Hippocampal microRNA transcriptome changes in obese insulin resistant mice after 12 weeks of high-fat diet

Obesity and its comorbidities such as insulin resistance represent global health threats. Central insulin resistance is associated with dementia and cognitive deficits. Since lifestyle plays a crucial role in disease etiology, we hypothesize that microRNAs as epigenetic mediators link obesity driven hippocampal insulin resistance to cognitive decline.

We analyzed the hippocampal microRNA transcriptome by microRNAseq in mice which were fed a high-fat diet (HFD) or chow diet for either 2 or 12 weeks and predicted potential target genes that are involved in insulin signaling and neurological pathways which are known to be affected in dementia.

Using miRDeep2 we identified 602 expressed microRNAs. 68 were significantly (q<0.15) altered after 12 weeks of HFD. By Spearman correlation we also identified eight microRNAs which were significantly (q<0.05) associated with fasting glucose and worsening of glucose tolerance. Some of these microRNAs such as miR-27a-3p were known regulators of genes involved in cognitive impairment and peripheral insulin resistance. Further pathway enrichment analysis of predicted target genes for miR-182-5p, which we previously identified as a link between lipid and glucose metabolism in obese liver ([1]), indicated a connection between both phenotypes. By using microRNA inference from public single cell data of hippocampal microglia ([2]) we observed a cell-type specific difference in activity for both microRNAs after 3 months of HFD. Also, a large proportion of dysregulated genes in microglia represent potential target genes of our identified microRNAs.

We identified candidate regulators which support our hypothesis that the two global health threats diabetes and dementia are linked by aberrant microRNA expression. Future work will include the validation of affected signaling pathways. Directed in vivo modulation of microRNAs and its effects on cognition need to be evaluated.

This work was supported by funding from the Section Medicine of the University of Lübeck (J07-2023) and Deutsche Forschungsgemeinschaft (KR 5753/2-1).

 

MissingLinkText

Interessenkonflikt

keine

• Literatur

• 1 Krause C, 1 Britsemmer JH, 1 Bernecker M, 1 Molenaar A, 1 Taege N, 1 Lopez-Alcantara N. 1 et al. Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity. eLife 2024; 12: RP92075
• 2 Henn RE, 1 Guo K, 1 Elzinga SE, 1 Noureldein MH, 1 Mendelson FE, 1 Hayes JM. 1 et al. Single-cell RNA sequencing identifies hippocampal microglial dysregulation in diet-induced obesity. iScience 2023; 26: 106164

Publication History

Article published online:
28 May 2025