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)


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.


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) 


  1. Belz, G.T., and S.L. Nutt. 2012. Transcriptional programming of the dendritic cell network. Nature Reviews. Immunology 12: 101–113. doi: 10.1038/nri3149.PubMedCrossRefGoogle Scholar
  2. Brandacher, G., C. Winkler, F. Aigner, H. Schwelberger, K. Schroecksnadel, R. Margreiter, D. Fuchs, and H.G. Weiss. 2006. Bariatric surgery cannot prevent tryptophan depletion due to chronic immune activation in morbidly obese patients. Obesity Surgery 16: 541–548. doi: 10.1381/096089206776945066.PubMedCrossRefGoogle Scholar
  3. Brandacher, G., E. Hoeller, D. Fuchs, and H.G. Weiss. 2007. Chronic immune activation underlies morbid obesity: Is IDO a key player? Current Drug Metabolism 8: 289–295.PubMedCrossRefGoogle Scholar
  4. Brosnan, J.T., and M.E. Brosnan. 2006. The sulfur-containing amino acids: An overview. The Journal of Nutrition 136: 1636S–1640S.PubMedGoogle Scholar
  5. Buttigieg, A., O. Flores, A. Hernández, P. Sáez-Briones, H. Burgos, and C. Morgan. 2014. Preference for high-fat diet is developed by young Swiss CD1 mice after short-term feeding and is prevented by NMDA receptor antagonists. Neurobiology of Learning and Memory 107: 13–18. doi: 10.1016/j.nlm.2013.10.018.PubMedCrossRefGoogle Scholar
  6. Chen, Y., S. Zhao, Y. Wang, Y. Li, L. Bai, R. Liu, J. Fan, and E. Liu. 2014. Homocysteine reduces protein S-nitrosylation in endothelium. International Journal of Molecular Medicine 34: 1277–1285. doi: 10.3892/ijmm.2014.1920.PubMedGoogle Scholar
  7. Cho, K.W., D.L. Morris, J.L. DelProposto, L. Geletka, B. Zamarron, G. Martinez-Santibanez, K.A. Meyer, K. Singer, R.W. O’Rourke, and C.N. Lumeng. 2014. An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. Cell Reports 9: 605–617. doi: 10.1016/j.celrep.2014.09.004.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Christensen, K.E., Q. Wu, X. Wang, L. Deng, M.A. Caudill, and R. Rozen. 2010. Steatosis in mice is associated with gender, folate intake, and expression of genes of one-carbon metabolism. The Journal of Nutrition 140: 1736–1741. doi: 10.3945/jn.110.124917.PubMedCrossRefGoogle Scholar
  9. Codoñer-Franch, P., S. Tavárez-Alonso, R. Murria-Estal, J. Megías-Vericat, M. Tortajada-Girbés, and E. Alonso-Iglesias. 2011. Nitric oxide production is increased in severely obese children and related to markers of oxidative stress and inflammation. Atherosclerosis 215: 475–480. doi: 10.1016/j.atherosclerosis.2010.12.035.PubMedCrossRefGoogle Scholar
  10. Cottam, D.R., P.A. Schaefer, G.W. Shaftan, L. Velcu, and L.D.G. Angus. 2002. Effect of surgically-induced weight loss on leukocyte indicators of chronic inflammation in morbid obesity. Obesity Surgery 12: 335–342.PubMedCrossRefGoogle Scholar
  11. Crabtree, M.J., A.B. Hale, and K.M. Channon. 2011. Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency. Free Radical Biology & Medicine 50: 1639–1646. doi: 10.1016/j.freeradbiomed.2011.03.010.CrossRefGoogle Scholar
  12. da Silva, V.R., D.B. Hausman, G.P.A. Kauwell, A. Sokolow, R.L. Tackett, S.L. Rathbun, and L.B. Bailey. 2013. Obesity affects short-term folate pharmacokinetics in women of childbearing age. International Journal of Obesity 2005(37): 1608–1610. doi: 10.1038/ijo.2013.41.CrossRefGoogle Scholar
  13. da Silva, R.P., K.B. Kelly, A. Al Rajabi, and R.L. Jacobs. 2014. Novel insights on interactions between folate and lipid metabolism. Biofactors 40: 277–283. doi: 10.1002/biof.1154.PubMedCrossRefGoogle Scholar
  14. Dang, Y., W.E. Dale, and O.R. Brown. 2000. Comparative effects of oxygen on indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase of the kynurenine pathway. Free Radical Biology & Medicine 28: 615–624.CrossRefGoogle Scholar
