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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
References
Association As. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 2022;18:700–89.
Braak H, Del Tredici K. The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease. Brain. 2015;138:2814–33.
Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science. 1984;225:1168–70.
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta analysis consortium. JAMA. 1997;278:1349–56.
Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, et al. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020;11:667.
Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313:1924–38.
Jansen WJ, Ossenkoppele R, Visser PJ. Amyloid pathology, cognitive impairment, and Alzheimer disease risk-reply. JAMA. 2015;314:1177–8.
Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005;62:1556–60.
Nianogo RA, Rosenwohl-Mack A, Yaffe K, Carrasco A, Hoffmann CM, Barnes DE. Risk factors associated with Alzheimer disease and related dementias by sex and race and ethnicity in the US. JAMA Neurol. 2022;79:584–91.
Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008;71:1057–64.
Finkelstein EA, Khavjou OA, Thompson H, Trogdon JG, Pan L, Sherry B, et al. Obesity and severe obesity forecasts through 2030. Am J Prev Med. 2012;42:563–70.
Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007–2008 to 2015–2016. JAMA. 2018;319:1723–5.
Loef M, Walach H. Midlife obesity and dementia: meta-analysis and adjusted forecast of dementia prevalence in the United States and China. Obesity. 2013;21:E51–E5.
Alford S, Patel D, Perakakis N, Mantzoros CS. Obesity as a risk factor for Alzheimer’s disease: weighing the evidence. Obes Rev. 2018;19:269–80.
Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, et al. Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem. 1997;272:17972–80.
Arbones-Mainar JM, Johnson LA, Altenburg MK, Maeda N. Differential modulation of diet-induced obesity and adipocyte functionality by human apolipoprotein E3 and E4 in mice. Int J Obes. 2008;32:1595–605.
Arbones-Mainar JM, Johnson LA, Torres-Perez E, Garcia AE, Perez-Diaz S, Raber J, et al. Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4. Int J Obes. 2016;40:1574–81.
Huebbe P, Dose J, Schloesser A, Campbell G, Glüer CC, Gupta Y, et al. Apolipoprotein E (APOE) genotype regulates body weight and fatty acid utilization-studies in gene-targeted replacement mice. Mol Nutr Food Res. 2015;59:334–43.
Johnson LA, Torres ER, Impey S, Stevens JF, Raber J. Apolipoprotein E4 and insulin resistance interact to impair cognition and alter the epigenome and metabolome. Sci Rep. 2017;7:43701.
Johnson LA, Torres ER, Weber Boutros S, Patel E, Akinyeke T, Alkayed NJ, et al. Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response. J Cereb Blood Flow Metab. 2019;39:770–81.
To AW, Ribe EM, Chuang TT, Schroeder JE, Lovestone S. The epsilon3 and epsilon4 alleles of human APOE differentially affect tau phosphorylation in hyperinsulinemic and pioglitazone treated mice. PLoS ONE. 2011;6:e16991.
Jones NS, Watson KQ, Rebeck GW. Metabolic disturbances of a high-fat diet are dependent on APOE genotype and sex. eNeuro. 2019;6:ENEURO.0267–19.2019.
Jones NS, Watson KQ, Rebeck GW. High-fat diet increases gliosis and immediate early gene expression in APOE3 mice, but not APOE4 mice. J Neuroinflamm. 2021;18:214.
Janssen CI, Jansen D, Mutsaers MP, Dederen PJ, Geenen B, Mulder MT, et al. The effect of a high-fat diet on brain plasticity, inflammation and cognition in female ApoE4-knockin and ApoE-knockout mice. PLoS ONE. 2016;11:e0155307.
Mattar JM, Majchrzak M, Iannucci J, Bartman S, Robinson JK, Grammas P. Sex differences in metabolic indices and chronic neuroinflammation in response to prolonged high-fat diet in ApoE4 knock-in mice. Int J Mol Sci. 2022;23:3921.
Yoon G, Cho KA, Song J, Kim YK. Transcriptomic analysis of high fat diet fed mouse brain cortex. Front Genet. 2019;10:83.
Nam KN, Wolfe CM, Fitz NF, Letronne F, Castranio EL, Mounier A, et al. Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice. Biochim Biophys Acta Mol Basis Dis. 2018;1864:152–61.
