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Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders

Author

Listed:
  • Stephen J. Gaudino

    (Stony Brook University)

  • Ankita Singh

    (Stony Brook University)

  • Huakang Huang

    (Stony Brook University)

  • Jyothi Padiadpu

    (Oregon State University)

  • Makheni Jean-Pierre

    (Stony Brook University)

  • Cody Kempen

    (Stony Brook University)

  • Tej Bahadur

    (Stony Brook University)

  • Kiyoshi Shiomitsu

    (Stony Brook University)

  • Richard Blumberg

    (Harvard Medical School)

  • Kenneth R. Shroyer

    (Stony Brook University)

  • Semir Beyaz

    (Cold Spring Harbor Laboratory)

  • Natalia Shulzhenko

    (Oregon State University)

  • Andrey Morgun

    (Oregon State University)

  • Pawan Kumar

    (Stony Brook University)

Abstract

IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.

Suggested Citation

  • Stephen J. Gaudino & Ankita Singh & Huakang Huang & Jyothi Padiadpu & Makheni Jean-Pierre & Cody Kempen & Tej Bahadur & Kiyoshi Shiomitsu & Richard Blumberg & Kenneth R. Shroyer & Semir Beyaz & Natali, 2024. "Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45568-6
    DOI: 10.1038/s41467-024-45568-6
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    References listed on IDEAS

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