  15. Eleftheriadis, T., G. Pissas, A. Karioti, G. Antoniadi, V. Liakopoulos, K. Dafopoulou, S. Pournaras, G. Koukoulis, and I. Stefanidis. 2012. The indoleamine 2,3-dioxygenase inhibitor 1-methyl-tryptophan suppresses mitochondrial function, induces aerobic glycolysis and decreases interleukin-10 production in human lymphocytes. Immunological Investigations 41: 507–520. doi: 10.3109/08820139.2012.682244.PubMedCrossRefGoogle Scholar
  16. Elshorbagy, A.K., H. Refsum, A.D. Smith, and I.M. Graham. 2009. The association of plasma cysteine and gamma-glutamyltransferase with BMI and obesity. Obesity (Silver Spring) 17: 1435–1440. doi: 10.1038/oby.2008.671.Google Scholar
  17. Elshorbagy, A.K., V. Kozich, A.D. Smith, and H. Refsum. 2012. Cysteine and obesity: Consistency of the evidence across epidemiologic, animal and cellular studies. Current Opinion in Clinical Nutrition and Metabolic Care 15: 49–57. doi: 10.1097/MCO.0b013e32834d199f.PubMedCrossRefGoogle Scholar
  18. Fathy, S.M., and G. Morshed. 2014. Peripheral blood lymphocyte subsets (CD4+, CD8+ T cells), leptin level and weight loss after laparoscopic greater curvature plication in morbidly obese patients. Archives of Medical Science. AMS 10: 886–890. doi: 10.5114/aoms.2014.46209.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Favennec, M., B. Hennart, R. Caiazzo, A. Leloire, L. Yengo, M. Verbanck, A. Arredouani, M. Marre, M. Pigeyre, A. Bessede, G.J. Guillemin, G. Chinetti, B. Staels, F. Pattou, B. Balkau, D. Allorge, P. Froguel, and O. Poulain-Godefroy. 2015. The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. Obesity (Silver Spring) 23: 2066–2074. doi: 10.1002/oby.21199.CrossRefGoogle Scholar
  20. Favero, G., A. Stacchiotti, S. Castrezzati, F. Bonomini, M. Albanese, R. Rezzani, and L.F. Rodella. 2015. Melatonin reduces obesity and restores adipokine patterns and metabolism in obese (ob/ob) mice. Nutrition Research 35: 891–900. doi: 10.1016/j.nutres.2015.07.001.PubMedCrossRefGoogle Scholar
  21. Frick, B., K. Schroecksnadel, G. Neurauter, F. Leblhuber, and D. Fuchs. 2004. Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clinical Biochemistry 37: 684–687. doi: 10.1016/j.clinbiochem.2004.02.007.PubMedCrossRefGoogle Scholar
  22. Frumento, G., R. Rotondo, M. Tonetti, G. Damonte, U. Benatti, and G.B. Ferrara. 2002. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. The Journal of Experimental Medicine 196: 459–468.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Fuchs, D., M. Jaeger, B. Widner, B. Wirleitner, E. Artner-Dworzak, and F. Leblhuber. 2001. Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake? Clinical Chemistry and Laboratory Medicine 39: 691–694. doi: 10.1515/CCLM.2001.113.PubMedCrossRefGoogle Scholar
  24. Gál, E.M., and A.D. Sherman. 1980. L-kynurenine: Its synthesis and possible regulatory function in brain. Neurochemical Research 5: 223–239.PubMedCrossRefGoogle Scholar
  25. García-Prieto, C.F., F. Hernández-Nuño, D.D. Rio, G. Ruiz-Hurtado, I. Aránguez, M. Ruiz-Gayo, B. Somoza, and M.S. Fernández-Alfonso. 2015. High-fat diet induces endothelial dysfunction through a down-regulation of the endothelial AMPK-PI3K-Akt-eNOS pathway. Molecular Nutrition & Food Research 59: 520–532. doi: 10.1002/mnfr.201400539.CrossRefGoogle Scholar
  26. Gershon, M.D., and J. Tack. 2007. The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology 132: 397–414. doi: 10.1053/j.gastro.2006.11.002.PubMedCrossRefGoogle Scholar
  27. Giorgini, F., S.-Y. Huang, K.V. Sathyasaikumar, F.M. Notarangelo, M.A.R. Thomas, M. Tararina, H.-Q. Wu, R. Schwarcz, and P.J. Muchowski. 2013. Targeted deletion of kynurenine 3-monooxygenase in mice: A new tool for studying kynurenine pathway metabolism in periphery and brain. The Journal of Biological Chemistry 288: 36554–36566. doi: 10.1074/jbc.M113.503813.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Griffith, O.W. 1999. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radical Biology & Medicine 27: 922–935.CrossRefGoogle Scholar
