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.

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.