AgRP neuron cis-regulatory analysis across hunger states reveals that IRF3 mediates leptin’s acute effects

Frankie D. Heyward (), Nan Liu, Christopher Jacobs, Natalia L. S. Machado, Rachael Ivison, Aykut Uner, Harini Srinivasan, Suraj J. Patel, Anton Gulko, Tyler Sermersheim, Linus Tsai and Evan D. Rosen ()
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Frankie D. Heyward: Beth Israel Deaconess Medical Center
Nan Liu: Dana-Farber Cancer Institute and Boston Children’s Hospital
Christopher Jacobs: Beth Israel Deaconess Medical Center
Natalia L. S. Machado: Harvard Medical School
Rachael Ivison: Beth Israel Deaconess Medical Center
Aykut Uner: Beth Israel Deaconess Medical Center
Harini Srinivasan: Beth Israel Deaconess Medical Center
Suraj J. Patel: Beth Israel Deaconess Medical Center
Anton Gulko: Beth Israel Deaconess Medical Center
Tyler Sermersheim: Beth Israel Deaconess Medical Center
Linus Tsai: Beth Israel Deaconess Medical Center
Evan D. Rosen: Beth Israel Deaconess Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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 generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles from male mice 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 18 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Measures of IRF3 activation in vitro and in vivo reveal an increase in IRF3 nuclear occupancy following leptin administration. Finally, gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons. Thus, our findings identify IRF3 as a key mediator of the acute hunger-suppressing effects of leptin in AgRP neurons.

Date: 2024
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DOI: 10.1038/s41467-024-48885-y

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