  29. Han, Q., T. Cai, D.A. Tagle, and J. Li. 2010. Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cellular and Molecular Life Sciences 67: 353–368. doi: 10.1007/s00018-009-0166-4.PubMedCrossRefGoogle Scholar
  30. Heyes, M.P., K. Saito, and S.P. Markey. 1992. Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid. The Biochemical Journal 283(Pt 3): 633–635.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Hirsch, S., J. Poniachick, M. Avendaño, A. Csendes, P. Burdiles, G. Smok, J.C. Diaz, and M.P. de la Maza. 2005. Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition 21: 137–141. doi: 10.1016/j.nut.2004.03.022.PubMedCrossRefGoogle Scholar
  32. Horton, A.A., and S. Fairhurst. 1987. Lipid peroxidation and mechanisms of toxicity. Critical Reviews in Toxicology 18: 27–79. doi: 10.3109/10408448709089856.PubMedCrossRefGoogle Scholar
  33. Iamopas, O., S. Ratanachu-ek, and S. Chomtho. 2014. Effect of folic acid supplementation on plasma homocysteine in obese children: A randomized, double-blind, placebo-controlled trial. Journal of the Medical Association of Thailand 97(Suppl 6): S195–S204.PubMedGoogle Scholar
  34. Irving, A.J., L. Wallace, D. Durakoglugil, and J. Harvey. 2006. Leptin enhances NR2B-mediated N-methyl-D-aspartate responses via a mitogen-activated protein kinase-dependent process in cerebellar granule cells. Neuroscience 138: 1137–1148. doi: 10.1016/j.neuroscience.2005.11.042.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Jhee, K.-H., and W.D. Kruger. 2005. The role of cystathionine beta-synthase in homocysteine metabolism. Antioxidants & Redox Signaling 7: 813–822. doi: 10.1089/ars.2005.7.813.CrossRefGoogle Scholar
  36. Kato, H., G. Tanaka, S. Masuda, J. Ogasawara, T. Sakurai, T. Kizaki, H. Ohno, and T. Izawa. 2015. Melatonin promotes adipogenesis and mitochondrial biogenesis in 3 T3-L1 preadipocytes. Journal of Pineal Research 59: 267–275. doi: 10.1111/jpi.12259.PubMedCrossRefGoogle Scholar
  37. Kim, H.-J., J.H. Kim, S. Noh, H.J. Hur, M.J. Sung, J.-T. Hwang, J.H. Park, H.J. Yang, M.-S. Kim, D.Y. Kwon, and S.H. Yoon. 2011. Metabolomic analysis of livers and serum from high-fat diet induced obese mice. Journal of Proteome Research 10: 722–731. doi: 10.1021/pr100892r.PubMedCrossRefGoogle Scholar
  38. Kintscher, U., M. Hartge, K. Hess, A. Foryst-Ludwig, M. Clemenz, M. Wabitsch, P. Fischer-Posovszky, T.F.E. Barth, D. Dragun, T. Skurk, H. Hauner, M. Blüher, T. Unger, A.-M. Wolf, U. Knippschild, V. Hombach, and N. Marx. 2008. T-lymphocyte infiltration in visceral adipose tissue: A primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arteriosclerosis, Thrombosis, and Vascular Biology 28: 1304–1310. doi: 10.1161/ATVBAHA.108.165100.PubMedCrossRefGoogle Scholar
  39. Kolb, A.F., and L. Petrie. 2013. Folate deficiency enhances the inflammatory response of macrophages. Molecular Immunology 54: 164–172. doi: 10.1016/j.molimm.2012.11.012.PubMedCrossRefGoogle Scholar
  40. Ledochowski, M., C. Murr, B. Widner, and D. Fuchs. 1999. Association between insulin resistance, body mass and neopterin concentrations. Clinica Chimica Acta 282: 115–123.CrossRefGoogle Scholar
  41. Lee, S.M., Y.H. Cho, S.Y. Lee, D.W. Jeong, A.R. Cho, J.S. Jeon, E.-J. Park, Y.J. Kim, J.G. Lee, Y.H. Yi, Y.J. Tak, H.R. Hwang, S.-H. Lee, and J. Han. 2015. Urinary Malondialdehyde Is Associated with Visceral Abdominal Obesity in Middle-Aged Men. Mediators of Inflammation 2015: 524291. doi: 10.1155/2015/524291.PubMedPubMedCentralGoogle Scholar
  42. Li, N., M.M. Young, C.J. Bailey, and M.E. Smith. 1999. NMDA and AMPA glutamate receptor subtypes in the thoracic spinal cord in lean and obese-diabetic ob/ob mice. Brain Research 849: 34–44.PubMedCrossRefGoogle Scholar
