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Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels

Author

Listed:
  • Shuai Yan

    (Beth Israel Deaconess Medical Center
    Harvard Medical School)

  • Anna Santoro

    (Beth Israel Deaconess Medical Center
    Harvard Medical School)

  • Micah J. Niphakis

    (Lundbeck La Jolla Research Center Inc.)

  • Antonio M. Pinto

    (The Salk Institute for Biological Studies)

  • Christopher L. Jacobs

    (Beth Israel Deaconess Medical Center
    Harvard Medical School)

  • Rasheed Ahmad

    (Dasman Diabetes Institute)

  • Radu M. Suciu

    (Lundbeck La Jolla Research Center Inc.)

  • Bryan R. Fonslow

    (Lundbeck La Jolla Research Center Inc.)

  • Rachel A. Herbst-Graham

    (Lundbeck La Jolla Research Center Inc.)

  • Nhi Ngo

    (Lundbeck La Jolla Research Center Inc.)

  • Cassandra L. Henry

    (Lundbeck La Jolla Research Center Inc.)

  • Dylan M. Herbst

    (Lundbeck La Jolla Research Center Inc.)

  • Alan Saghatelian

    (The Salk Institute for Biological Studies)

  • Barbara B. Kahn

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

  • Evan D. Rosen

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

Abstract

Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.

Suggested Citation

  • Shuai Yan & Anna Santoro & Micah J. Niphakis & Antonio M. Pinto & Christopher L. Jacobs & Rasheed Ahmad & Radu M. Suciu & Bryan R. Fonslow & Rachel A. Herbst-Graham & Nhi Ngo & Cassandra L. Henry & Dy, 2024. "Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48220-5
    DOI: 10.1038/s41467-024-48220-5
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    References listed on IDEAS

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