Fenofibrate has been reported to slow diabetic retinopathy (DR), but the precise mechanisms in retinal tissue remain unclear. As an agonist of peroxisome proliferator-activated receptor alpha (PPARα), a key regulator of metabolism, inflammation, and oxidative stress, fenofibrate was hypothesized to protect against early retinal damage through PPARα activation. Using the db/db mouse model of type 2 diabetes, we found that six-month-old diabetic mice showed elevated blood lipids, reactive gliosis in the retina, and electroretinography (ERG) abnormalities, including diminished b-wave amplitudes and delayed oscillatory potentials, compared with non-diabetic littermates. Oral fenofibrate ameliorated these retinal dysfunctions. Surprisingly, fenofibrate did not trigger expression of PPARα target genes in either whole retina or isolated Müller glial cells. Further experiments using the PPARα agonist GW590735 in mice carrying a PPRE-luciferase reporter demonstrated robust activation in the liver but no detectable response in the retina. These results suggest that fenofibrate can limit early retinal pathology in type 2 diabetes through mechanisms independent of retinal PPARα activation.
