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

Author

Listed:
  • Frankie D. Heyward

    (Beth Israel Deaconess Medical Center
    Broad Institute of MIT and Harvard
    Harvard Medical School
    UT Southwestern Medical Center)

  • Nan Liu

    (Dana-Farber Cancer Institute and Boston Children’s Hospital
    Zhejiang University School of Medicine
    Zhejiang University)

  • Christopher Jacobs

    (Beth Israel Deaconess Medical Center
    Broad Institute of MIT and Harvard)

  • Natalia L. S. Machado

    (Harvard Medical School
    Beth Israel Deaconess Medical Center)

  • Rachael Ivison

    (Beth Israel Deaconess Medical Center
    Broad Institute of MIT and Harvard)

  • Aykut Uner

    (Beth Israel Deaconess Medical Center
    Harvard Medical School
    UT Southwestern Medical Center)

  • Harini Srinivasan

    (Beth Israel Deaconess Medical Center
    Broad Institute of MIT and Harvard)

  • Suraj J. Patel

    (Beth Israel Deaconess Medical Center
    UT Southwestern Medical Center
    UT Southwestern Medical, Center)

  • Anton Gulko

    (Beth Israel Deaconess Medical Center)

  • Tyler Sermersheim

    (Beth Israel Deaconess Medical Center)

  • Linus Tsai

    (Beth Israel Deaconess Medical Center
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Evan D. Rosen

    (Beth Israel Deaconess Medical Center
    Broad Institute of MIT and Harvard
    Harvard Medical School)

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.

Suggested Citation

  • 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 & Evan D. Ro, 2024. "AgRP neuron cis-regulatory analysis across hunger states reveals that IRF3 mediates leptin’s acute effects," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48885-y
    DOI: 10.1038/s41467-024-48885-y
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    References listed on IDEAS

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    1. Sarah H. Bates & Walter H. Stearns & Trevor A. Dundon & Markus Schubert & Annette W. K. Tso & Yongping Wang & Alexander S. Banks & Hugh J. Lavery & Asma K. Haq & Eleftheria Maratos-Flier & Benjamin G., 2003. "STAT3 signalling is required for leptin regulation of energy balance but not reproduction," Nature, Nature, vol. 421(6925), pages 856-859, February.
    2. Jie Xu & Christopher L. Bartolome & Cho Shing Low & Xinchi Yi & Cheng-Hao Chien & Peng Wang & Dong Kong, 2018. "Genetic identification of leptin neural circuits in energy and glucose homeostases," Nature, Nature, vol. 556(7702), pages 505-509, April.
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