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

Fiona H Mclean,Fiona M Campbell,Amanda C Morris,Christine Grant,Alasdair Mackenzie,Claus D Mayer,Rosamund F Langston,Lynda M Williams,Elizabeth A Hay,Domenico Sergi

doi:10.1186/s12986-019-0387-y

Fiona H Mclean, Fiona M Campbell + Show 8 more

Open Access

https://doi.org/10.1186/s12986-019-0387-y

Copy DOI

Abstract

BackgroundThe 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.MethodsIn 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.ResultsHFD-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.ConclusionThis 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.

Highlights

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)
We have recently shown rapid cognitive decline in hippocampaldependent episodic memory, in mice, within 1 day of a high-fat diet (HFD), which persisted for the time that animals remained on the diet [12]
When HFD mice were switched to a low-fat diet (LFD), caloric intake was the same as those on a LFD (Fig. 1a-h)

Summary

Introduction

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). Previous studies have shown that in mice fed a high-fat diet (HFD) episodic memory is rapidly but reversibly impaired. Animal studies show that a high-fat diet (HFD) leads to obesity and causes cognitive impairment [9,10,11]. These studies and others have mostly looked at the relatively long-term impact of a HFD on memory from around 5 days onwards. In order to understand the potential mechanisms underlying the rapid and reversible onset of this cognitive impairment, changes in the hippocampal proteome were examined in a cohort of mice from the same experiment. Primary hippocampal cell culture was used to confirm the influence of different dietary fatty acids (FAs) on dendritic morphology

Methods

Results

Conclusion