Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia

BackgroundSignificant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms...

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Autores: Zheng, HL, Mizokami, A, Romera-Giner, S, Llera-Oyola, J, Yamawaki, Y, Sano, T, Jimi, E, García-García, F, Kanematsu, T
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2025
País:España
Recursos:Centro de Investigación Principe Felipe (CIPF)
Repositório:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
OAI Identifier:oai:cipf.fundanetsuite.com:p4507
Acesso em linha:https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4507
Access Level:Acceso aberto
Palavra-chave:Fatty acid synthesis
Inflammation
Microglia
miRNA
Sex differences
Testosterone
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spelling Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microgliaZheng, HLMizokami, ARomera-Giner, SLlera-Oyola, JYamawaki, YSano, TJimi, EGarcía-García, FKanematsu, TFatty acid synthesisInflammationMicrogliamiRNASex differencesTestosteroneBackgroundSignificant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.MethodsMicroglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.ResultsSex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-kappa B/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.ConclusionsThese findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.BMC2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4507Biology of Sex DifferencesISSN: 20426410reponame:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)instname:Centro de Investigación Principe Felipe (CIPF)Inglésinfo:eu-repo/semantics/openAccessoai:cipf.fundanetsuite.com:p45072026-06-17T11:19:47Z
dc.title.none.fl_str_mv Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
title Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
spellingShingle Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
Zheng, HL
Fatty acid synthesis
Inflammation
Microglia
miRNA
Sex differences
Testosterone
title_short Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
title_full Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
title_fullStr Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
title_full_unstemmed Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
title_sort Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
dc.creator.none.fl_str_mv Zheng, HL
Mizokami, A
Romera-Giner, S
Llera-Oyola, J
Yamawaki, Y
Sano, T
Jimi, E
García-García, F
Kanematsu, T
author Zheng, HL
author_facet Zheng, HL
Mizokami, A
Romera-Giner, S
Llera-Oyola, J
Yamawaki, Y
Sano, T
Jimi, E
García-García, F
Kanematsu, T
author_role author
author2 Mizokami, A
Romera-Giner, S
Llera-Oyola, J
Yamawaki, Y
Sano, T
Jimi, E
García-García, F
Kanematsu, T
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Fatty acid synthesis
Inflammation
Microglia
miRNA
Sex differences
Testosterone
topic Fatty acid synthesis
Inflammation
Microglia
miRNA
Sex differences
Testosterone
description BackgroundSignificant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.MethodsMicroglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.ResultsSex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-kappa B/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.ConclusionsThese findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4507
url https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4507
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv Biology of Sex Differences
ISSN: 20426410
reponame:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
instname:Centro de Investigación Principe Felipe (CIPF)
instname_str Centro de Investigación Principe Felipe (CIPF)
reponame_str r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
collection r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
repository.name.fl_str_mv
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