Loss Of Rod Sensitivity And Gene Expression Changes In The Retina Of Fructose-fed Insulin-resistant Mice

Abstract

Purpose: : Metabolic syndrome is of major concern in Western countries since it predisposes individuals to the development of diabetes. Insulin resistance is one of the biochemical features of the metabolic syndrome. Fructose feeding has been used to elicit insulin resistance in rodents. Our purpose was to characterize the functional and gene expression changes in the retina after long term feeding mice with a fructose-enriched diet.

Methods: : Control and ApoB₁₀₀,LDLR^-/- mice, a murine model of aging of the human retina, were fed with a 60%-rich fructose diet for 8 months. Scotopic single flash and Flicker electroretinograms were recorded to monitor the response of the retina to flash stimuli. Fundus autofluorescence, as well as fluorescein and indocyanin green angiography were assessed by using a confocal scanning laser ophthalmoscope. Gene expression was analyzed in the neurosensory retina (NR) and retinal pigment epithelium+choroid (RPE/Ch) by RT-qPCR, focusing on lipid metabolism, nuclear receptors and VEGF.

Results: : Under standard conditions of breeding, ABCG1, HTRA1 and VEGF genes were up-regulated in the NR of ApoB₁₀₀,LDLR^-/- mice compared to wild type animals. In RPE/Ch, ABCA1 was upregulated, ACAT1 and HMGCoA reductase down-regulated in ApoB₁₀₀,LDLR^-/- mice compared to wild type mice. Fructose feeding significantly up-regulated gene expression of ApoE, ABCA4, ABCG1, SR-B1, CYP46A1, CYP27A1, LRP-1, LCAT, HMGcoA reductase, insig1, NFΚB1, NFΚB2, LXRα, PPARΔ, BAX, GFAP, hexokinase, HTRA1 and VEGF in the NR from both strains of mice. LDL-receptor was up-regulated by fructose in the NR of wild type mice. No similar effect was observed in RPE/Ch.Fructose feeding significantly reduced a- and b-waves amplitude of the electroretinograms and the sensitivity of rods to light stimulus by 0.3 log unit in both strains of mice. No clinical signs of retinal vasculature abnormalities were observed in fructose-fed mice. Our model of aging of the human retina did not exhibit a greater reactivity to fructose feeding than wild type animals.

Conclusions: : Our data demonstrate that, at early stages of insulin resistance and metabolic syndrome, the function of the neurosensory retina is impaired and gene expression is altered. These data outline several molecular lipid-associated mechanisms that would predispose the retina to the consequences of metabolic syndrome, including vascular changes.

Keywords: gene/expression • lipids • nutritional factors