Journal of Neuroimmune Pharmacology

, Volume 9, Issue 2, pp 209–217 | Cite as

High Fat Diet Exacerbates Neuroinflammation in an Animal Model of Multiple Sclerosis by Activation of the Renin Angiotensin System

  • Silke Timmermans
  • Jeroen F. J. Bogie
  • Tim Vanmierlo
  • Dieter Lütjohann
  • Piet Stinissen
  • Niels Hellings
  • Jerome J. A. Hendriks


Epidemiological studies suggest a positive correlation between the incidence and severity of multiple sclerosis (MS) and the intake of fatty acids. It remains to be clarified whether high fat diet (HFD) indeed can exacerbate the disease pathology associated with MS and what the underlying mechanisms are. In this study, we determined the influence of HFD on the severity and pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Mice were fed either normal diet (ND) or HFD and subsequently induced with EAE. Immunohistochemical staining and real-time PCR were used to determine immune cell infiltration and inflammatory mediators in the central nervous system (CNS). Our data show that HFD increases immune cell infiltration and inflammatory mediator production in the CNS and thereby aggravates EAE. Moreover, our data demonstrate that activation of the renin angiotensin system (RAS) is associated with the HFD-mediated effects on EAE severity. These results show that HFD exacerbates an autoreactive immune response within the CNS. This indicates that diets containing excess fat have a significant influence on neuroinflammation in EAE, which may have important implications for the treatment and prevention of neuroinflammatory disorders.


Experimental autoimmune encephalomyelitis Renin angiotensin system Inflammation High fat diet 



We thank W. Leyssens, K. Wauterickx and A. Kerksiek for their technical assistance and animal handling. This work was supported by grants from the Agentschap voor Innovatie door Wetenschap en Technologie (IWT) and Fonds Wetenschappelijk Onderzoek (FWO).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11481_2013_9502_MOESM1_ESM.docx (13 kb)
ESM 1 (DOCX 13 kb)


