Genomic and epigenomic mapping of leptin-responsive neuronal populations involved in body weight regulation

Genome-wide association studies in obesity have identified a large number of non-coding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, few obesity-associated single-nucleotide polymorphisms have been functionally characterized. Leptin-responsive neurons in the hypothalamus are essential in controlling energy homoeostasis and body weight. Here, we combine fluorescence-activated cell sorting of leptin-responsive hypothalamic neuron nuclei with genomic and epigenomic approaches (RNA sequencing, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing) to generate a comprehensive map of leptin response-specific regulatory elements, several of which overlap obesity-associated genome-wide association study variants. We demonstrate the usefulness of our leptin response neuron regulome, by functionally characterizing an enhancer near Socs3, a leptin response-associated transcription factor. We envision our data to serve as a useful resource and a blueprint for functionally characterizing obesity-associated single-nucleotide polymorphisms in the hypothalamus.