DYSREGULATION OF LIPID HANDLING AND NEURONAL ACTIVITY-DEPENDENT GENES IN HIPPOCAMPUS OF PRECLINICAL MODELS OF DIABETES

Type 2 Diabetes and obesity are major risk factors for cognitive decline and dementia, associated with neuroinflammation, and driven by disrupted glucose and lipid homeostasis. Here, we used RNA sequencing to decipher early hippocampal transcriptomic alterations in a genetic model of severe diabetes and in a model of insulin resistance by diet-induced obesity (DIO), both also displaying altered cognition.
Male db/db mice aged 4-5 months were compared to their age-matched db/m controls; and six-week-old male C57BL/6J mice were fed either a normal chow diet or high-fat diet (HFD; 60% kcal from fat) for 27 weeks. Metabolic parameters were assessed, and RNA-seq of hippocampal tissue was performed.
In the db/db model, RNA-seq analysis identified 126 differentially expressed genes (DEGs; 63 upregulated, 63 downregulated), and the DIO model resulted in 19 DEGs (12 upregulated, 7 downregulated) (adjusted p<0.05, |log2 Fold change| ≥1.2). Notably, Plin4 was upregulated in both models, suggesting a convergent alteration in lipid handling. Conversely, Erg2 and Fos, genes associated with neuronal activity and plasticity, were downregulated in both models, indicating suppression of activity-dependent pathways in hippocampi of mice with systemic dysmetabolism.
These findings demonstrated that metabolic dysfunction induces hippocampal transcriptional changes. These are common to nutritional and genetic models of insulin resistance and diabetes, yet are more pronounced in the genetic case. Shared dysregulation of lipid-associated and neuronal activity-dependent genes suggest mechanisms that may initiate and potentially contribute to cognitive vulnerability associated with type 2 diabetes.