Diet-Based Strategies for Mitigating Obesity-Induced Corneal Dysregulation: Timing of Diet Intake vs. Macronutrient Composition of Diet

Purpose: Diet-induced obesity in mice causes corneal nerve sensitivity and density loss. It also impairs corneal wound healing. Time-restricted feeding and diet reversal are diet-based strategies that target the timing of diet intake and the macronutrient composition of diet, respectively. Although these strategies mitigate cardiometabolic complications of diet-induced obesity, their utility against corneal complications in diet-induced obesity is unknown. Here, a diet-induced obesity mouse model was used to examine the impact of diet's timing and macronutrient composition on obesity-induced corneal dysregulation. Methods: 6-week-old C57BL/6 male mice were used. For the time-restricted feeding experiment, mice were fed either a normal chow diet ad libitum, high-fat/sucrose diet ad libitum (diet-induced obesity), or high-fat/sucrose diet on a time-restricted regimen (8h feed/16h fast period) for 10 days. For the diet reversal experiment, mice were fed either a normal chow diet ad libitum or high-fat/sucrose diet ad libitum for 20 weeks or a high-fat/sucrose diet for 10 weeks and then reversed to a normal chow diet for an additional 10 weeks (diet reversal group). Corneal nerve sensitivity was assessed with a Cochet-Bonnet aesthesiometer. A 2-mm diameter corneal epithelial abrasion wound was created, and wound closure was monitored using sodium fluorescein staining. Neutrophil and platelet recruitment was assessed by immunofluorescence microscopy. Results: Corneal nerve sensitivity was reduced, corneal wound healing was impaired, and inflammation was dysregulated in ad libitum high-fat/sucrose diet-fed mice compared to ad libitum normal diet-fed mice. Time-restricted feeding did not attenuate corneal dysregulation. Corneal nerve sensitivity was reduced, wound closure was delayed, and platelet extravasation at the limbus and neutrophil migration to the center of the cornea were impaired in time-restricted high-fat/sucrose diet-fed mice, similar to that observed in ad libitum high-fat/sucrose diet-fed mice. Diet reversal halted the progression of corneal nerve sensitivity loss, restored normal wound closure and neutrophil and platelet influx in the injured cornea. Conclusion: These data show the cornea is highly responsive to the diet’s macronutrient composition, suggesting compositional changes to the diet may be an effective diet-based therapeutic strategy for maintaining or restoring corneal health.