RNAseq Analysis of FABP4 Knockout Mouse Hippocampal Transcriptome Suggests a Role for WNT/β-Catenin in Preventing Obesity-Induced Cognitive Impairment

Abstract

Microglial fatty-acid binding protein 4 (FABP4) is a regulator of neuroinflammation. We hypothesized that the link between lipid metabolism and inflammation indicates a role for FABP4 in regulating high fat diet (HFD)-induced cognitive decline. We have previously shown that obese FABP4 knockout mice exhibit decreased neuroinflammation and cognitive decline. FABP4 knockout and wild type mice were fed 60% HFD for 12 weeks starting at 15 weeks old. Hippocampal tissue was dissected and RNA-seq was performed to measure differentially expressed transcripts. Reactome molecular pathway analysis was utilized to examine differentially expressed pathways. Results showed that HFD-fed FABP4 knockout mice have a hippocampal transcriptome consistent with neuroprotection, including associations with decreased proinflammatory signaling, ER stress, apoptosis, and cognitive decline. This is accompanied by an increase in transcripts upregulating neurogenesis, synaptic plasticity, long-term potentiation, and spatial working memory. Pathway analysis revealed that mice lacking FABP4 had changes in metabolic function that support reduction in oxidative stress and inflammation, and improved energy homeostasis and cognitive function. Analysis suggested a role for WNT/β-Catenin signaling in the protection against insulin resistance, alleviating neuroinflammation and cognitive decline. Collectively, our work shows that FABP4 represents a potential target in alleviating HFD-induced neuroinflammation and cognitive decline and suggests a role for WNT/β-Catenin in this protection.

Early Life Obesity Increases Neuroinflammation, Amyloid Beta Deposition, and Cognitive Decline in a Mouse Model of Alzheimer’s Disease

“…In microglia, the immune cells of the brain, exposure to dietary saturated fatty acids triggers a shift towards active inflammatory phenotypes. We have previously shown that a high fat diet (HFD) leads to increased hippocampal microgliosis and cognitive decline in mice [9,10]. As neuroinflammation and microglial activation are factors implicated in the etiology of AD [11], we hypothesize that proinflammatory activation of brain microglia in obese young adult mice exacerbates AD pathology and increases accumulation of the amyloid beta (Aβ) plaques characteristic of AD [6].…”