Inflammation Research

, Volume 67, Issue 2, pp 139–146 | Cite as

Diet-induced obesity leads to pro-inflammatory alterations to the vitreous humour of the eye in a rat model

  • Kelsey H. Collins
  • Walter Herzog
  • Raylene A. Reimer
  • Carol R. Reno
  • Bryan J. Heard
  • David A. Hart
Original Research Paper


Objective and design

The purpose of this study was to investigate if diet-induced obesity (DIO) and subsequent low-level systemic inflammation would result in local increases in pro-inflammatory mediators in the vitreous humour (VH) of the eyes of rats.


Sixteen male Sprague–Dawley rats were fed a high-fat/high-sucrose (n = 9) or chow control-diet (n = 7) for 12-weeks. RT-qPCR was conducted on RNA from VH cells and a 27-plex Luminex® Assay was conducted on VH fluid and serum.


Increased protein levels for IL-1β, IL-6, and IL-18 in both serum and VH fluid were observed. VH protein levels for IL-13 and IL-17 were also increased. All mediators significantly increased in VH fluid were also positively correlated with percent body fat. Increased mRNA levels in VH cells for an oxidative stress molecule were accompanied by decreased mRNA levels for an antioxidant scavenger, suggesting an antioxidant/oxidant imbalance in the VH with DIO. In addition, decreased mRNA levels for TRAIL, FAS-L and TGF-β, molecules associated with immune privilege, were also significantly depressed.


DIO-related metabolic disturbances disrupt VH homeostasis in a manner that reflects development of a pro-inflammatory environment. Prolonged exposure to such an environment may lead to overt pathologies with compromised eye function.


Obesity Vitreous humour NLRP3 inflammasome Chronic inflammation Antioxidant defense Rat 



The authors thank Carolyn Hewitt, Ruth Seerattan and Jaqueline Rios for technical contributions to this paper.

Compliance with ethical standards


This work was supported by the Canadian Institutes of Health Research # RT736475 and MOP 115,076, the Canada Research Chair Program, the Alberta Innovates Health Solutions Osteoarthritis Team Grant, Alberta Innovates Health Solutions, Alberta Health Services, Canadian Institutes of Health Research Banting and Best Canada Graduate Scholarship, and the Killam Foundation.

Conflict of interest

The authors declare no competing financial interest.


