Abstract
High-fat diet-induced metabolic changes are not restricted to the onset of cardiovascular diseases, but also include effects on brain functions related to learning and memory. This study aimed to evaluate mitochondrial markers and function, as well as cognitive function, in a rat model of metabolic dysfunction. Eight-week-old male Wistar rats were subjected to either a control diet or a two-hit protocol combining a high fat diet (HFD) with the nitric oxide synthase inhibitor L-NAME in the drinking water. HFD plus L-NAME induced obesity, hypertension, and increased serum cholesterol. These rats exhibited bioenergetic dysfunction in the hippocampus, characterized by decreased oxygen (O2) consumption related to ATP production, with no changes in H2O2 production. Furthermore, OPA1 protein expression was upregulated in the hippocampus of HFD + L-NAME rats, with no alterations in other morphology-related proteins. Consistently, HFD + L-NAME rats showed disruption of performance in the Morris Water Maze Reference Memory test. The neocortex did not exhibit either bioenergetic changes or alterations in H2O2 production. Calcium uptake rate and retention capacity in the neocortex of HFD + L-NAME rats were not altered. Our results indicate that hippocampal mitochondrial bioenergetic function is disturbed in rats exposed to a HFD plus L-NAME, thus disrupting spatial learning, whereas neocortical function remains unaffected.
Highlights
A two-hit protocol using HFD + L-NAME induces metabolic dysfunction in rats.
Spatial memory is impacted in HFD + L-NAME rats.
Hippocampal but not neocortex bioenergetics is affected in HFD + L-NAME rats.
OPA-1 expression is upregulated in the hippocampus of HFD + L-NAME rats.
Cortical calcium dynamics was not affected by HFD + L-NAME.
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Data availability
The data that support the findings of this study are available from the first author, W.R.V and the corresponding author, A.F.B., upon reasonable request.
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Acknowledgements
We gratefully acknowledge Dra. Paula Maria Quaglio Bellozi for the support in graphic design.
Funding
This study was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (13/07937-8, 20/06970-5); Fundação de Apoio à Pesquisa do Distrito Federal (FAPDF grants: 00193–00000884/2021-89, 00193–0000002348/2022-07); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq grant 424809-2018-4); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/STINT grant 88881.465507/2019-01); and Instituto Nacional de Ciência e Tecnologia e Neuro-ImunoModulação (INCT-NIM grant 485489/2014-1).
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W.R.V.: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing - original draft preparation, Visualization. L.S.R.: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Visualization. L.R.G.B.: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Visualization. J.V.C-C.: Investigation, Methodology, Visualization. J.D.C.S.: Investigation, Methodology, Visualization. A.J.K.: Conceptualization, Methodology, Resources, Writing - review & editing, Visualization. G.F.X.: Conceptualization, Methodology, Resources, Data curation, Writing - review & editing, Visualization. J.C.B.F.: Conceptualization, Methodology, Validation, Resources, Supervision, Project administration, Funding acquisition, Visualization. A.F.B.: Conceptualization, Methodology, Validation, Resources, Data curation, Writing - review & editing, Supervision, Project administration, Funding acquisition, Visualization.
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The procedures fulfilled the guidelines for animal care from the NIH (National Research Council, 2011) and were approved by the Ethics Committee on the Use of Animals at the University of São Paulo (CEUA/USP No 9236210120).
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Alicia J. Kowaltowski declare that she is editor of the Journal of Bioenergetics and Biomembranes. The authors declare that they have no known competing financial interests or personal relationships that could have influenced this work.
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Vilela, W.R., Ramalho, L.S., Bechara, L.R.G. et al. Metabolic dysfunction induced by HFD + L-NAME preferentially affects hippocampal mitochondria, impacting spatial memory in rats. J Bioenerg Biomembr 56, 87–99 (2024). https://doi.org/10.1007/s10863-024-10005-2
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DOI: https://doi.org/10.1007/s10863-024-10005-2