  1. Alter M, Yamoor M, Harshe M (1974) Multiple sclerosis and nutrition. Arch Neurol 31:267–272PubMedCrossRefGoogle Scholar
  2. Antonovsky A, Leibowitz U, Smith HA, Medalie JM, Balogh M, Kats R, Halpern L, Alter M (1965) Epidemiologic Study of Multiple Sclerosis in Israel. I. An Overall Review of Methods and Findings. Arch Neurol 13:183–193PubMedCrossRefGoogle Scholar
  3. Aranami T, Yamamura T (2008) Th17 Cells and autoimmune encephalomyelitis (EAE/MS). Allergol Int Off J Jpn Soc Allergol 57:115–120CrossRefGoogle Scholar
  4. Bachmanov AA, Reed DR, Beauchamp GK, Tordoff MG (2002) Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet 32:435–443PubMedCentralPubMedCrossRefGoogle Scholar
  5. Bar-Or A, Oliveira EM, Anderson DE, Hafler DA (1999) Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 100:252–259PubMedCrossRefGoogle Scholar
  6. Berr C, Puel J, Clanet M, Ruidavets JB, Mas JL, Alperovitch A (1989) Risk factors in multiple sclerosis: a population-based case–control study in Hautes-Pyrenees, France. Acta Neurol Scand 80:46–50PubMedCrossRefGoogle Scholar
  7. Bruce-Keller AJ, Keller JN, Morrison CD (2009) Obesity and vulnerability of the CNS. Biochim Biophys Acta 1792:395–400PubMedCentralPubMedCrossRefGoogle Scholar
  8. Calder PC et al (2011) Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr 106(Suppl 3):S5–S78PubMedCrossRefGoogle Scholar
  9. Diestel A, Aktas O, Hackel D, Hake I, Meier S, Raine CS, Nitsch R, Zipp F, Ullrich O (2003) Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J Exp Med 198:1729–1740PubMedCentralPubMedCrossRefGoogle Scholar
  10. Fernandez-Real JM, Pickup JC (2008) Innate immunity, insulin resistance and type 2 diabetes. Trends Endocrinol Metab: TEM 19:10–16PubMedCrossRefGoogle Scholar
  11. Grimm MO, Grimm HS, Patzold AJ, Zinser EG, Halonen R, Duering M, Tschape JA, De Strooper B, Muller U, Shen J, Hartmann T (2005) Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nat Cell Biol 7:1118–1123PubMedCrossRefGoogle Scholar
  12. Grobe JL, Xu D, Sigmund CD (2008) An intracellular renin-angiotensin system in neurons: fact, hypothesis, or fantasy. Physiology (Bethesda) 23:187–193CrossRefGoogle Scholar
  13. Hellings N, Raus J, Stinissen P (2002) Insights into the immunopathogenesis of multiple sclerosis. Immunol Res 25:27–51PubMedCrossRefGoogle Scholar
  14. Kolb H, Mandrup-Poulsen T (2010) The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation. Diabetologia 53:10–20PubMedCrossRefGoogle Scholar
  15. Lanz TV, Ding Z, Ho PP, Luo J, Agrawal AN, Srinagesh H, Axtell R, Zhang H, Platten M, Wyss-Coray T, Steinman L (2010) Angiotensin II sustains brain inflammation in mice via TGF-beta. J Clin Investig 120:2782–2794PubMedCentralPubMedCrossRefGoogle Scholar
  16. Lauer K (1997) Diet and multiple sclerosis. Neurology 49:S55–S61PubMedCrossRefGoogle Scholar
  17. Lavin DN, Joesting JJ, Chiu GS, Moon ML, Meng J, Dilger RN, Freund GG (2011) Fasting induces an anti-inflammatory effect on the neuroimmune system which a high-fat diet prevents. Obesity (Silver Spring) 19:1586–1594CrossRefGoogle Scholar
  18. Ledesma MD, Abad-Rodriguez J, Galvan C, Biondi E, Navarro P, Delacourte A, Dingwall C, Dotti CG (2003) Raft disorganization leads to reduced plasmin activity in Alzheimer’s disease brains. EMBO Rep 4:1190–1196PubMedCentralPubMedCrossRefGoogle Scholar
  19. Mateos L, Ismail MA, Gil-Bea FJ, Schule R, Schols L, Heverin M, Folkesson R, Bjorkhem I, Cedazo-Minguez A (2011) Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism. J Biol Chem 286:25574–25585PubMedCentralPubMedCrossRefGoogle Scholar
  20. Mehta LR, Dworkin RH, Schwid SR (2009) Polyunsaturated fatty acids and their potential therapeutic role in multiple sclerosis. Nat Clin Pract Neurol 5:82–92PubMedCrossRefGoogle Scholar
  21. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DM, Anhe G, Amaral ME, Takahashi HK, Curi R, Oliveira HC, Carvalheira JB, Bordin S, Saad MJ, Velloso LA (2009) Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci Off J Soc Neurosci 29:359–370CrossRefGoogle Scholar
  22. Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, White CL, Purpera MN, Uranga RM, Bruce-Keller AJ, Keller JN (2010) High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J Neurochem 114:1581–1589PubMedCentralPubMedCrossRefGoogle Scholar
  23. Mueller AM, Pedre X, Stempfl T, Kleiter I, Couillard-Despres S, Aigner L, Giegerich G, Steinbrecher A (2008) Novel role for SLPI in MOG-induced EAE revealed by spinal cord expression analysis. J Neuroinflammation 5:20PubMedCentralPubMedCrossRefGoogle Scholar
  24. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC, Ascherio A (2004) Vitamin D intake and incidence of multiple sclerosis. Neurology 62:60–65PubMedCrossRefGoogle Scholar
  25. Piccio L, Stark JL, Cross AH (2008) Chronic calorie restriction attenuates experimental autoimmune encephalomyelitis. J Leukocyte Biol 84:940–948PubMedCentralPubMedCrossRefGoogle Scholar
  26. Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219:25–32PubMedCentralPubMedCrossRefGoogle Scholar
