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

TL;DR

This study shows that interleukin-22 in the intestines helps control blood sugar by boosting GLP-1 production in mice on high-fat diets.

Contribution

The study reveals a new role for IL-22 in regulating GLP-1 and glucose homeostasis via the STAT3 pathway in obesity.

Findings

IL-22 deficiency in mice reduces GLP-1 and worsens glucose tolerance on high-fat diets.

IL-22 activates STAT3 to directly increase GLP-1 production in the gut.

Butyrate boosts IL-22 and GLP-1 in an IL-22R-dependent manner, linking gut microbes to metabolic health.

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.

Here the authors report that intestinal interleukin-22 promotes GLP-1 production through STAT3 signaling in male mice. This mechanism improves glucose regulation in diet-induced obesity and provides insight into the role of IL-22–GLP-1 signaling in metabolic regulation.

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