrahydrofolate Tryptophan 2,3-dioxygenase (TDO2) Tryptophan Neopterin Kynurenine Tumor necrosis factor-alpha (TNF-alpha) 

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Faculty of Pharmacy, Department of ToxicologyGazi UniversityHipodromTurkey
  2. 2.Faculty of Medicine, Department of General SurgeryGazi UniversityBesevlerTurkey
  3. 3.CankayaTurkey

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