Early and reversible changes to the hippocampal proteome in mice on a high-fat diet

Background: The rise in global obesity makes it crucial to understand how diet drives obesity-related health conditions, such as premature cognitive decline and Alzheimer's disease (AD). In AD hippocampal-dependent episodic memory is one of the first types of memory to be impaired. Previous studies have shown that in mice fed a high-fat diet (HFD) episodic memory is rapidly but reversibly impaired.Methods: In this study we use hippocampal proteomics to investigate the effects of HFD in the hippocampus. Mice were fed either a low-fat diet (LFD) or HFD containing either 10% or 60% (Kcal) from fat for 3 days, 1 week or 2 weeks. One group of mice were fed the HFD for 1 week and then returned to the LFD for a further week. Primary hippocampal cultures were challenged with palmitic acid (PA), the most common long-chain saturated FA in the Western diet, and with the anti-inflammatory, n-3 polyunsaturated FA, docosahexaenoic acid (DHA), or a combination of the two to ascertain effects of these fatty acids on dendritic structure.Results: HFD-induced changes occur in hippocampal proteins involved in metabolism, inflammation, cell stress, cell signalling, and the cytoskeleton after 3 days, 1 week and 2 weeks of HFD. Replacement of the HFD after 1 week by a low-fat diet (LFD) for a further week resulted in partial recovery of the hippocampal proteome. Microtubule-associated protein 2 (MAP2), one of the earliest proteins changed, was used to investigate the impact of fatty acids (FAs) on hippocampal neuronal morphology. PA challenge resulted in shorter and less arborised dendrites while DHA had no effect when applied alone but counteracted the effects of PA when FAs were used in combination. Dendritic morphology recovered when PA was removed from the cell culture media.Conclusion: This study provides evidence for the rapid and reversible effects of diet on the hippocampal proteome and the impact of PA and DHA on dendritic structure.