Abstract
Purpose :
Previously, we showed that intermittent fasting (IF) for a duration of 7-months and using a regimen of 24-hrs of feeding alternating with 24-hrs of fasting prevented the development of diabetic retinopathy in a type 2 diabetes mouse model (Beli E. et al Diabetes 2018). IF, also termed “Time restricted feeding” or “TRF” has been shown to increase insulin sensitivity, decrease inflammatory markers and oxidative stress and reinstate cellular molecular clocks and mitochondrial function when performed chronically. We asked if short-term TRF could modulate retinal inflammation in mice with diet induced obesity (DIO), a model of prediabetes.
Methods :
To evaluate this, we utilized three cohorts of male mice: 1) C57BL6J mice fed either a normal nutrient balanced (ND) diet; 2) DIO mice that were given a high fat diet (HFD) consisting of 40% fat (n=27) for 20 weeks; and 3) DIO mice placed on TRF for 2 weeks after 20 weeks of HFD feeding. TRF mice were only given food during their active period from 8PM to 6AM. Eyes were collected, and retinas prepared for flat mounts and cross sections. We usedimmunohistochemistry to identify resting vs. activated microglia, and to determine microglia localization.
Results :
Ad-lib access to a HFD for 20 weeks increased body weight and fat mass, and daytime meal consumption. Importantly, two weeks of TRF at the end of the chronic HFD protocol reduced retinal inflammation, even though there was no change in body composition or total daily caloric intake between the DIO alone and the DIO/TRF cohorts. Iba1 immunohistochemistry of retinal cross-sections showed a 39% increase (p<0.05) in the number of microglia in the outer plexiform layer of the retina in the DIO group compared to control (ND), and detected a 32% decrease in microglia the DIO/TRF group compared to the DIO group (p<0.01). Immunofluorescence staining of retinal flat mounts showed that there were fewer activated IBA-1+ microglia in the retinas of the DIO/TRF group than in the retinas of the DIO group (p<0.05).
Conclusions :
These studies provide support for the use of TRF in reversing microglia pathology, a major driver of retinal neuro and vascular degeneration. Even short term TRF showed dramatic benefit on reducing retinal inflammation supporting that TRF may represent a safe adjuvant therapy to existing strategies for retinal diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.