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Interleukin (IL)\u221222 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\u2013fed 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\n                    <jats:italic>Gcg<\/jats:italic>\n                    promoter, indicating a direct role in GLP-1 induction. Butyrate supplementation increased IL-22 levels and enhanced GLP-1 production in an IL-22R\u2013dependent manner, suggesting that microbial metabolites contribute to IL-22\u2013mediated 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\u2013dependent 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\u2013GLP-1 signaling as a potential therapeutic axis for metabolic disorders.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-69734-0","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T11:04:51Z","timestamp":1771671891000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["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"],"prefix":"10.1038","volume":"17","author":[{"given":"Chae-Won","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hee","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo Ra","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0046-4449","authenticated-orcid":false,"given":"Hong Min","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngjoo","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hyeon","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaewon","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunjin","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae-Joon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Eun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6746-6364","authenticated-orcid":false,"given":"Jeon-Kyung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Bin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Min","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8282-852X","authenticated-orcid":false,"given":"Hye Hyun","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Hye","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Ryeon","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Bong","family":"Ha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Soo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2916-2524","authenticated-orcid":false,"given":"Mi-Na","family":"Kweon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong Pyo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7336-9245","authenticated-orcid":false,"given":"Sun-Young","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choon Hee","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3844-928X","authenticated-orcid":false,"given":"Hyun-Jeong","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,21]]},"reference":[{"key":"69734_CR1","doi-asserted-by":"publisher","first-page":"e1373208","DOI":"10.1080\/21688370.2017.1373208","volume":"5","author":"T Takiishi","year":"2017","unstructured":"Takiishi, T., Fenero, C. 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