  43. Liu, H., L. Liu, K. Liu, P. Bizargity, W.W. Hancock, and G.A. Visner. 2009. Reduced cytotoxic function of effector CD8+ T cells is responsible for indoleamine 2,3-dioxygenase-dependent immune suppression. The Journal of Immunolog 1950(183): 1022–1031. doi: 10.4049/jimmunol.0900408.CrossRefGoogle Scholar
  44. Liu, J.J., S. Raynal, D. Bailbé, B. Gausseres, C. Carbonne, V. Autier, J. Movassat, M. Kergoat, and B. Portha. 2015. Expression of the kynurenine pathway enzymes in the pancreatic islet cells. Activation by cytokines and glucolipotoxicity. Biochimica et Biophysica Acta 1852: 980–991. doi: 10.1016/j.bbadis.2015.02.001.PubMedCrossRefGoogle Scholar
  45. Melillo, G., G.W. Cox, A. Biragyn, L.A. Sheffler, and L. Varesio. 1994. Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acid. The Journal of Biological Chemistry 269: 8128–8133.PubMedGoogle Scholar
  46. Mellor, A.L., and D.H. Munn. 2004. IDO expression by dendritic cells: Tolerance and tryptophan catabolism. Nature Reviews. Immunology 4: 762–774. doi: 10.1038/nri1457.PubMedCrossRefGoogle Scholar
  47. Merad, M., P. Sathe, J. Helft, J. Miller, and A. Mortha. 2013. The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annual Review of Immunology 31: 563–604. doi: 10.1146/annurev-immunol-020711-074950.PubMedCrossRefGoogle Scholar
  48. Meraz, M.A., J.M. White, K.C. Sheehan, E.A. Bach, S.J. Rodig, A.S. Dighe, D.H. Kaplan, J.K. Riley, A.C. Greenlund, D. Campbell, K. Carver-Moore, R.N. DuBois, R. Clark, M. Aguet, and R.D. Schreiber. 1996. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84: 431–442.PubMedCrossRefGoogle Scholar
  49. Mikael, L.G., J. Pancer, X. Jiang, Q. Wu, M. Caudill, and R. Rozen. 2013. Low dietary folate and methylenetetrahydrofolate reductase deficiency may lead to pregnancy complications through modulation of ApoAI and IFN-γ in spleen and placenta, and through reduction of methylation potential. Molecular Nutrition & Food Research 57: 661–670. doi: 10.1002/mnfr.201200152.CrossRefGoogle Scholar
  50. Ming, Z., D.J. Legare, and W.W. Lautt. 2009. Obesity, syndrome X, and diabetes: The role of HISS-dependent insulin resistance altered by sucrose, an antioxidant cocktail, and age. Canadian Journal of Physiology and Pharmacology 87: 873–882. doi: 10.1139/Y09-079.PubMedCrossRefGoogle Scholar
  51. Morris, D.L., K.W. Cho, J.L. Delproposto, K.E. Oatmen, L.M. Geletka, G. Martinez-Santibanez, K. Singer, and C.N. Lumeng. 2013. Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes 62: 2762–2772. doi: 10.2337/db12-1404.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Morris, D.L., K.E. Oatmen, T.A. Mergian, K.W. Cho, J.L. DelProposto, K. Singer, C. Evans-Molina, R.W. O’Rourke, and C.N. Lumeng. 2016. CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity. Journal of Leukocyte Biology 99: 1107–1119. doi: 10.1189/jlb.3A0115-009R.PubMedCrossRefGoogle Scholar
  53. Murr, C., B. Widner, B. Wirleitner, and D. Fuchs. 2002. Neopterin as a marker for immune system activation. Current Drug Metabolism 3: 175–187.PubMedCrossRefGoogle Scholar
  54. Namkung, J., H. Kim, and S. Park. 2015. Peripheral serotonin: A new player in systemic energy homeostasis. Molecules and Cells 38: 1023–1028. doi: 10.14348/molcells.2015.0258.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Németh, H., J. Toldi, and L. Vécsei. 2005. Role of kynurenines in the central and peripheral nervous systems. Current Neurovascular Research 2: 249–260.PubMedCrossRefGoogle Scholar
  56. Nijhuis, J., S.S. Rensen, Y. Slaats, F.M.H. van Dielen, W.A. Buurman, and J.W.M. Greve. 2009. Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring) 17: 2014–2018. doi: 10.1038/oby.2009.113.CrossRefGoogle Scholar
  57. Nishimura, S., I. Manabe, M. Nagasaki, K. Eto, H. Yamashita, M. Ohsugi, M. Otsu, K. Hara, K. Ueki, S. Sugiura, K. Yoshimura, T. Kadowaki, and R. Nagai. 2009. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Medicine 15: 914–920. doi: 10.1038/nm.1964.PubMedCrossRefGoogle Scholar
