AgRP neuron epigenomes across hunger states reveal novel transcriptional effectors of leptin

AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we I generated mouse AgRP neuron-specific transcriptomic and chromatin accessibility profiles during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of numerous putative hunger-promoting and hunger-suppressing transcriptional regulators in AgRP neurons, a number of which were predicted to be transcriptional effectors of leptin. Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. My gain- and loss-of-function experiments in vivo confirmed the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons, while my live-cell imaging in vitro experiment indicates that leptin can activate neuronal IRF3 in a cell autonomous manner. Finally, I employed CUT&RUN to uncover direct transcriptional targets of IRF3 in AgRP neurons in vivo. Thus, my findings identify AgRP neuron-expressed IRF3 as a key transcriptional effector of the hunger-suppressing effects of leptin.