**Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes**

**Bright Asare-Bediako 1, Sunil K. Noothi 2, Sergio Li Calzi 2, Baskaran Athmanathan 3, Cristiano P. Vieira 2, Yvonne Adu-Agyeiwaah 1, Mariana Dupont 1, Bryce A. Jones 4, Xiaoxin X. Wang 5, Dibyendu Chakraborty 2, Moshe Levi 5, Prabhakara R. Nagareddy 3 and Maria B. Grant 2,\***


Received: 9 January 2020; Accepted: 13 February 2020; Published: 18 February 2020

**Abstract:** We sought to delineate the retinal features associated with the high-fat diet (HFD) mouse, a widely used model of obesity. C57BL/6 mice were fed either a high-fat (60% fat; HFD) or low-fat (10% fat; LFD) diet for up to 12 months. The effect of HFD on body weight and insulin resistance were measured. The retina was assessed by electroretinogram (ERG), fundus photography, permeability studies, and trypsin digests for enumeration of acellular capillaries. The HFD cohort experienced hypercholesterolemia when compared to the LFD cohort, but not hyperglycemia. HFD mice developed a higher body weight (60.33 g vs. 30.17g, *p* < 0.0001) as well as a reduced insulin sensitivity index (9.418 vs. 62.01, *p* = 0.0002) compared to LFD controls. At 6 months, retinal functional testing demonstrated a reduction in a-wave and b-wave amplitudes. At 12 months, mice on HFD showed evidence of increased retinal nerve infarcts and vascular leakage, reduced vascular density, but no increase in number of acellular capillaries compared to LFD mice. In conclusion, the HFD mouse is a useful model for examining the effect of prediabetes and hypercholesterolemia on the retina. The HFD-induced changes appear to occur slower than those observed in type 2 diabetes (T2D) models but are consistent with other retinopathy models, showing neural damage prior to vascular changes.

**Keywords:** retinal phenotype; neural infarcts; vascular leakage
