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Obesity affects brain cortex gene expression in an APOE genotype and sex dependent manner

International Journal of Obesity (2024)Cite this article

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Abstract

Objective

Obesity is the top modifiable risk factor for Alzheimer’s disease. We hypothesized that high fat diet (HFD)-induced obesity alters brain transcriptomics in APOE-genotype and sex dependent manners. Here, we investigated interactions between HFD, APOE, and sex, using a knock-in mouse model of the human APOE3 and APOE4 alleles.

Methods

Six-month-old APOE3-TR and APOE4-TR mice were treated with either HFD or control chow. After 4 months, total RNA was extracted from the cerebral cortices and analyzed by poly-A enriched RNA sequencing on the Illumina platform.

Results

Female mice demonstrated profound HFD-induced transcriptomic changes while there was little to no effect in males. In females, APOE3 brains demonstrated about five times more HFD-induced transcriptomic changes (399 up-regulated and 107 down-regulated genes) compared to APOE4 brains (30 up-regulated and 60 down-regulated). Unsupervised clustering analysis revealed two gene sets that responded to HFD in APOE3 mice but not in APOE4 mice. Pathway analysis demonstrated that HFD in APOE3 mice affected cortical pathways related to feeding behavior, blood circulation, circadian rhythms, extracellular matrix, and cell adhesion.

Conclusions

Female mice and APOE3 mice have the strongest cortical transcriptomic responses to HFD related to feeding behavior and extracellular matrix remodeling. The relative lack of response of the APOE4 brain to stress associated with obesity may leave it more susceptible to additional stresses that occur with aging and in AD.

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Fig. 1: APOE3/4 TR mouse model.
Fig. 2: RNA sequencing workflow and PCA analysis.
Fig. 3: Female sex and APOE3 genotype exhibit more differentially expressed genes (DEGs) in HFD group.
Fig. 4: Clustering analysis revealed APOE4 genotype specific impact on transcriptome.
Fig. 5: Shared APOE DEGs, including HFD interactions.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. All next-generation sequencing raw data for RNA-seq experiments are available from NCBI-SRA, BioProject accession # PRJNA1033375.

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Acknowledgements

This work is supported by NIH grants R21 AG074139, R01 AG067258 and R01 NS100704. Authors also would like to acknowledge the Georgetown University Medical Center for providing continuous research support and infrastructure.

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  1. Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road N.W., Washington, DC, 20007, USA

    Harshul Pandit, Nahdia S. Jones & G. William Rebeck

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Contributions

HP and GWR wrote the manuscript. HP was responsible for cortical tissue processing, RNA extractions for RNA-sequencing, and bioinformatics analysis. NJ and GWR designed and executed animal experiments. HP and GWR analyzed the data, identified outliers, and interpreted the results. GWR mentored HP and NJ, and supported this study. All authors read and approved the final manuscript.

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Correspondence to G. William Rebeck.

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Pandit, H., Jones, N.S. & Rebeck, G.W. Obesity affects brain cortex gene expression in an APOE genotype and sex dependent manner. Int J Obes (2024). https://doi.org/10.1038/s41366-024-01481-y

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