Genetic deconstruction of the mechanisms promoting high-sugar diet induced obesity

Obesity and its associated metabolic syndrome have become a global epidemic in the past twenty years. Excessive dietary intake is the main driver for the current rise in obesity, referred to as diet-induced obesity (DIO). DIO has been associated with numerous co-morbidities and many genetic factors, however, the complicated molecular mechanisms underlying DIO are incompletely elucidated. The most widely-used, unbiased, high-throughput approach to study obesity is through Genome-Wide Association Studies (GWAS), which identify genetic variants or expression variants that are associated with measures of obesity in human populations. Nevertheless, GWAS do not provide a causal link between the associated variants identified and obesity. In the past two years, we have developed and optimized the DIO in vivo RNAi screen using the model animal Caenorhabditis elegans, to causally test the genetic factors involved in DIO in a high throughput manner. Using this method, we have screened 1535 metabolic genes under regular and high sugar diet conditions, followed by fat imaging and data analysis with the machine learning software CellProfiler and CellProfiler Analyst. We have identified >100 hits, or instances where the gene-knockdown was able to rescue the obesity phenotype. The target genes of these hits will be further validated through pathway-specific analysis or tissue specific experiments to elucidate the function of these genes in DIO. Moreover, the top genetic candidates will be characterized and validated as anti-obesity targets using mammalian systems with the goal of yielding potentially druggable targets for therapeutic agents to help prevent or treat obesity.