Abstract
Metabolic disorders such as obesity and diabetes are influenced by glucagon-like peptide-1 (GLP-1), which regulates insulin secretion. Interleukin (IL)−22 maintains intestinal barrier function, yet its role in metabolic regulation remains unclear. Here, we show that intestinal IL-22 deficiency reduces GLP-1 production and impairs glucose tolerance in high-fat diet–fed male mice, whereas long-term IL-22 administration restores GLP-1 levels, improves glucose tolerance, and normalizes insulin secretion and pancreatic islet size. IL-22 activates STAT3 binding to the Gcg promoter, indicating a direct role in GLP-1 induction. Butyrate supplementation increased IL-22 levels and enhanced GLP-1 production in an IL-22R–dependent manner, suggesting that microbial metabolites contribute to IL-22–mediated metabolic regulation. Direct IL-22 administration elevated circulating GLP-1 and improved glucose intolerance, while GLP-1 agonist treatment rescued metabolic defects associated with reduced IL-22 signaling. Conversely, the GLP-1 receptor antagonist exendin-9-39 abolished the glucose-lowering effects of IL-22, demonstrating that IL-22 acts primarily through GLP-1–dependent pathways. These findings identify IL-22 as an important regulator of intestinal GLP-1 production and glucose homeostasis during diet-induced obesity and highlight IL-22–GLP-1 signaling as a potential therapeutic axis for metabolic disorders.
Data availability
The RNA sequencing datasets analyzed in this study are publicly available in the Gene Expression Omnibus (GEO) under the accession codes GSE165512 (unpublished), GSE13283153, and GSE12597054. The generated sequencing data have been deposited in the NCBI Sequence Read Archive (SRA) under accession number PRJNA1392864. All other data supporting the findings of this study are available within the paper and its Supplementary Information. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) of Korea (Grant No. NRF-2020R1A5A8019180, RS-2024-00345147). We would like to thank Editage (www.editage.co.kr) for English language editing. Flow cytometry(Instrument No. NFEC-2022-09-281363) was performed at the Core-Facility for Innovative Cancer Drug Discovery (CFICDD) at Kangwon National University.
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C.-W.K. contributed to investigation, data curation, formal analysis, visualization, and wrote the original draft. J.-H.A. contributed to investigation, methodology, formal analysis, writing of the original draft, and review and editing. B.R.L. and H.M.K. conceptualized the study. Y.H. was responsible for investigation, validation, and resources. S.-E.K., H.J., J.-H.J., D.-J.K., Y.-B.L., S.M.K., H.H.Y., E.H.L., S.R.S., K.B.H., and E.S.L. conducted investigation. J.C. and J.-K.K. contributed to data curation. H.P.K. and M.-N.K. contributed to writing—review and editing. S.-Y.C. contributed to data curation, formal analysis, visualization, and writing—review and editing. C.H.C. was responsible for conceptualization and writing—review and editing. H.-J.K. supervised the study, acquired funding, conceptualized the study, and contributed to writing—review and editing.
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Kim, CW., Ahn, JH., Lee, B.R. et al. Intestinal interleukin-22 enhances GLP-1 production via the STAT3 pathway to improve glucose homeostasis during high-fat diet induced obesity in a study with male mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69734-0
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DOI: https://doi.org/10.1038/s41467-026-69734-0
