This project aims to uncover the genes and genetic variants that control visceral (abdominal) fat, which is a major driver of obesity-related diseases like diabetes and cardiovascular disease. While many genes linked to obesity have already been found in humans, most of the genetic contributors remain unknown because their effects are small and hard to detect in human studies. To overcome this, the researchers use a highly diverse rat model (heterogeneous stock rats) that allows them to pinpoint genetic regions linked to fat distribution with much higher precision. They have already narrowed dozens of these regions to very small genomic intervals and successfully identified at least one causal gene affecting glucose and insulin levels. In this proposal, the team hypothesizes that these rats carry specific genes and DNA variants that directly influence adiposity-related traits.
They will combine gene expression analysis (RNA-seq), expression quantitative trait locus (eQTL) mapping, and network analysis to identify candidate genes whose expression changes drive fat-related traits. They will also analyze DNA sequence variation to pinpoint single genetic variants that may cause these effects. Finally, the most promising genes and variants will be experimentally tested using genome-editing tools (CRISPR/Cas9 or zinc-finger nucleases) to confirm their causal role. Overall, the work is expected to accelerate discovery of the genetic networks that regulate visceral fat and help lay the groundwork for improved prevention and treatment of obesity-related disease.