  58. Oh, C.-M., J. Namkung, Y. Go, K.E. Shong, K. Kim, H. Kim, B.-Y. Park, H.W. Lee, Y.H. Jeon, J. Song, M. Shong, V.K. Yadav, G. Karsenty, S. Kajimura, I.-K. Lee, S. Park, and H. Kim. 2015. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nature Communications 6: 6794. doi: 10.1038/ncomms7794.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Okamoto, H. 2003. Recent advances in physiological and pathological significance of tryptophan-NAD+ metabolites: Lessons from insulin-producing pancreatic beta-cells. Adv. Exp. Med. Biol. 527: 243–252.PubMedCrossRefGoogle Scholar
  60. Orabona, C., P. Puccetti, C. Vacca, S. Bicciato, A. Luchini, F. Fallarino, R. Bianchi, E. Velardi, K. Perruccio, A. Velardi, V. Bronte, M.C. Fioretti, and U. Grohmann. 2006. Toward the identification of a tolerogenic signature in IDO-competent dendritic cells. Blood 107: 2846–2854. doi: 10.1182/blood-2005-10-4077.PubMedCrossRefGoogle Scholar
  61. Orgeron, M.L., K.P. Stone, D. Wanders, C.C. Cortez, N.T. Van, and T.W. Gettys. 2014. The impact of dietary methionine restriction on biomarkers of metabolic health. Progress in Molecular Biology and Translational Science 121: 351–376. doi: 10.1016/B978-0-12-800101-1.00011-9.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Oxenkrug, G.F. 2007. Genetic and hormonal regulation of tryptophan kynurenine metabolism: Implications for vascular cognitive impairment, major depressive disorder, and aging. Annals of the New York Academy of Sciences 1122: 35–49. doi: 10.1196/annals.1403.003.PubMedCrossRefGoogle Scholar
  63. ———. 2010. Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: The serotonin hypothesis revisited 40 years later. The Israel Journal of Psychiatry and Related Sciences 47: 56–63.PubMedPubMedCentralGoogle Scholar
  64. Oxenkrug, G. 2013. Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Molecular Neurobiology 48: 294–301. doi: 10.1007/s12035-013-8497-4.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Oxenkrug, G., K.L. Tucker, P. Requintina, and P. Summergrad. 2011. Neopterin, a Marker of Interferon-Gamma-Inducible Inflammation, Correlates with Pyridoxal-5′-Phosphate, Waist Circumference, HDL-Cholesterol, Insulin Resistance and Mortality Risk in Adult Boston Community Dwellers of Puerto Rican Origin. American Journal of Neuroprotection and Neuroregeneration 3: 48–52. doi: 10.1166/ajnn.2011.1024.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Pacifico, L., L. Di Renzo, C. Anania, J.F. Osborn, F. Ippoliti, E. Schiavo, and C. Chiesa. 2006. Increased T-helper interferon-gamma-secreting cells in obese children. European Journal of Endocrinology 154: 691–697. doi: 10.1530/eje.1.02138.PubMedCrossRefGoogle Scholar
  67. Prodinger, J., L.J. Loacker, R.L.J. Schmidt, F. Ratzinger, G. Greiner, N. Witzeneder, G. Hoermann, S. Jutz, W.F. Pickl, P. Steinberger, R. Marculescu, and K.G. Schmetterer. 2016. The tryptophan metabolite picolinic acid suppresses proliferation and metabolic activity of CD4+ T cells and inhibits c-Myc activation. Journal of Leukocyte Biology 99: 583–594. doi: 10.1189/jlb.3A0315-135R.PubMedCrossRefGoogle Scholar
  68. Robinson, C.M., P.T. Hale, and J.M. Carlin. 2005. The role of IFN-gamma and TNF-alpha-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase. Journal of Interferon & Cytokine Research 25: 20–30. doi: 10.1089/jir.2005.25.20.CrossRefGoogle Scholar
  69. Rocha, V.Z., E.J. Folco, G. Sukhova, K. Shimizu, I. Gotsman, A.H. Vernon, and P. Libby. 2008. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: A role for adaptive immunity in obesity. Circulation Research 103: 467–476. doi: 10.1161/CIRCRESAHA.108.177105.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Rybnikova, N.A., A. Haim, and B.A. Portnov. 2016. Does artificial light-at-night exposure contribute to the worldwide obesity pandemic? International Journal of Obesity 2005(40): 815–823. doi: 10.1038/ijo.2015.255.CrossRefGoogle Scholar
