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.
