High-Fat Diet Rapidly triggers Lipotoxicity, Hippocampal Neuroinflammation, CA1 Astrogliosis and Neuronal Injury in Rats.
DOI:
https://doi.org/10.22399/ijcesen.5294Keywords:
High-fat diet, Hippocampus, Oxidative stress, Astrogliosis, Spatial memory, CA1Abstract
While diet-induced obesity is firmly associated with cognitive decline, the early mechanisms linking peripheral metabolic dysfunction to central neurotoxicity remain poorly defined. This study investigated the rapid impact of systemic lipotoxicity on hippocampal functional and structural integrity. Male Wistar rats were administered either a standard diet or a high-fat diet (HFD) lipid emulsion for ten weeks. We evaluated systemic metabolic profiles, spatial working memory via the Y-maze, hippocampal transaminase activity, oxidative stress markers, neuroinflammation (IL-6), and structural alterations in the CA1 (Cornu Ammonis 1) subfield using Nissl and GFAP (Glial Fibrillary Acidic Protein) staining. The results showed that HFD intervention induced systemic dyslipidemia without altering fasting glucose or insulin levels. Behaviorally, HFD rats demonstrated significant spatial memory deficits. Biochemically, peripheral lipid overload prompted central metabolic distress, characterized by elevated hippocampal transaminase (ALT/AST) activity, a failure of endogenous antioxidant defenses, doubled lipid peroxidation, and a significant increase in pro-inflammatory IL-6 (Interleukine-6). Histologically, these biochemical disruptions translated into marked neuronal distress and widespread reactive astrogliosis within the CA1 pyramidal layer. Our findings revealed that the HFD consumption impairs spatial memory through a strictly lipotoxic mechanism, prior to the onset of overt hyperglycemia. Early systemic dyslipidemia severely disrupts central metabolic homeostasis, driving oxidative stress, neuroinflammation, Astrogliosis and consequent CA1 neuronal injury.
References
[1] Kullmann, S. Kleinridders, A. Small D.M, Fritsche, A. Harin H.U, Preissl H. Heni M. (2020). Central nervous pathways of insulin action in the control of metabolism and food intake. Lancet Diabetes Endocrinol. (6): 524–534. DOI: https://doi.org/10.1016/S2213-8587(20)30113-3
[2] Mackey-Alfonso, S. E and Barrientos, R. M. (2025). Neuroinflammatory mechanisms linking high-fat diets to Alzheimer's disease vulnerability: Beyond the amyloid hypothesis. Alzheimers Dement. 21: e70911. DOI: https://doi.org/10.1002/alz.70911
[3] Cobley, J. N. Fiorello, M. L. & Bailey D. M. (2018). 13 reasons why the brain is susceptible to oxidative stress. Redox Biology. 15: 490-503. DOI: https://doi.org/10.1016/j.redox.2018.01.008
[4] Díaz, M. Valdés-Baizabal, C. de Pablo, DP. Marin, R. (2024). Age-dependent changes in Nrf2/Keap1 and target antioxidant protein expression correlate to lipoxidative adducts and are modulated by dietary N-3 LCPUFA in the hippocampus of mice. Antioxidants Basel. 13:2. DOI: https://doi.org/10.3390/antiox13020206
[5] de Paula, GC. Brunetta, HS. Engel, DF. Gaspar, JM. Velloso LA. Engblom D. (2021). Hippocampal function is impaired by a short-term High-Fat Diet in mice: increased blood-brain barrier permeability and Neuroinflammation as triggering events. Front Neurosci-Switz. 15 :734158. DOI: https://doi.org/10.3389/fnins.2021.734158
[6] Teleanu, D. M. Niculescu, A. G, Lungu, I.I, Radu C.I, Vladâcenco O. Roza E. Costăchescu B. Grumezescu A. M, Teleanu R. I. (2022). An Overview of Oxidative Stress, Neuroinflammation, and neurodegenerative diseases. Int. J. Mol. Sci. 23: 5938. DOI: https://doi.org/10.3390/ijms23115938
[7] Dmytriv, T. Duve, K. Lushchak V. (2024). Vicious cycle of oxidative stress and neuroinflammation in pathophysiology of chronic vascular encephalopathy. Front. Physiol. 15:1443604. DOI: https://doi.org/10.3389/fphys.2024.1443604
[8] Chun H. H, Kang Y. Kim Y. Shin J. (2020). Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2 production. Nat. Neurosci. 23:1555–66. DOI: https://doi.org/10.1038/s41593-020-00735-y
[9] Escartin, C. Galea E. Lakatos, A. O’Callaghan J. Petzold G. (2021). Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24:312–25.
