2285-PUB: Hippocampal Transcriptomic Changes Due to High-Fat Diet in Prediabetic Mice

Abstract

The metabolic syndrome, prediabetes, and type 2 diabetes are increasingly common conditions worldwide, which predispose patients to the development of significant complications in both the central and peripheral nervous systems. Recently, our integrated lipidomics and transcriptomics study revealed an important role for lipid signaling pathways in peripheral nerves of mouse models of prediabetes and type 2 diabetes. While these data point to possible mechanisms of nerve damage peripherally, less is known about damage due to prediabetes and diabetes in the brain. This is of particular interest as growing evidence indicates that these conditions negatively affect cognition. Therefore, we performed RNA-Seq on hippocampi, a major site of learning and memory in the brain. Samples were isolated from a model of prediabetes and cognitive decline, wherein mice are fed a 60% high-fat diet (HFD). We identified various differentially expressed genes (DEGs) due to HFD, particularly after 11 wks (n=886), with fewer after 19 wks (n=111). Pathway analysis showed enrichment of pathways previously identified in the peripheral nervous system in response to HFD, including inflammatory and MAPK signaling pathways. Of interest, ∼31% of DEGs due to 11 wks of HFD overlapped with DEGs due to age (control animals only, comparing 19 to 11 wks of diet). These overlapping DEGs included genes such as fatty acid elongase 6 and hyccin (leukodystrophy protein FAM126A), which have roles in lipid metabolism and myelination, respectively. Enrichment analysis revealed multiple metabolic and protein processing pathways, such as oxidative phosphorylation and the proteasome. These data suggest that, like the peripheral nervous system, HFD effects similar pathways in the brain and may accelerate age-related gene expression changes in the hippocampus. However, more robust studies are needed to fully understand the influence of HFD on possible premature brain aging and how gene expression changes may contribute to cognitive decline.