Leptin responsive neurons

Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, very few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we show that by combining FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic approaches (RNA-seq, ChIP-seq, ATAC-seq), we can provide a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. Further demonstrating the robustness of our leptin-response neuron regulome, we functionally characterize a novel enhancer near Socs3, a leptin response-associated transcription factor. Combined, our results provide a comprehensive map of active genomic regions in leptin-responsive neurons and present a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus. RNA-seq, ChIP-seq and ATAC of LepR sorted neurons, treated with and without Leptin.