Hyperglycemic microenvironment compromises the homeostasis of communication between the bone-brain axis by the epigenetic repression of the osteocalcin receptor, Gpr158 in the hippocampus

dc.contributor.authorPatricia da Silva, Ericka
dc.contributor.authorda Silva Feltran, Geórgia [UNESP]
dc.contributor.authorAlexandre Alcântara dos Santos, Sérgio [UNESP]
dc.contributor.authorCardoso de Oliveira, Rodrigo
dc.contributor.authorAssis, Rahyza I.F.
dc.contributor.authorAntônio Justulin Junior, Luis [UNESP]
dc.contributor.authorCarleto Andia, Denise
dc.contributor.authorZambuzzi, Willian F. [UNESP]
dc.contributor.authorLatini, Alexandra
dc.contributor.authorFoganholi da Silva, Rodrigo A.
dc.contributor.institutionPaulista University – UNIP
dc.contributor.institutionUniversity of Taubaté – UNITAU
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionFederal University of Espírito Santo
dc.contributor.institutionUniversidade Federal de Santa Catarina (UFSC)
dc.date.accessioned2023-07-29T14:00:31Z
dc.date.available2023-07-29T14:00:31Z
dc.date.issued2023-03-15
dc.description.abstractDiabetes mellitus (DM) is a chronic metabolic disease, mainly characterized by increased blood glucose and insulin dysfunction. In response to the persistent systemic hyperglycemic state, numerous metabolic and physiological complications have already been well characterized. However, its relationship to bone fragility, cognitive deficits and increased risk of dementia still needs to be better understood. The impact of chronic hyperglycemia on bone physiology and architecture was assessed in a model of chronic hyperglycemia induced by a single intraperitoneal administration of streptozotocin (STZ; 55 mg/kg) in Wistar rats. In addition, the bone-to-brain communication was investigated by analyzing the gene expression and methylation status of genes that encode the main osteokines released by the bone [Fgf23 (fibroblast growth factor 23), Bglap (bone gamma-carboxyglutamate protein) and Lcn2 (lipocalin 2) and their receptors in both, the bone and the brain [Fgfr1 (fibroblast growth factor receptor 1), Gpr6A (G-protein coupled receptor family C group 6 member A), Gpr158 (G protein-coupled receptor 158) and Slc22a17 (Solute carrier family 22 member 17)]. It was observed that chronic hyperglycemia negatively impacted on bone biology and compromised the balance of the bone-brain endocrine axis. Ultrastructural disorganization was accompanied by global DNA hypomethylation and changes in gene expression of DNA-modifying enzymes that were accompanied by changes in the methylation status of the osteokine promoter region Bglap and Lcn2 (lipocalin 2) in the femur. Additionally, the chronic hyperglycemic state was accompanied by modulation of gene expression of the osteokines Fgf23 (fibroblast growth factor 23), Bglap (bone gamma-carboxyglutamate protein) and Lcn2 (lipocalin 2) in the different brain regions. However, transcriptional regulation mediated by DNA methylation was observed only for the osteokine receptors, Fgfr1(fibroblast growth factor receptor 1) in the striatum and Gpr158 (G protein-coupled receptor 158) in the hippocampus. This is a pioneer study demonstrating that the chronic hyperglycemic state compromises the crosstalk between bone tissue and the brain, mainly affecting the hippocampus, through transcriptional silencing of the Bglap receptor by hypermethylation of Gpr158 gene.en
dc.description.affiliationCEEpiRG Program in Environmental and Experimental Pathology Paulista University – UNIP, São Paulo
dc.description.affiliationDepartment of Dentistry University of Taubaté – UNITAU, São Paulo
dc.description.affiliationLaboratory of Bioassays and Cellular Dynamics Department of Chemical and Biological Sciences Institute of Biosciences São Paulo State University – UNESP, São Paulo
dc.description.affiliationSchool of Dentistry Health Science Institute Paulista University – UNIP, São Paulo
dc.description.affiliationDepartment of Biological Sciences Bauru School of Dentistry University of São Paulo –FOB, São Paulo
dc.description.affiliationDepartment of Clinical Dentistry Federal University of Espírito Santo, ES
dc.description.affiliationLABOX Department of Biochemistry Center for Biological Sciences Federal University of Santa Catarina – UFSC
dc.description.affiliationDepartment of Structural and Functional Biology Institute of Biosciences São Paulo State University – UNESP, São Paulo
dc.description.affiliationUnespLaboratory of Bioassays and Cellular Dynamics Department of Chemical and Biological Sciences Institute of Biosciences São Paulo State University – UNESP, São Paulo
dc.description.affiliationUnespDepartment of Structural and Functional Biology Institute of Biosciences São Paulo State University – UNESP, São Paulo
dc.identifierhttp://dx.doi.org/10.1016/j.brainres.2023.148234
dc.identifier.citationBrain Research, v. 1803.
dc.identifier.doi10.1016/j.brainres.2023.148234
dc.identifier.issn1872-6240
dc.identifier.issn0006-8993
dc.identifier.scopus2-s2.0-85146094181
dc.identifier.urihttp://hdl.handle.net/11449/249029
dc.language.isoeng
dc.relation.ispartofBrain Research
dc.sourceScopus
dc.subjectBone-brain axis
dc.subjectCognitive deficit
dc.subjectFGF23
dc.subjectLipocalin 2
dc.subjectOsteocalcin
dc.titleHyperglycemic microenvironment compromises the homeostasis of communication between the bone-brain axis by the epigenetic repression of the osteocalcin receptor, Gpr158 in the hippocampusen
dc.typeArtigo
unesp.departmentCiências Biológicas - FCpt

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