Maternal High-Fat Diet Induces Sex- and Estrous Cycle–Specific Glial Dysregulation in the Peripheral Offspring Retina

Abstract

Purpose: A maternal high-fat diet (mHFD) induces metabolic disturbances that lead to inflammatory responses in the offspring's brain. The retina, as part of the central nervous system, may be similarly affected. This study aimed to determine how mHFD affects microglial and Müller cell activity in the retinas of offspring and assess how these effects depend on sex and the female estrous cycle. Methods: Female C57Bl/6J mice were fed a control diet (10% fat) or a high-fat diet (60% fat) from weaning to lactation. The offspring were weaned to a normal rodent diet. Retinal structure and glial cells were assessed using immunohistochemical labeling of retinal ganglion cells, Müller glia, and phagocytic and inflammatory markers. Observed retinal changes in female offspring were correlated with the estrous cycle stages. Results: mHFD induced subtle retinal structural changes and sex-specific alterations in glial cells of offspring peripheral retina. Male offspring exhibited a reduced microglial area, accompanied by an increased lysosomal/phagolysosomal profile, whereas females showed the opposite pattern. Under the maternal control diet, the microglial area and its phagocytic and metabolic immunoreactivity fluctuated with the female estrous cycle, whereas mHFD diminished the differences between phases. Additionally, mHFD reduced Müller glial immunoreactivity in females, suggesting altered glial communication. Conclusions: Our findings demonstrate that mHFD has a sex-specific effect on the offspring's peripheral retina, affecting the response of retinal microglia to female reproductive hormones.