In Vivo Retinal Structural Lesions, Functional Deficits and Peripheral Blood Cell phenotype in Mice with High-Fat Diet-Induced Retinopathy

Abstract

Purpose : Mice fed a high fat diet (HFD) are known to exhibit insulin resistance and glucose intolerance and have retinal characteristics similar to diabetic retinopathy such as decreased electroretinography (ERG) responses and increased capillary degeneration. The purpose of this study was to investigate the functional and in vivo structural changes in the retina associated with this model and to characterize changes in the peripheral blood of the HFD mice that may contribute to retinal pathology.

Methods : Wild-type C57BL/6J mice were fed either high fat diet (60% fat, 20% protein, 20% carbohydrate) or low fat diet (LFD) (10% fat, 70% carbohydrate, 20% protein (controls) for 7 months. Body weight and glycated hemoglobin (HbA1c) levels were measured. Retinal function was tested by ERG. Fluorescein angiography (FA), funduscopy and optical coherence tomography (OCT) were performed to assess the structural integrity of the retina. Vascular density and lacunarity (avascular spaces) were measured using the Angiotool software. Levels of CD45-positive cells, circulating angiogenic cells (CACs), classical and non-classical monocytes were measured in the peripheral blood.

Results : Compared to LFD mice (32.8 ± 1.3g), HFD mice (61.9 ± 2.9g) had significantly increased body weight (p<0.0001) but not an increase in HbA1c levels and no significant increase in vascular leakage, vascular density or lacunarity was observed. However, HFD mice demonstrated a significant reduction in the ERG scotopic response (194±27.9µV, p=0.02), photopic response (45.3±,3.7µV, p=0.003,) and retinal thickness (0.17± 0.004mm, p=0.01) compared to controls (294±28.2µV, 67.9± 5.6µV, 0.20±.0.01mm respectively). In addition, HFD mice showed increased levels of CACs (0.017± 0.003%, p=0.002) and non-classical monocytes (56.6± 5.4%, p=0.01) compared to controls (0.002±.0.0004% and 37.6±3.0% respectively).

Conclusions : Prolonged high-fat feeding leads to reduced neural retinal function and retinal thickness however with no evidence of retinal vascular damage. This may be due to compensatory and protective effects of increased circulating levels of vascular reparative cells (CACs) and non-classical monocytes. Our findings provide further insight into high-fat induced retinopathy as it suggests that non-vascular retinal damage precedes significant vascular changes in high-fat fed mice.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.