Genome-wide association studies in obesity haveidentified a large number of non-coding loci located near genesexpressed in the central nervous system. However, due to thedifficulties in isolating and characterizing specific neuronalsubpopulations, few obesity-associated single-nucleotidepolymorphisms have been functionally characterized.Leptin-responsive neurons in the hypothalamus are essential incontrolling energy homoeostasis and body weight. Here, we combinefluorescence-activated cell sorting of leptin-responsivehypothalamic neuron nuclei with genomic and epigenomic approaches(RNA sequencing, chromatin immunoprecipitation sequencing, assay fortransposase-accessible chromatin sequencing) to generate acomprehensive map of leptin response-specific regulatory elements,several of which overlap obesity-associated genome-wide associationstudy variants. We demonstrate the usefulness of our leptin responseneuron regulome, by functionally characterizing an enhancer nearSocs3, a leptin response-associated transcription factor. Weenvision our data to serve as a useful resource and a blueprint forfunctionally characterizing obesity-associated single-nucleotidepolymorphisms in the hypothalamus.
Inoue et al. use genetic and epigenetic tools to mapactive gene regulatory elements in leptin-responsive neurons in themouse hypothalamus. These regulatory elements overlap with severalobesity-associated GWAS SNPs.