  1. 1.
    Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:766–81. Accessed 19 Jul 2017.
  2. 2.
    Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105:141–50. Accessed 29 Apr 2014.
  3. 3.
    Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: executive summary. Crit Pathw Cardiol. 2005;4:198–203. Accessed 14 Dec 2013.
  4. 4.
    Lumeng CN, Saltiel AR, Fucho R, Hotamisligil G, Karin M, Hotamisligil G. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011;121:2111–7. Accessed 19 Jul 2017.
  5. 5.
    Collins KH, Paul HA, Hart DA, Reimer RA, Smith IC, Rios JL, et al. A high-fat high-sucrose diet rapidly alters muscle integrity, inflammation and gut microbiota in male rats. Sci Rep. 2016;6:37278. doi: 10.1038/srep37278.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Collins KH, Hart DA, Reimer RA, Seerattan RA, Banker CW, Sibole SC, et al. High-fat high-sucrose diet leads to dynamic structural and inflammatory alterations in the rat vastus lateralis muscle. J Orthop Res. 2016;34:2069–78. Accessed 21 Mar 2016.
  7. 7.
    Collins KH, Reimer RA, Seerattan R-AA, Leonard TR, Herzog W. Using diet-induced obesity to understand a metabolic subtype of osteoarthritis in rats. Osteoarthr Cartil. 2015;23:957–65. Accessed 26 Aug 2015.
  8. 8.
    Collins KH, Paul HA, Reimer RA, Seerattan R-A, Hart DA, Herzog W. Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model. Osteoarthr Cartil. 2015;23:1989–98.CrossRefPubMedGoogle Scholar
  9. 9.
    Collins KH, Hart DA, Reimer RA, Seerattan RA, Herzog W. Response to diet-induced obesity produces time-dependent induction and progression of metabolic osteoarthritis in rat knees. J Orthop Res. 2016;34:1010–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Poh S, Mohamed Abdul RBB, Lamoureux EL, Wong TY, Sabanayagam C. Metabolic syndrome and eye diseases. Diabetes Res Clin Pract. 2016;113:86–100. Accessed 10 Apr 2017.
  11. 11.
    Tang Y-L, Cheng Y-L, Ren Y-P, Yu X-N, Shentu X-C. Metabolic syndrome risk factors and dry eye syndrome: a meta-analysis. Int J Ophthalmol. 2016;9:1038–45. Accessed 10 Apr 2017.
  12. 12.
    Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol. 1948;29:58–69. Accessed 10 Apr 2017.
  13. 13.
    Sonoda K, Nakamura T, Young HA, Hart D, Carmeliet P, Stein-streilein J. NKT cell-derived urokinase-type plasminogen activator promotes peripheral tolerance associated with eye. J Immunol. 2007;1–8.Google Scholar
  14. 14.
    Niederkorn JY. Immune mechanisms of corneal allograft rejection. Curr Eye Res. 2007;32:1005–16.
  15. 15.
    Stein-Streilein J, Streilein JW. Anterior chamber associated immune deviation (ACAID): regulation, biological relevance, and implications for therapy. Int Rev Immunol. 2002;21:123–52. doi: 10.1080/08830180212066.
  16. 16.
    Angi M, Kalirai H, Coupland SE, Damato BE, Semeraro F, Romano MR. Proteomic analyses of the vitreous humour. Mediators Inflamm. 2012;2012:1–7. Accessed 10 Apr 2017.
  17. 17.
    Reno C, Marchuk L, Sciore P, Frank CB, Hart DA. Rapid isolation of total RNA from small samples of hypocellular, dense connective tissues. Biotechniques. 1997;22:1082–6. Accessed 24 Apr 2015.
  18. 18.
    Niederkorn JY. Ocular immune privilege and ocular melanoma: parallel universes or immunological plagiarism? Front Immunol. 2012;3:148. doi: 10.3389/fimmu.2012.00148/abstract.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Collins KH, Hart D, Smith I, Issler A, Reimer R, Seerattan R, et al. Acute and chronic changes in rat soleus muscle after high-fat high-sucrose diet. Physiol Rep. 2017.Google Scholar
  20. 20.
    Murray PJ. The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci USA. 2005;102:8686–91.,
  21. 21.
    Wang JF, Olson ME, Reno CR, Wright JB, Hart DA. The pig as a model for excisional skin wound healing: characterization of the molecular and cellular biology, and bacteriology of the healing process. Comp Med. 2001;51:341–8. Accessed 1 Sep 2017.
  22. 22.
    Ishimoto T, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Orlicky DJ, Cicerchi C, et al. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology. 2013;58:1632–43. Accessed 1 Sep 2017.
  23. 23.
    Bradley RL, Jeon JY, Liu F-F, Maratos-Flier E. Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice. Am J Physiol Endocrinol Metab. 2008;295. Accessed 1 Sep 2017.
  24. 24.
    Cottam DR, Schaefer PA, Shaftan GW, Angus LDG. Dysfunctional immune-privilege in morbid obesity: implications and effect of gastric bypass surgery. Obes Surg. 2003;13:49–57. doi: 10.1381/096089203321136584.CrossRefPubMedGoogle Scholar
  25. 25.
    Wu CW, Sauter JL, Johnson PK, Chen C-D, Olsen TW, Herbert J. Identification and localization of major soluble vitreous proteins in human ocular tissue. Am J Ophthalmol. 2004;137:655–61. Accessed 9 Apr 2017.
  26. 26.
    Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7. Accessed 14 Dec 2013.
  27. 27.