[10] Yang, G. Xu, X. Gao, W. Wang, X. Zhao, Y. Xu Y. (2025). Microglia-Orchestrated Neuroinflammation and Synaptic Remodeling: Roles of pro-Inflammatory Cytokines and Receptors Neurodegeneration. Front. Cell. Neurosci. 19:1700692. DOI: https://doi.org/10.3389/fncel.2025.1700692
[11] Srokowska, M. Zwierello, W. Wszolek, A. Gutowska I. (2025). Neurobiochemical Effects of a High-Fat Diet: Implications for the Pathogenesis of Neurodegenerative Diseases. Biology. 14: 1317. DOI: https://doi.org/10.3390/biology14101317
[12] Gao, Q.L, Zha, H., Liu, Z.J. (2025). Hippocampal CA1 neuron, a crucial regulator for chronic stress exacerbating alzheimer’s disease progression. Cell Biosci. 15:73. DOI: https://doi.org/10.1186/s13578-025-01420-y
[13] Teng, S.F, Lee, M.T, Lee, L.J, Hwang, L.L, Chen, C.P, Lee H.J, Chen, C.T, Chiou L.C. (2025). High-fat diet impairs the dendritic morphology of hippocampal CA1 pyramidal neurons in male but not female mice. Front Nutr. 12:1687060. DOI: https://doi.org/10.3389/fnut.2025.1687060
[14] Arnold, S.E, Lucki, I, Brookshire, B.R et al. (2014). High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behaviour in mice. Neurobiol Dis. 67:79–87. DOI: https://doi.org/10.1016/j.nbd.2014.03.011
[15] Mostafa, M.D, Amer, M.E, ElKomy, M.A, Othman, A.I, El-Missiry, M.A. (2025). controlled obesity and invigorated cognitive and memory performance in rats consuming a high-fat diet via modulating oxidative stress, inflammation and apoptosis. Sci Rep. 15(1): 20171. DOI: https://doi.org/10.1038/s41598-025-05716-4
[16] Singh, T, Kwatra, M, Kushwah, P, Pant, R, Bezbaruah B.K. (2022). Jangra Binge alcohol consumption exacerbates high-fat diet-induced neurobehavioral anomalies: possible underlying mechanisms Chem. Biol. Interact. 364: 110039. DOI: https://doi.org/10.1016/j.cbi.2022.110039
[17] Custodio, R.J, Hobloss, P. Z, and Myllys, M. (2023). Cognitive Functions, Neurotransmitter Alterations, and Hippocampal Microstructural Changes in Mice Caused by Feeding on Western Diet. Cells. 12(18). DOI: https://doi.org/10.3390/cells12182331
[18] Treviño, S, Díaz, A, González-López, G, Guevara, J. (2022). Differential biochemical-inflammatory patterns in the astrocyte-neuron axis of the hippocampus and frontal cortex in wistar rats with metabolic syndrome induced by high fat or carbohydrate diets. J Chem Neuroanat. 126: 102186. DOI: https://doi.org/10.1016/j.jchemneu.2022.102186
[19] Deacon, R.M, Rawlins, J.N. (2006). T-maze alternation in the rodent. Nature Protocols. 1(1) :7–12. DOI: https://doi.org/10.1038/nprot.2006.2
[20] Swonger, A, and Rech, R. (1972). Serotonergic and cholinergic involvement in habituation of activity and spontaneous alternation of rats in a Y maze. J Comp Psychol. 81: 509–522. DOI: https://doi.org/10.1037/h0033690
[21] Friedewald, W, Levy, R, Fredrickson, D. (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 18: 499-502. DOI: https://doi.org/10.1093/clinchem/18.6.499
[22] Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry. 72(1-2): 248-254. DOI: https://doi.org/10.1016/0003-2697(76)90527-3
[23] Bergmeyer, H. U, Scheibe, P, & Wahlefeld, A. W. (1978). Optimization of methods for aspartate aminotransferase and alanine aminotransferase. Clinical Chemistry. 24(1): 58-73. DOI: https://doi.org/10.1093/clinchem/24.1.58
[24] Buege, J. A, & Aust, S. D. (1984). Microsomal lipid peroxidation. Methods in Enzymology. 105: 302-10. DOI: https://doi.org/10.1016/S0076-6879(78)52032-6
[25] Ellman, G. L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics. 82(1): 70-7. DOI: https://doi.org/10.1016/0003-9861(59)90090-6
[26] Jollow, D. J, Mitchell, J. R, Zampaglione, N, & Gillette, J. R. (1974). Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3, bromobenzene oxide as the hepatotoxic metabolite. Pharmacology. 11(3): 151-69. DOI: https://doi.org/10.1159/000136485
[27] Aebi, H. (1984). Catalase in vitro. Methods in Enzymology. 105: 121-6. DOI: https://doi.org/10.1016/S0076-6879(84)05016-3
[28] Flohe, L, Gunzler, W.A. (1984). Analysis of glutathione peroxidase. Methods in Enzymology. 105: 114-21. DOI: https://doi.org/10.1016/S0076-6879(84)05015-1
