**5. Conclusions**

Our study demonstrates that HFD feeding generates a useful prediabetes model. Specifically, the combination of hypercholesterolemia and insulin resistance are su fficient to induce retinal dysfunction with a slower time course of development compared to T2D models such as the db/db mouse. In agreemen<sup>t</sup> with reports describing diabetes models, we show that neural functional deficits are the earliest indicator of damage in the retina of this prediabetes model before vascular changes. Key molecular targets such as HIF-1 α and the LXRs provide insights into the retinal pathobiology observed in this hypercholesterolemic, hyperinsulinemic model. The appearance and frequency of neural infarcts or "lipid-laden lesions" in the retina of HFD mice could represent a novel endpoint for evaluation of therapeutic interventions.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2073-4409/9/2/464/s1, Table S1: Detailed Composition of high-fat diet (HFD), Western diet (WD), and low-fat diet (LFD).

**Author Contributions:** Conceptualization, M.L., P.R.N., and M.B.G.; data curation, B.A.-B. and S.K.N.; formal analysis, B.A.-B., S.K.N., B.A.J., and M.B.G.; funding acquisition, M.B.G.; investigation, B.A.-B., S.K.N., S.L.C., B.A., C.P.V., Y.A.-A., M.D., B.A.J., X.X.W., D.C., and M.B.G.; methodology, B.A.-B., S.K.N., P.R.N., and M.B.G.; project administration, P.R.N. and M.B.G.; resources, M.L., P.R.N., and M.B.G.; supervision, M.L. and P.R.N.; validation, B.A.-B. and S.L.C.; visualization, B.A.-B.; writing—original draft, B.A.-B., S.K.N., P.R.N., and M.B.G.; writing—review and editing, B.A.-B., S.K.N., S.L.C., B.A., C.P.V., Y.A.-A., B.A.J., M.L., P.R.N., and M.B.G. All authors have read and agreed to the published version of the manuscript.

**Funding:** M.G is supported by NIH funding (EY012601, EY028037, and EY028858). P.R.N is supported by NIH funding (HL122505, HL137799); M.L is supported by NIH funding (DK116567). BAJ is supported by the National Center for Advancing Translational Sciences of the NIH under award number TL1TR001431.

**Conflicts of Interest:** The authors declare no conflict of interest.
