Analysis of hippocampal miRNA expression changes and the effect of metformin treatment in diet-induced obese mice after 18 weeks

Obesity, a worldwide chronic disease, is associated with a higher risk of developing type 2 diabetes and dementia ([1] [2]). Type 2 diabetes, which is characterized by chronic hyperglycemia, results from insufficient insulin production due to peripheral and central insulin resistance. Central insulin resistance itself is associated with dementia as it causes hippocampal brain atrophy ([3]). Interestingly, metformin, the first-line antihyperglycemic drug for type 2 diabetes, has shown neuroprotective effects and reduces the risk of developing dementia ([4]). The connection between insulin resistance and dementia is poorly understood. Epigenetic mechanisms such as microRNAs (miRNAs) might explain the connection by targeting pathways involved in both pathologies. We hypothesize that obesity induced central insulin resistance could affect the miRNA expression in the hippocampus, leading to a dysregulation of pathways involved in both insulin signaling and cognitive functions. This could be reversed by metformin treatment.

Male C57BL/6N mice were fed a normal chow or high-fat diet (HFD) for 18 weeks, or a HFD for 18 weeks with six weeks of metformin treatment (n=10 per group). The expression of hippocampal miRNAs and predicted and validated target genes were quantified by RT-qPCR. The target gene selection was based on a self-written pipeline which includes an established target gene prediction tool and further pre-selection based on their involvement in metabolic and brain functions ([5]).

HFD feeding for 18 weeks led to significantly increased body weight and insulin resistance in mice. In addition, the expression of hippocampal miR-34a-5p, miR-223-3p and miR-487b-3p was significantly downregulated in HFD fed mice. The metformin treatment could improve the insulin resistance and reversed the miRNA expression without reducing the body weight. Differentially expressed miRNAs correlated with increasing insulin resistance and fasting glucose levels indicating their involvement in metabolic functions. The expression correlated with genes involved in insulin signaling and neuronal functions. However, no significant differences were observed in the direct mRNA target gene expression.

We demonstrated that hippocampal miRNAs are associated with whole-body insulin resistance which may influence brain functions and the development of dementia. Metformin reversed the changes in miRNA expression which might be a mechanism of its neuroprotective effect. We could not observe effects on mRNA level of our selected target genes, which is in line with the fact that miRNAs often only regulate the protein but not mRNA levels. In the future it is still needed to determine the critical timepoint at which obesity and insulin resistance begin to affect the brain function. In addition, the memory performance of mice fed a HFD needs to be analyzed and whether these results correlate with the expression of relevant miRNAs.

Publication History

Article published online:
28 May 2025

• Literatur

• 1 Abdullah A.. et al. ‘The magnitude of association between overweight and obesity and the risk of diabetes: A meta-analysis of prospective cohort studies’. Diabetes Research and Clinical Practice 2010; 89 pp 309-319
• 2 Pedditizi E., Peters R., Beckett N.. ‘The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies’. Age and Ageing 2016; 45 pp 14-21
• 3 Talbot K.. et al. ‘Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline’. The Journal of Clinical Investigation 2012; 122 pp 1316-1338
• 4 Campbell J.M.. et al. ‘Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis’. Journal of Alzheimer’s Disease 2018; 65 pp 1225-1236
• 5 Krause C.. et al. ‘Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity’, eLife. Edited by M.A. Mori and P.K. Mistry. 2024. 12. p RP92075