2293-PUB: Epigenomic Analysis of AgRP Neurons Reveals That Leptin Induces Satiety via IRF3

AgRP neurons in the arcuate nucleus (ARC) of the hypothalamus play a dominant role in maintaining energy balance and are dysregulated in obesity, but prior studies examining their transcriptional regulation have been confounded by the rich cellular diversity of the ARC and the low abundance of these neurons. We have employed AgRP neuron-specific Translating Ribosomal Affinity Purification followed by RNA-sequencing (TRAP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to determine the transcriptomic and epigenomic landscape of these neurons during the fed, fasted and leptin-treated states. These rich datasets were computationally integrated to identify candidate transcription factors (TFs) potentially mediating the homeostatic control of food intake, of which the Interferon Regulatory Factor (IRF) family of TFs were enriched during the leptin-treated state. Cell-type specific functional studies have revealed that IRF3 plays a key role in mediating the satiety-inducing effects of leptin. Thus, we have identified a novel role for AgRP-neuron expressed IRF3 in regulating the satiety-evoking effects of leptin.