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

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 generate...

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Bibliographic Details
Published in:Nature communications 2024-02, Vol.15 (1), p.1597-18, Article 1597
Main Authors: Gaudino, Stephen J., Singh, Ankita, Huang, Huakang, Padiadpu, Jyothi, Jean-Pierre, Makheni, Kempen, Cody, Bahadur, Tej, Shiomitsu, Kiyoshi, Blumberg, Richard, Shroyer, Kenneth R., Beyaz, Semir, Shulzhenko, Natalia, Morgun, Andrey, Kumar, Pawan
Format: Article
Language:English
Subjects:
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Adipose tissue
Epithelium
Glucose
Glucose metabolism
High fat diet
Humanities and Social Sciences
Interleukin 22
Intestine
Lipid metabolism
Lipids
Liver
Macrophages
Metabolic disorders
multidisciplinary
Obesity
Science
Science (multidisciplinary)
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Summary: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. Interleukin (IL)-22 is critical in ameliorating obesity-induced metabolic disorders; however, it is unclear where IL-22 acts to mediate these outcomes. Here, the authors show in tissue-specific IL-22 receptor knockout mice a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating obesity-associated disorders.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-45568-6