    Jager J, Grémeaux T, Cormont M, Le Marchand-Brustel Y, Tanti J-F. Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology. 2007;148:241–51. Accessed 1 Sep 2017.
  28. 28.
    Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013;2013:139239. Accessed 1 Sep 2017.
  29. 29.
    Schmidt FM, Weschenfelder J, Sander C, Minkwitz J, Thormann J, Chittka T, et al. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS One. 2015;10:e0121971. doi: 10.1371/journal.pone.0121971.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Esposito K, Pontillo A, Giugliano F, Giugliano G, Marfella R, Nicoletti G, et al. Association of low interleukin-10 levels with the metabolic syndrome in obese women. J Clin Endocrinol Metab. 2003;88:1055–8. Accessed 1 Sep 2017.
  31. 31.
    Jung SH, Park HS, Kim K-S, Choi WH, Ahn CW, Kim BT, et al. Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss. J Nutr Biochem. 2008;19:371–5. Accessed 1 Sep 2017.
  32. 32.
    Gao M, Zhang C, Ma Y, Bu L, Yan L, Liu D. Hydrodynamic delivery of mIL10 gene protects mice from high-fat diet-induced obesity and glucose intolerance. Mol Ther. 2013;21:1852–61. Accessed 1 Sep 2017.
  33. 33.
    Barry JC, Shakibakho S, Durrer C, Simtchouk S, Jawanda KK, Cheung ST, et al. Hyporesponsiveness to the anti-inflammatory action of interleukin-10 in type 2 diabetes. Sci Rep. 2016;6:21244.,
  34. 34.
    Cheung N, Mitchell P, Wong TY, al. et, Karczewicz D, Machalinski B. Diabetic retinopathy. Lancet (London, England). 2010;376:124–36. Accessed 9 Apr 2017.
  35. 35.
    Kowluru RA, Odenbach S. Role of interleukin-1 in the pathogenesis of diabetic retinopathy. Br J Ophthalmol. 2004;88:1343–7. Accessed 9 Apr 2017.
  36. 36.
    Liu Y, Biarnés Costa M, Gerhardinger C, Guo X, Dou H. IL-1β is upregulated in the diabetic retina and retinal vessels: cell-specific effect of high glucose and IL-1β autostimulation. PLoS One. 2012;7:e36949. doi: 10.1371/journal.pone.0036949.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Loukovaara S, Piippo N, Kinnunen K, Hytti M, Kaarniranta K, Kauppinen A. NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy. Acta Ophthalmol. 2017; Accessed 9 Apr 2017.
  38. 38.
    Vandanmagsar B, Youm Y-H, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NALP3/NLRP3 inflammasome instigates obesity-induced autoinflammation and insulin resistance HHS public access. Nat Med. 2011;17:179–88. Accessed 9 Apr 2017.
  39. 39.
    Takeuchi M, Sato T, Tanaka A, Muraoka T, Taguchi M, Sakurai Y, et al. Elevated levels of cytokines associated with Th2 and Th17 cells in vitreous fluid of proliferative diabetic retinopathy patients. PLoS One. 2015;10:e0137358. doi: 10.1371/journal.pone.0137358.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2011;107:1058–70.CrossRefGoogle Scholar
  41. 41.
    Kowluru RA, Chan P-S. Oxidative stress and diabetic retinopathy. Exp. Diabetes Res. 2007;43603. Accessed 9 Apr 2017.
  42. 42.
    Vincent AM, Russell JW, Sullivan KA, Backus C, Hayes JM, McLean LL, et al. SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy. Exp Neurol. 2007;208:216–27. Accessed 10 Apr 2017.
  43. 43.
    Qu N, Xu M, Mizoguchi I, Furusawa J, Kaneko K, Watanabe K, et al. Pivotal roles of T-helper 17-related cytokines, IL-17, IL-22, and IL-23, in inflammatory diseases. Clin Dev Immunol. 2013;2013:968549. Accessed 9 Apr 2017.
  44. 44.
    Amadi-Obi A, Yu C-R, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med. 2007;13:711–8. doi: 10.1038/nm1585.CrossRefPubMedGoogle Scholar
  45. 45.
    Horai R, Zárate-Bladés CR, Dillenburg-Pilla P, Chen J, Kielczewski JL, Silver PB, et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity. 2015;43:343–53. Accessed 9 Apr 2017.
  46. 46.
    Kemmochi Y, Miyajima K, Ohta T, Sasase T, Yasui Y, Toyoda K, et al. Ocular inflammation in uveal tract in aged obese type 2 diabetic rats (Spontaneously Diabetic Torii fatty rats). J Diabetes Res. 2014:629016. Accessed 9 Apr 2017.
  47. 47.
    El-Mollayess GM, Saadeh JS, Salt HI. Exogenous endophthalmitis in diabetic patients: a systemic review. ISRN Ophthalmol. 2012:1–7. Accessed 9 Apr 2017.

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Kelsey H. Collins
    • 1
    • 2
    • 4
  • Walter Herzog
    • 1
    • 2
    • 4
  • Raylene A. Reimer
    • 1
    • 5
  • Carol R. Reno
    • 2
  • Bryan J. Heard
    • 2
  • David A. Hart
    • 1
    • 2
    • 3
    • 4
    • 6
    • 7
  1. 1.Human Performance Laboratory, Faculty of KinesiologyUniversity of CalgaryCalgaryCanada
  2. 2.McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryCanada
  3. 3.The Centre for Hip Health and Mobility, Department of Family PracticeUniversity of British ColumbiaVancouverCanada
  4. 4.Biomedical Engineering ProgramUniversity of CalgaryCalgaryCanada
  5. 5.Department of Biochemistry and Molecular BiologyUniversity of CalgaryCalgaryCanada
  6. 6.Alberta Health Services Bone and Joint Health Strategic Clinical NetworkCalgaryCanada
  7. 7.CalgaryCanada

Personalised recommendations