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

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.

SUBMITTER: Gaudino SJ

PROVIDER: S-EPMC10881576 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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

Gaudino Stephen J SJ Singh Ankita A Huang Huakang H Padiadpu Jyothi J Jean-Pierre Makheni M Kempen Cody C Bahadur Tej T Shiomitsu Kiyoshi K Blumberg Richard R Shroyer Kenneth R KR Beyaz Semir S Shulzhenko Natalia N Morgun Andrey A Kumar Pawan P

Nature communications 20240221 1

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 systemi ...[more]

PMID: 38383607

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Dataset Information

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

Publications

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

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