Obesity affects half of United States adults and represents an estimated 77 billion USD market in the next decade. Therapeutic progress with gut peptides has highlighted the potential for successful treatment of obesity. However, additional therapeutic targets and strategies are needed to effectively address the obesity phenotype. We identified reduced brain dopamine system responsiveness in subjects with obesity. Concurrent studies in animal models demonstrate that VDR ligands can increase dopamine and reduce body weight in multiple models of obesity. We propose to identify novel brain-specific VDR ligands variants for treatment of obesity.