  71. Sarna, L.K., N. Wu, P. Wang, S.-Y. Hwang, Y.L. Siow, and K. O. 2012. Folic acid supplementation attenuates high fat diet induced hepatic oxidative stress via regulation of NADPH oxidase. Canadian Journal of Physiology and Pharmacology 90: 155–165. doi: 10.1139/y11-124.PubMedCrossRefGoogle Scholar
  72. Schoedon, G., J. Troppmair, G. Adolf, C. Huber, and A. Niederwieser. 1986. Interferon-gamma enhances biosynthesis of pterins in peripheral blood mononuclear cells by induction of GTP-cyclohydrolase I activity. Journal of Interferon Research 6: 697–703.PubMedCrossRefGoogle Scholar
  73. Schröcksnadel, K., B. Wirleitner, C. Winkler, and D. Fuchs. 2006. Monitoring tryptophan metabolism in chronic immune activation. Clinica Chimica Acta 364: 82–90. doi: 10.1016/j.cca.2005.06.013.CrossRefGoogle Scholar
  74. Schroecksnadel, K., B. Frick, C. Winkler, F. Leblhuber, B. Wirleitner, and D. Fuchs. 2003. Hyperhomocysteinemia and immune activation. Clinical Chemistry and Laboratory Medicine 41: 1438–1443. doi: 10.1515/CCLM.2003.221.PubMedCrossRefGoogle Scholar
  75. Schroecksnadel, K., B. Frick, B. Wirleitner, C. Winkler, H. Schennach, and D. Fuchs. 2004. Moderate hyperhomocysteinemia and immune activation. Current Pharmaceutical Biotechnology 5: 107–118.PubMedCrossRefGoogle Scholar
  76. Schroecksnadel, K., B. Frick, C. Winkler, and D. Fuchs. 2006. Crucial role of interferon-gamma and stimulated macrophages in cardiovascular disease. Current Vascular Pharmacology 4: 205–213.PubMedCrossRefGoogle Scholar
  77. Schwarcz, R., and R. Pellicciari. 2002. Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities. The Journal of Pharmacology and Experimental Therapeutics 303: 1–10. doi: 10.1124/jpet.102.034439.PubMedCrossRefGoogle Scholar
  78. Sharma, S., M. Singh, and P.L. Sharma. 2013. Mechanism of hyperhomocysteinemia-induced vascular endothelium dysfunction - possible dysregulation of phosphatidylinositol-3-kinase and its downstream phosphoinositide dependent kinase and protein kinase B. European Journal of Pharmacology 721: 365–372. doi: 10.1016/j.ejphar.2013.08.028.PubMedCrossRefGoogle Scholar
  79. Skurk, T., C. Alberti-Huber, C. Herder, and H. Hauner. 2007. Relationship between adipocyte size and adipokine expression and secretion. The Journal of Clinical Endocrinology and Metabolism 92: 1023–1033. doi: 10.1210/jc.2006-1055.PubMedCrossRefGoogle Scholar
  80. Stipanuk, M.H., and I. Ueki. 2011. Dealing with methionine/homocysteine sulfur: Cysteine metabolism to taurine and inorganic sulfur. Journal of Inherited Metabolic Disease 34: 17–32. doi: 10.1007/s10545-009-9006-9.PubMedCrossRefGoogle Scholar
  81. Strasser, B., K. Berger, and D. Fuchs. 2015. Effects of a caloric restriction weight loss diet on tryptophan metabolism and inflammatory biomarkers in overweight adults. European Journal of Nutrition 54: 101–107. doi: 10.1007/s00394-014-0690-3.PubMedCrossRefGoogle Scholar
  82. Strasser, B., K. Becker, D. Fuchs, and J.M. Gostner. 2017. Kynurenine pathway metabolism and immune activation: Peripheral measurements in psychiatric and co-morbid conditions. Neuropharmacology 112: 286–296. doi: 10.1016/j.neuropharm.2016.02.030.PubMedCrossRefGoogle Scholar
  83. Sugiyama, T., B.D. Levy, and T. Michel. 2009. Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. The Journal of Biological Chemistry 284: 12691–12700. doi: 10.1074/jbc.M809295200.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Szewczyk-Golec, K., A. Woźniak, and R.J. Reiter. 2015. Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: Implications for obesity. Journal of Pineal Research 59: 277–291. doi: 10.1111/jpi.12257.PubMedCrossRefGoogle Scholar
  85. Tejas-Juárez, J.G., A.M. Cruz-Martínez, V.E. López-Alonso, B. García-Iglesias, J.M. Mancilla-Díaz, B. Florán-Garduño, and R.E. Escartín-Pérez. 2014. Stimulation of dopamine D4 receptors in the paraventricular nucleus of the hypothalamus of male rats induces hyperphagia: Involvement of glutamate. Physiology & Behavior 133: 272–281. doi: 10.1016/j.physbeh.2014.04.040.CrossRefGoogle Scholar
