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

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 (February 2024) Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders. Nature Communications, 15 (1). p. 1597. ISSN 2041-1723 (Public Dataset)

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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.

Item Type:	Paper
Subjects:	diseases & disorders organism description > animal diseases & disorders > inflammation organs, tissues, organelles, cell types and functions > organs types and functions > liver organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent
CSHL Authors:	Beyaz, Semir
Communities:	CSHL Cancer Center Shared Resources > Sequencing Technology & Analysis Service CSHL labs > Beyaz lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	21 February 2024
Date Deposited:	01 Mar 2024 13:33
Last Modified:	29 Apr 2024 17:44
PMCID:	PMC10881576
Related URLs:	Publisher
Dataset ID:	BioProject: PRJNA944165 SRA: PRJNA1055251 GEO: GSE67324
URI:	https://repository.cshl.edu/id/eprint/41449

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