Effects of high-fat diets on microglia morphology and lipid droplet accumulation in the mouse hippocampus

Half of the world’s population is expected to develop obesity within 2035 and the elderly population (age<60) may double within 2050. These numbers are alarming as both advanced age and obesity increase the risk for a broad range of disabling or deadly diseases such as heart diseases, stroke, and neurodegenerative diseases. Therefore, discovering the pathological processes behind brain ageing and the effects of obesity on the brain is of great importance in order to identify novel therapeutic or preventive strategies. The rate of obesity is rising due to an increasingly sedentary lifestyle and intake of energy-dense diets. The prolonged caloric excess from these diets lead to the storage of fat in tissues other than the adipose tissue, in specialized organelles called lipid droplets (LDs). It is unclear to what extent circulating free fatty acids accumulate in the brain. However, it is well known that obesity is associated with systemic inflammation and microglia seem to react to high fat diets, which could lead to prolonged inflammation in the brain, these factors increase the risk of developing neurodegenerative diseases, such as Alzheimer’s disease. Recent advances in the field have shown that brain cells accumulate LDs, especially in the hippocampus. The exact consequences of this LD accumulation are yet to be fully understood. Both protective and harmful roles have been suggested in the literature. In this study, 20 months old female C57/Bl6 mice were divided into three groups and fed different diets for 17 consecutive months: A low-fat control diet, a high-fat diet, and a high-fat diet with polyunsaturated fatty acids supplementation. Brain sections were marked with a fluorescent antibody targeted against microglial cells and the LD stain BODIPY. Through state-of-the-art confocal microscopy and semi-automated image analysis, we were able to investigate microglial reactivity and microglial LD accumulation in both the dorsal and ventral hippocampus. Quite surprisingly, we found no effect from diet on microglial reactivity. Similarly, dietary intervention did not affect microglial LD accumulation. However, we found that both the reactivity of, and LD accumulation in, microglia differed between hippocampal subregions: Microglia from the ventral hippocampus were more reactive than microglia from the dorsal hippocampus, while there was no difference between the dorsal CA1 and dorsal CA3. Differences in microglia morphology were also observed within the CA1 sub-fields, as microglia from the stratum pyramidale were more reactive and accumulated more LDs than microglia from the adjacent stratum radiatum. Overall, these results suggest that high-fat diets have a limited effect on microglia in an ageing brain. Furthermore, the microglial morphology and LD accumulation may be dependent on the location along the dorsal-ventral axis and the sub-fields independent of dietary interventions.