Nam KN, Mounier A, Wolfe CM, Fitz NF, Carter AY, Castranio EL, et al. Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer’s model mice. Sci Rep. 2017;7:4307.
So SW, Nixon JP, Bernlohr DA, Butterick TA. RNAseq analysis of FABP4 knockout mouse hippocampal transcriptome suggests a role for WNT/beta-catenin in preventing obesity-induced cognitive impairment. Int J Mol Sci. 2023;24:3381.
Balu D, Karstens AJ, Loukenas E, Maldonado Weng J, York JM, Valencia-Olvera AC, et al. The role of APOE in transgenic mouse models of AD. Neurosci Lett. 2019;707:134285.
Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, et al. APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem. 2012;287:41774–86.
Betthauser TJ, Bilgel M, Koscik RL, Jedynak BM, An Y, Kellett KA, et al. Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts. Brain. 2022;145:4065–79.
Zhao N, Ren Y, Yamazaki Y, Qiao W, Li F, Felton LM, et al. Alzheimer’s risk factors age, APOE genotype, and sex drive distinct molecular pathways. Neuron. 2020;106:727–42.e6.
Flores-Dorantes MT, Diaz-Lopez YE, Gutierrez-Aguilar R. Environment and gene association with obesity and their impact on neurodegenerative and neurodevelopmental diseases. Front Neurosci. 2020;14:863.
Timshel PN, Thompson JJ, Pers TH. Genetic mapping of etiologic brain cell types for obesity. Elife. 2020;9:e55851.
Kalin S, Heppner FL, Bechmann I, Prinz M, Tschop MH, Yi CX. Hypothalamic innate immune reaction in obesity. Nat Rev Endocrinol. 2015;11:339–51.
Beach TG. A history of senile plaques: from Alzheimer to amyloid imaging. J Neuropathol Exp Neurol. 2022;81:387–413.
Aloe L, Rocco ML, Balzamino BO, Micera A. Nerve growth factor: a focus on neuroscience and therapy. Curr Neuropharmacol. 2015;13:294–303.
Fifel K, Videnovic A. Circadian and sleep dysfunctions in neurodegenerative disorders-an update. Front Neurosci. 2020;14:627330.
Yu F, Wang Y, Stetler AR, Leak RK, Hu X, Chen J. Phagocytic microglia and macrophages in brain injury and repair. CNS Neurosci Ther. 2022;28:1279–93.
Crapser JD, Arreola MA, Tsourmas KI, Green KN. Microglia as hackers of the matrix: sculpting synapses and the extracellular space. Cell Mol Immunol. 2021;18:2472–88.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.
Baumgarner KM, Setti S, Diaz C, Littlefield A, Jones A, Kohman RA. Diet-induced obesity attenuates cytokine production following an immune challenge. Behav Brain Res. 2014;267:33–41.
Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, et al. Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol. 2010;219:25–32.
Rivera P, Perez-Martin M, Pavon FJ, Serrano A, Crespillo A, Cifuentes M, et al. Pharmacological administration of the isoflavone daidzein enhances cell proliferation and reduces high fat diet-induced apoptosis and gliosis in the rat hippocampus. PLoS ONE. 2013;8:e64750.
Wanrooy BJ, Kumar KP, Wen SW, Qin CX, Ritchie RH, Wong CHY. Distinct contributions of hyperglycemia and high-fat feeding in metabolic syndrome-induced neuroinflammation. J Neuroinflamm. 2018;15:293.
Maric T, Woodside B, Luheshi GN. The effects of dietary saturated fat on basal hypothalamic neuroinflammation in rats. Brain Behav Immun. 2014;36:35–45.
Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012;122:153–62.
Parhizkar S, Holtzman DM. APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease. Semin Immunol. 2022;59:101594.
Lambert JC, Ramirez A, Grenier-Boley B, Bellenguez C. Step by step: towards a better understanding of the genetic architecture of Alzheimer’s disease. Mol Psychiatry. 2023;28:2716–27.
Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E, et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023;615:668–77.
Perez-Nievas BG, Stein TD, Tai HC, Dols-Icardo O, Scotton TC, Barroeta-Espar I, et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain. 2013;136:2510–26.
Cummings JL, Osse AML, Kinney JW. Alzheimer’s disease: novel targets and investigational drugs for disease modification. Drugs. 2023;83:1387–408.
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.
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41366-024-01481-y