[29] Habig, W.H, Pabst, M.J, & Jakoby, W.B. (1974). Glutathione- Stransferase the first step in mercapturic acid formation. Journal of Biological Chemistry. 249(22): 7130-9. DOI: https://doi.org/10.1016/S0021-9258(19)42083-8
[30] Marques, C, Meireles, M, Norberto, S, Leite, J, Freitas, J, Pestana, D, Faria, A, Calhau, C. (2015). High-fat diet-induced obesity rat model: a comparison between Wistar and Sprague-Dawley rat. Adipocyte. 5(1):11–21. DOI: https://doi.org/10.1080/21623945.2015.1061723
[31] Sanguinetti, E, Guzzardi, M.A, Panetta, D, Tripodi, M, De Sena, V, Quaglierini, M, et al. (2019). Combined Effect of Fatty Diet and Cognitive Decline on Brain Metabolism, Food Intake, Body Weight, and Counteraction by Intranasal Insulin Therapy in 3xTg Mice. Front Cell Neurosci. 13:188. DOI: https://doi.org/10.3389/fncel.2019.00188
[32] Zou, Y, Li J, Lu, C, Wan,g J, Ge J, Huang, Y, Zhang, L, Wang, Y. (2006). High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life Sci. 79:1100–1107. DOI: https://doi.org/10.1016/j.lfs.2006.03.021
[33] Ribeiro, R, Silva, E. G, Moreira, F. C, Gomes, G. F, Cussat, G. R, Silva, B. S. R, da Silva, M. et al. (2023). Chronic hyperpalatable diet induces impairment of hippocampal-dependent memories and alters glutamatergic and fractalkine axis signaling. Scientific Reports. 13(1): 16358. DOI: https://doi.org/10.1038/s41598-023-42955-9
[34] Butler, M.J, Muscat, S.M, Caetano-Silva M.E, Shrestha, A, Olmo B.M.G, Mackey-Alfonso S.E, Massa N, Alvarez B.D, Blackwell J.A, Bettes M.N, et al. (2025). Obesity-associated memory impairment and neuroinflammation precede widespread peripheral perturbations in aged rats. Immun. Ageing. 22: 2. DOI: https://doi.org/10.1186/s12979-024-00496-3
[35] Rhea, E.M, Banks, W.A. (2021). Interactions of Lipids, Lipoproteins, and Apolipoproteins with the Blood-Brain Barrier. Pharm. Res. 38: 1469–1475. DOI: https://doi.org/10.1007/s11095-021-03098-6
[36] Hsu, T.M, Kanoski, S.E. (2014). Blood-Brain Barrier Disruption: Mechanistic Links between Western Diet Consumption and Dementia. Front. Aging Neurosci. 6: 88. DOI: https://doi.org/10.3389/fnagi.2014.00088
[37] Leidmaa, E, Zimmer, A, Stein, V, Gellner, A.-K. (2025). Acute High-Fat High-Sugar Diet Rapidly Increases Blood–Brain Barrier Permeability in Mice. J. Nutr. Health Aging. 29: 100574. DOI: https://doi.org/10.1016/j.jnha.2025.100574
[38] Berghoff, S.A, Spieth, L, and Saher, G. (2022). Local cholesterol metabolism orchestrates remyelination. Trends Neurosci. 45: 272–283. DOI: https://doi.org/10.1016/j.tins.2022.01.001
[39] Vanherle, S, Loix, M, Miron, V.E, Hendriks, J.J.A, and Bogie, J.F.J. (2025). Lipid metabolism, remodelling and intercellular transfer in the CNS. Nat. Rev. Neurosci. 26: 214–231. DOI: https://doi.org/10.1038/s41583-025-00908-3
[40] Alkan, I, Altunkaynak, B. Z, Gültekin, G. İ & Bayçu, C. (2021). Hippocampal neural cell loss in high-fat diet-induced obese rats-exploring the protein networks, ultrastructure, biochemical and bioinformatical markers. J. Chem. Neuroanat. 114: 101947. DOI: https://doi.org/10.1016/j.jchemneu.2021.101947
[41] Mota, B, Brás, A.R, Araújo-Andrade, L, Silva, A, Pereira, P.A, Madeira, M.D, Cardoso, A. (2024). High-Caloric Diets in Adolescence Impair Specific GABAergic Subpopulations, Neurogenesis, and Alter Astrocyte Morphology. Int. J. Mol. Sci. 25: 5524. DOI: https://doi.org/10.3390/ijms25105524
[42] Pajarillo E, Rizor A, Lee J, Aschner M, Lee E. (2019). The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics. Neuropharmacology. 161: 107559. DOI: https://doi.org/10.1016/j.neuropharm.2019.03.002
[43] Tsai, S.F, Hsu, P.L, Chen, Y.W, Hossain M.S, Chen, P.C, Tzeng, S.F, Chen, P.S, Kuo, Y.M. (2022). High-fat diet induces depression-like phenotype via astrocyte-mediated hyperactivation of ventral hippocampal glutamatergic afferents to the nucleus accumbens. Mol. Psychiatry. 27: 4372–4384. DOI: https://doi.org/10.1038/s41380-022-01787-1
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 International Journal of Computational and Experimental Science and Engineering
This work is licensed under a Creative Commons Attribution 4.0 International License.
