While thousands of genome-wide association studies (GWAS) have now been published, a systematic validation of these efforts is lacking. Our aim in this study was to systematically test candidate conserved obesity genes (from the GIANT consortium) for a role in regulating metabolism in fruit flies. Meta-analysis of the GIANT body mass index data from 339,224 individuals has identified hundreds of single nucleotide polymorphisms (SNPs) of varying p-values (<10-7), which corresponded to ~300 Drosophila melanogaster orthologs. Pathway analysis of these SNPs has suggested a supportive role of central nervous system in energy homeostasis. We targeted each conserved candidate specifically in the fruit fly nervous system, and then evaluated body weight, food intake, triglyceride level and starvation survival. Assessment of this dataset has allowed us to identify many neuronal genes that cause or prevent obesity in vivo, the majority of which have previously not been functionally implicated in the regulation of metabolism. Functional validation of human BMI data has confirmed many novel GWAS candidates do act in the nervous system to regulate energy homeostasis, and these data inform our basic understanding of metabolic health and in some cases may be targeted as novel therapies for obesity.