  27. Platten M, Youssef S, Hur EM, Ho PP, Han MH, Lanz TV, Phillips LK, Goldstein MJ, Bhat R, Raine CS, Sobel RA, Steinman L (2009) Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc Natl Acad Sci U S A 106:14948–14953PubMedCentralPubMedCrossRefGoogle Scholar
  28. Rao AV, Rao LG (2007) Carotenoids and human health. Pharmacol Res Off J Ital Pharmacol Soc 55:207–216Google Scholar
  29. Saavedra JM (2011) Angiotensin II AT(1) Receptor blockers ameliorate inflammatory stress: a beneficial effect for the treatment of brain disorders. Cell Mol NeurobiolGoogle Scholar
  30. Schwarz S, Leweling H (2005) Multiple sclerosis and nutrition. Mult Scler 11:24–32PubMedCrossRefGoogle Scholar
  31. Sena A, Sarlieve LL, Rebel G (1985) Brain myelin of genetically obese mice. J Neurol Sci 68:233–243PubMedCrossRefGoogle Scholar
  32. Sepcic J, Mesaros E, Materljan E, Sepic-Grahovac D (1993) Nutritional factors and multiple sclerosis in Gorski Kotar, Croatia. Neuroepidemiology 12:234–240PubMedCrossRefGoogle Scholar
  33. Smolders J, Damoiseaux J, Menheere P, Hupperts R (2008) Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol 194:7–17PubMedCrossRefGoogle Scholar
  34. Stegbauer J, Lee DH, Seubert S, Ellrichmann G, Manzel A, Kvakan H, Muller DN, Gaupp S, Rump LC, Gold R, Linker RA (2009) Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system. Proc Natl Acad Sci U S A 106:14942–14947PubMedCentralPubMedCrossRefGoogle Scholar
  35. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J (2003) Inflammation and angiotensin II. Int J Biochem Cell Biol 35:881–900PubMedCrossRefGoogle Scholar
  36. Swank RL, Lerstad O, Strom A, Backer J (1952) Multiple sclerosis in rural Norway its geographic and occupational incidence in relation to nutrition. N Engl J Med 246:722–728PubMedCrossRefGoogle Scholar
  37. Teunissen CE, Dijkstra CD, Polman CH, Hoogervorst EL, von Bergmann K, Lutjohann D (2003) Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients. Neurosci Lett 347:159–162PubMedCrossRefGoogle Scholar
  38. Thompson AJ (2008) Multiple sclerosis–a global disorder and still poorly managed. Lancet Neurol 7:1078–1079PubMedCrossRefGoogle Scholar
  39. Thompson RH (1966) A biochemical approach to the problem of multiple sclerosis. Proc R Soc Med 59:269–276PubMedCentralPubMedGoogle Scholar
  40. Tola MR, Granieri E, Malagu S, Caniatti L, Casetta I, Govoni V, Paolino E, Cinzia Monetti V, Canducci E, Panatta GB (1994) Dietary habits and multiple sclerosis. A retrospective study in Ferrara, Italy. Acta Neurol 16:189–197Google Scholar
  41. Uranga RM, Bruce-Keller AJ, Morrison CD, Fernandez-Kim SO, Ebenezer PJ, Zhang L, Dasuri K, Keller JN (2010) Intersection between metabolic dysfunction, high fat diet consumption, and brain aging. J Neurochem 114:344–361PubMedCentralPubMedCrossRefGoogle Scholar
  42. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034Google Scholar
  43. von Bohlen und Halbach O, Albrecht D (2006) The CNS renin-angiotensin system. Cell Tissue Res 326:599–616CrossRefGoogle Scholar
  44. Wheeler D, Bandaru VV, Calabresi PA, Nath A, Haughey NJ (2008) A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis. Brain J Neurol 131:3092–3102CrossRefGoogle Scholar
  45. White CL, Pistell PJ, Purpera MN, Gupta S, Fernandez-Kim SO, Hise TL, Keller JN, Ingram DK, Morrison CD, Bruce-Keller AJ (2009) Effects of high fat diet on Morris maze performance, oxidative stress, and inflammation in rats: contributions of maternal diet. Neurobiol Dis 35:3–13PubMedCentralPubMedCrossRefGoogle Scholar
  46. Winer S, Paltser G, Chan Y, Tsui H, Engleman E, Winer D, Dosch HM (2009) Obesity predisposes to Th17 bias. Eur J Immunol 39:2629–2635PubMedCrossRefGoogle Scholar
  47. Wright HP, Thompson RH, Zilkha KJ (1965) Platelet adhesiveness in multiple sclerosis. Lancet 2:1109–1110PubMedCrossRefGoogle Scholar
  48. Wu A, Molteni R, Ying Z, Gomez-Pinilla F (2003) A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor. Neuroscience 119:365–375PubMedCrossRefGoogle Scholar
  49. Yamakawa H, Jezova M, Ando H, Saavedra JM (2003) Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 23:371–380CrossRefGoogle Scholar
  50. Zhang SM, Willett WC, Hernan MA, Olek MJ, Ascherio A (2000) Dietary fat in relation to risk of multiple sclerosis among two large cohorts of women. Am J Epidemiol 152:1056–1064PubMedCrossRefGoogle Scholar
  51. Zhang X, Dong F, Ren J, Driscoll MJ, Culver B (2005) High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. Exp Neurol 191:318–325PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Silke Timmermans
    • 1
  • Jeroen F. J. Bogie
    • 1
  • Tim Vanmierlo
    • 1
  • Dieter Lütjohann
    • 2
  • Piet Stinissen
    • 1
  • Niels Hellings
    • 1
  • Jerome J. A. Hendriks
    • 1
  1. 1.Biomedical Research Institute, School of Life SciencesHasselt University/Transnational University LimburgDiepenbeekBelgium
  2. 2.Laboratory for Special Lipid Diagnostics/Center, Institute of Clinical Chemistry and Clinical PharmacologyUniversity Clinics of BonnBonnGermany

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