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

Purpose 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 (CD, 10% fat) or a high-fat diet (HFD, 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, astrocytes, 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 increased phagocytic capacity, whereas females showed the opposite pattern. Under mCD, the microglial area and its phagocytic and metabolic activity fluctuated with the female estrous cycle, while mHFD diminished the differences between phases. Additionally, mHFD reduced Müller glial reactivity in females, indicating disrupted 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.