Aims: G protein-coupled receptors (GPCRs) in the intestinal enteroendocrine cells (EECs) regulate gut hormone secretion by responding to nutritional, microbial, and inflammatory factors, which contributes to the maintenance of glucose and energy homeostasis. We investigated the expression of GPR17, an orphan GPCR, in human and murine gastrointestinal tract and determined its metabolic roles using intestinal specific Gpr17 knockout mice.

Methods: Gpr17 expression was profiled by quantitative RT-PCR, immunohistochemistry and flow cytometry. To elucidate the metabolic function of intestinal Gpr17, we generated constitutive (Vil1Cre,Gpr17-/-) and inducible (Vil1Cre-ERT2,Gpr17-/-) intestine-specific Gpr17 knockout mice and analyzed their metabolic features, including glucose tolerance, indirection calorimetry, feeding and microbiome composition. We measured nutrient-stimulated incretin secretion in Gpr17 knockout mice and cultured intestinal organoids.

Results: We found that Gpr17 was enriched in Glucagon-like peptide 1 (GLP-1) expressing EECs in human and rodent intestine. Both constitutive and inducible Gpr17 intestinal knockout mice displayed improved glucose tolerance without alterations in pancreatic function and microbiota. In addition, Gpr17 intestinal knockout mice exhibited reduced foraging activity and less rebound hyperphagia in a fasting-refeeding paradigm. Notably, Gpr17 deficient mice and intestinal organoids responded to nutritional cues with enhanced GLP-1, but not GIP, secretion. Forskolin induced cAMP production was significantly inhibited by a synthetic Gpr17 agonist in GLUTag cells overexpressing Gpr17.

Conclusions: Our work suggests GPR17 signaling in the enteroendocrine cells fine-tunes GLP-1 secretion. Targeting intestinal GPR17 for appetite and glucose metabolism represents a potential therapeutic strategy for type 2 diabetes and obesity.


S. Yan: None. A. Reilly: None. J.M. Conley: None. H. Ren: None.


National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120772, R00DK098294); Indiana Diabetes Center (P30DK097512); Indiana Clinical and Translational Sciences Institute (UL1TR002529)

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