  86. Tiemessen, M.M., A.L. Jagger, H.G. Evans, M.J.C. van Herwijnen, S. John, and L.S. Taams. 2007. CD4+ CD25+ Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proceedings of the National Academy of Sciences of the United States of America 104: 19446–19451. doi: 10.1073/pnas.0706832104.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Tinker, S.C., H.C. Hamner, R.J. Berry, L.B. Bailey, and C.M. Pfeiffer. 2012. Does obesity modify the association of supplemental folic acid with folate status among nonpregnant women of childbearing age in the United States? Birth Defects Research. Part A, Clinical and Molecular Teratology 94: 749–755. doi: 10.1002/bdra.23024.PubMedCrossRefGoogle Scholar
  88. Üner, A., G.H.M. Gonçalves, W. Li, M. Porceban, N. Caron, M. Schönke, E. Delpire, K. Sakimura, and C. Bjørbæk. 2015. The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis. Molecular Metabolism 4: 678–691. doi: 10.1016/j.molmet.2015.06.010.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Valladolid-Acebes, I., B. Merino, A. Principato, A. Fole, C. Barbas, M.P. Lorenzo, A. García, N. Del Olmo, M. Ruiz-Gayo, and V. Cano. 2012. High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission. American Journal of Physiology. Endocrinology and Metabolism 302: E396–E402. doi: 10.1152/ajpendo.00343.2011.PubMedCrossRefGoogle Scholar
  90. Valle, A., V. Catalán, A. Rodríguez, F. Rotellar, V. Valentí, C. Silva, J. Salvador, G. Frühbeck, J. Gómez-Ambrosi, P. Roca, and J. Oliver. 2012. Identification of liver proteins altered by type 2 diabetes mellitus in obese subjects. Liver international 32: 951–961. doi: 10.1111/j.1478-3231.2012.02765.x.PubMedCrossRefGoogle Scholar
  91. van den Berg, S.M., T.T.P. Seijkens, P.J.H. Kusters, B. Zarzycka, L. Beckers, M. den Toom, M.J.J. Gijbels, A. Chatzigeorgiou, C. Weber, M.P.J. de Winther, T. Chavakis, G.A.F. Nicolaes, and E. Lutgens. 2015. Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice. International Journal of Obesity 2005(39): 782–790. doi: 10.1038/ijo.2014.198.CrossRefGoogle Scholar
  92. van der Weerd, K., W.A. Dik, B. Schrijver, D.H. Schweitzer, A.W. Langerak, H.A. Drexhage, R.M. Kiewiet, M.O. van Aken, A. van Huisstede, J.J.M. van Dongen, A.-J. van der Lelij, F.J.T. Staal, and P.M. van Hagen. 2012. Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype. Diabetes 61: 401–408. doi: 10.2337/db11-1065.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Vayá, A., L. Rivera, A. Hernández-Mijares, M. de la Fuente, E. Solá, M. Romagnoli, R. Alis, and B. Laiz. 2012. Homocysteine levels in morbidly obese patients: Its association with waist circumference and insulin resistance. Clinical Hemorheology and Microcirculation 52: 49–56. doi: 10.3233/CH-2012-1544.PubMedGoogle Scholar
  94. Virdis, A. 2016. Endothelial dysfunction in obesity: Role of inflammation. High Blood Pressure & Cardiovascular Prevention 23: 83–85. doi: 10.1007/s40292-016-0133-8.CrossRefGoogle Scholar
  95. Vitvitsky, V., E. Mosharov, M. Tritt, F. Ataullakhanov, and R. Banerjee. 2003. Redox regulation of homocysteine-dependent glutathione synthesis. Redox Report 8: 57–63. doi: 10.1179/135100003125001260.PubMedCrossRefGoogle Scholar
  96. Wanders, D., S. Ghosh, K.P. Stone, N.T. Van, and T.W. Gettys. 2014. Transcriptional impact of dietary methionine restriction on systemic inflammation: Relevance to biomarkers of metabolic disease during aging. Biofactors 40: 13–26. doi: 10.1002/biof.1111.PubMedCrossRefGoogle Scholar
