Effect of a maternal high-fat diet on the peripheral retina in mice

A European study reported that a maternal high-fat diet caused subtle retinal structural changes and sex-specific glial alterations, mainly in the peripheral retina of murine offspring. Female offspring showed different changes than the male offspring, according to Gintare Urbonaite, PhD, and colleagues. She is from the Institute of Biosciences, Vilnius University Life Sciences Center, Vilnius, Lithuania. The investigators published their findings in Investigative Ophthalmology and Visual Science.¹

The authors explained that a high-fat diet contributes to development of obesity, glucose intolerance, insulin resistance, and chronic inflammation.^2-5 Evidence suggests that the negative effects may also reach the central nervous system.^6,7

“The retina is one of the most metabolically active neural tissues, relying heavily on fatty acid stores as an energy source. Alterations in nutrient supply to the retina can drive pathological changes, suggesting that metabolic disturbances induced by a high-fat diet may also adversely affect retinal health.⁸

Previous animal studies^9-11 reported that a high-fat diet may retinal inflammation, oxidative stress, and neurodegenerative changes. “One of the first cells to respond to stress in the retina is the microglia. A high-fat diet can disrupt microglial function, leading to an increase in microglial soma size, a morphologic shift from a ramified to an amoeboid (activated) state, and an overall increase in microglial area and cell number.^12,13 Some studies link increased microglial density and metabolic dysfunction to high-fat-diet-induced inflammation and oxidative stress in the retina, enhancing microglial phagocytosis,”^11,14 they said.

The results of previous studies also suggested that the glial responses are sex-dependent. “Animal studies have shown that microglial activation, density, and morphology, as well as Müller cell gliosis, differ between males and females, both during development and in response to inflammation.^15,16 The underlying mechanisms driving these sex-specific differences are likely linked to the influence of sex hormones,” Urbonaite and colleagues said, with testosterone protective against inflammation and estradiol possibly enhancing microglial phagocytic activity.^17,18

Hormone study methodology and results

The investigators wanted to determine how a maternal high-fat diet affects microglial and Müller cell activity in the retinas of offspring and assess how these effects depend on sex and the female estrous cycle.

Female mice were given either a control diet that included 10% fat or a high-fat diet that contained 60% fat from weaning to lactation. The murine offspring were weaned to a normal rodent diet. The investigators assessed the retinal structure and glial cells using immunohistochemistry labeling of retinal ganglion cells, Müller glia, and phagocytic and inflammatory markers. The retinal changes were correlated with the estrous cycle stages, they explained.

The investigators observed that the maternal high-fat diet induced “subtle retinal structural changes and sex-specific alterations in the glial cells of offspring peripheral retina.”

The microglial area was smaller in the male offspring along with an increased lysosomal/phagolysosomal profile; in the female offspring, the picture observed was opposite that in the males.

“Under the maternal control diet, the microglial area and its phagocytic and metabolic immunoreactivity fluctuated with the female estrous cycle, whereas the maternal high-fat diet diminished the differences between the phases. The maternal high-fat diet also decreased the Müller glial immunoreactivity in the females, suggesting altered glial communication,” Urbonaite and colleagues reported.

The findings demonstrated that the maternal high-fat diet had long-term, sex- and hormone-specific effects on the offspring's peripheral retina, affecting the response of retinal microglia to female reproductive hormones.

“These effects primarily occur in the peripheral retina and precede overt neurodegeneration, suggesting that glial dysregulation is an early event in retinal stress,” they said.

They pointed out that assessment of visual function or behavior was not conducted and only the microglial area was evaluated without considering the underlying reason for changes in the area.

The investigators suggested that future studies are needed to look at the functional and morphologic microglial profile and determine if modulation of microglial metabolism or hormone signaling can restore retinal homeostasis and reduce vulnerability to metabolic stress.

References
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