Metabolic syndrome (MetS) is becoming an increasing public health challenge. Many of the individual components of MetS are associated with ocular changes, but it is not yet clear what the association is. It is known that MetS can lead to diabetes and hence its consequences such as retinopathy. Osteopontin (OPN) is a phosphoglycoprotein that appears to be implicated in diabetic retinopathy. Given the involvement of OPN in retinal damage, the aim of this research was to evaluate OPN expression and its variation over time in a model of MetS induced by 30% fructose consumption for 1, 2 and 3 months. The weight of the animals and the consumption of food and fructose/water were evaluated during the experiment. The results showed a time-dependent increase in weight and liquid consumption in animals treated with fructose, while there was no significant difference in food consumption. Subsequently, the biochemical parameters confirmed that the animals treated with fructose, over time, underwent alterations like those found in patients with MetS. We then moved on to the evaluation of OPN and microglia. In both cases, we observed a time-dependent increase in OPN and Iba-1 in fructose consumption. Furthermore, the results showed a gradual loss of ZO-1 and occludin levels over time. Thus identification of OPN in patients with MetS could be used as an early marker of retinal damage, and this could help to prevent the complications related to the progression of this pathology.© 2024 The Author(s). International Journal of Experimental Pathology published by John Wiley & Sons Ltd on behalf of Company of the International Journal of Experimental Pathology (CIJEP).