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<p>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 <i>Gcg</i> 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.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月21日

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  • Chae-Won Kim,
  • Jae-Hee Ahn,
  • Bo Ra Lee,
  • Hong Min Kim,
  • Youngjoo Han,
  • Jae-Hyeon Jeong,
  • Jaewon Cho,
  • Hyunjin Jeong,
  • Dae-Joon Kim,
  • Seong-Eun Kim,
  • Jeon-Kyung Kim,
  • Yu-Bin Lee,
  • Su Min Kim,
  • Hye Hyun Yoo,
  • Eun Hye Lee,
  • Su Ryeon Seo,
  • Kyung Bong Ha,
  • Eun Soo Lee,
  • Mi-Na Kweon,
  • Hong Pyo Kim,
  • Sun-Young Chang,
  • Choon Hee Chung,
  • Hyun-Jeong Ko

摘要

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.