  97. Wellen, K.E., and G.S. Hotamisligil. 2003. Obesity-induced inflammatory changes in adipose tissue. The Journal of Clinical Investigation 112: 1785–1788. doi: 10.1172/JCI20514.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Wensveen, F.M., V. Jelenčić, S. Valentić, M. Šestan, T.T. Wensveen, S. Theurich, A. Glasner, D. Mendrila, D. Štimac, F.T. Wunderlich, J.C. Brüning, O. Mandelboim, and B. Polić. 2015a. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nature Immunology 16: 376–385. doi: 10.1038/ni.3120.PubMedCrossRefGoogle Scholar
  99. Wensveen, F.M., S. Valentić, M. Šestan, T. Turk Wensveen, and B. Polić. 2015b. The “Big Bang” in obese fat: Events initiating obesity-induced adipose tissue inflammation. European Journal of Immunology 45: 2446–2456. doi: 10.1002/eji.201545502.PubMedCrossRefGoogle Scholar
  100. Whitsett, J., A. Rangel Filho, S. Sethumadhavan, J. Celinska, M. Widlansky, and J. Vasquez-Vivar. 2013. Human endothelial dihydrofolate reductase low activity limits vascular tetrahydrobiopterin recycling. Free Radical Biology & Medicine 63: 143–150. doi: 10.1016/j.freeradbiomed.2013.04.035.CrossRefGoogle Scholar
  101. Widner, B., B. Wirleitner, G. Baier-Bitterlich, G. Weiss, and D. Fuchs. 2000. Cellular immune activation, neopterin production, tryptophan degradation and the development of immunodeficiency. Archivum Immunologiae et Therapiae Experimentalis (Warsz) 48: 251–258.Google Scholar
  102. Widner, B., C. Enzinger, A. Laich, B. Wirleitner, and D. Fuchs. 2002. Hyperhomocysteinemia, pteridines and oxidative stress. Current Drug Metabolism 3: 225–232.PubMedCrossRefGoogle Scholar
  103. Winer, S., Y. Chan, G. Paltser, D. Truong, H. Tsui, J. Bahrami, R. Dorfman, Y. Wang, J. Zielenski, F. Mastronardi, Y. Maezawa, D.J. Drucker, E. Engleman, D. Winer, and H.-M. Dosch. 2009. Normalization of obesity-associated insulin resistance through immunotherapy. Nature Medicine 15: 921–929. doi: 10.1038/nm.2001.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Wolowczuk, I., B. Hennart, A. Leloire, A. Bessede, M. Soichot, S. Taront, R. Caiazzo, V. Raverdy, M. Pigeyre, ABOS Consortium, G.J. Guillemin, D. Allorge, F. Pattou, P. Froguel, and O. Poulain-Godefroy. 2012. Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: An attempt to maintain immune homeostasis and vascular tone. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 303: R135–R143. doi: 10.1152/ajpregu.00373.2011.PubMedCrossRefGoogle Scholar
  105. Yan, T.-T., Q. Li, X.-H. Zhang, W.-K. Wu, J. Sun, L. Li, Q. Zhang, and H.-M. Tan. 2010. Homocysteine impaired endothelial function through compromised vascular endothelial growth factor/Akt/endothelial nitric oxide synthase signalling. Clinical and Experimental Pharmacology & Physiology 37: 1071–1077. doi: 10.1111/j.1440-1681.2010.05438.x.CrossRefGoogle Scholar
  106. Yi, P., S. Melnyk, M. Pogribna, I.P. Pogribny, R.J. Hine, and S.J. James. 2000. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. The Journal of Biological Chemistry 275: 29318–29323. doi: 10.1074/jbc.M002725200.PubMedCrossRefGoogle Scholar
  107. Yin, Z., T. Deng, L.E. Peterson, R. Yu, J. Lin, D.J. Hamilton, P.R. Reardon, V. Sherman, G.E. Winnier, M. Zhan, C.J. Lyon, S.T.C. Wong, and W.A. Hsueh. 2014. Transcriptome analysis of human adipocytes implicates the NOD-like receptor pathway in obesity-induced adipose inflammation. Molecular and Cellular Endocrinology 394: 80–87. doi: 10.1016/j.mce.2014.06.018.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Zawilska, J.B., J. Rosiak, M. Senderecka, and J.Z. Nowak. 1997. Suppressive effect of NMDA receptor antagonist MK-801 on nocturnal serotonin N-acetyltransferase activity in the rat pineal gland. Polish Journal of Pharmacology 49: 479–483.PubMedGoogle Scholar
  109. Zhang, M., J. Wen, X. Wang, and C. Xiao. 2014. High-dose folic acid improves endothelial function by increasing tetrahydrobiopterin and decreasing homocysteine levels. Molecular Medicine Reports 10: 1609–1613. doi: 10.3892/mmr.2014.2332.PubMedGoogle Scholar

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

Personalised recommendations