Obesity leads to an increased risk for type 2 diabetes, heart attack, many types of cancer, hypertension, stroke, and is estimated to soon be the leading cause of death in the US. Through twin and family studies, obesity has been found to have a 40-70% heritability rate, pointing to a strong genetic etiology. The long-term objective of our studies is to determine how genetic variation predisposes humans to obesity and what the therapeutic implications are for this condition. To find common genetic variants associated with obesity, numerous genome-wide association studies (GWAS) have been performed. Over 500 loci have been found to associate with increased body weight index (BMI), all of which reside in noncoding regions of the genome . However, little progress has been made in outlining the causal SNPs and understanding the mechanisms by which they actually cause obesity. In this proposal, we explore the hypothesis that obesity-associated SNPs affect regulatory regions that are active in neuronal sub-population implicated in the regulation of food intake and body weight. Using state-of-the-art approaches that we have recently pioneered through collaborations between the Ahituv and Vaisse laboratories we propose to: - Extend and refine the regulatory landscape of hypothalamic neuronal subpopulations implicated in body weight regulation to identify candidate regulatory elements overlapping obesity GWAS single nucleotide polymorphisms (SNPs). - Use CRISPR inactivation (CRISPRi) in mice to directly test the functional role of regulatory elements that encompass obesity-associated SNPs. - Use CRISPR activation (CRISPRa) in mice to test the therapeutic potential of activity modulation of identified target regulatory regions. Combined, our work will not only provide a regulatory map of neuronal subtypes associated obesity, but also functionally characterize these regions and show their therapeutic potential.
Obesity is a major public health concern as it increases the risk for a number of common diseases such as type 2 diabetes, heart disease, stroke and certain forms of cancer. Obesity results from the interaction of the environment with a genetic predisposition and large-scale efforts have recently pointed at regions in the human genome in which genetic variations predispose humans to obesity. Our studies are aimed at determining how these genetic variations are involved in obesity and how this knowledge could be harvested for new obesity treatments.
