A link between obesity and dementia - Development of behavioral and cognitive deficits caused by central insulin resistance

In recent years, the global prevalence of obesity and associated metabolic comorbidities like insulin resistance and type 2 diabetes is drastically increasing. This occurrence is moreover accompanied by an increase in cognitive deficits such as Alzheimer’s disease (AD). Although longitudinal studies in obese human subjects identified an increased risk to develop AD, the molecular mechanisms connecting both, dementia and obesity-induced central insulin resistance, are poorly understood. Consequently, the therapeutic potential to treat both diseases are incompletely exploited. Interestingly, AD and central insulin resistance were shown to affect similar molecular pathways. Recently, I identified different epigenetic mechanisms as regulators of hepatic lipid and glucose metabolism in the manifestation of type 2 diabetes. Therefore, I hypothesize epigenetics are also altered in obesity-induced central insulin resistance and that these mechanisms are simultaneously affecting neurological pathways. This assumption is furthermore supported by recent findings of differentially expressed hippocampal microRNAs in memory formation of mice. To test my hypothesis, I isolated RNA from the hippocampus of lean control and obese insulin resistant mice. I identified the overexpression of two microRNAs, which correlated significantly with a reduced expression of three target genes, which are either involved in fatty acid synthesis or reduced uptake of neurotransmitters. In my proposed project, I aim to analyze the time course and molecular cause of dysregulated hippocampal microRNAs in obesity, as well the influence of these microRNAs on cognitive functions in a mouse model. Moreover, novel target genes should be identified in the hippocampus and evaluated in a region-specific resolution. Finally, I aim to translate these findings into a clinical application by measuring circulating microRNAs in human serum samples and evaluate their potential as biomarkers for the detection of obesity-induced hippocampal atrophy which is associated to central insulin resistance and cognitive deficits. The identification of a molecular connection between obesity and dementia, as well as the identification of potentially predictive biomarkers to identify early malfunctions of pathways, is of high clinical relevance concerning the globally increased prevalence of metabolic and mental diseases. Thus, the here proposed project lays the foundation for a deeper insight of the conjunction between both diseases and to reveal novel therapeutic approaches to prevent disease manifestation.