摘要：SummaryThe ability of propionate, a short-chain fatty acid produced from the fermentation of non-digestible carbohydrates in the colon, to stimulate the release of anorectic gut hormones, such as glucagon like peptide-1 (GLP-1), is an attractive approach to enhance appetite regulation, weight management, and glycemic control. Propionate induces GLP-1 release via its G protein-coupled receptor (GPCR), free fatty acid receptor 2 (FFA2), a GPCR that activates Gαi and Gαq/11. However, how pleiotropic GPCR signaling mechanisms in the gut regulates appetite is poorly understood. Here, we identify propionate-mediated G protein signaling is spatially directed within the cell whereby FFA2 is targeted to very early endosomes. Furthermore, propionate activates a Gαi/p38 signaling pathway, which requires receptor internalization and is essential for propionate-induced GLP-1 release in enteroendocrine cells and colonic crypts. Our study reveals that intestinal metabolites engage membrane trafficking pathways and that receptor internalization could orchestrate complex GPCR pathways within the gut.Graphical AbstractDisplay OmittedHighlights•Propionate activates Gαi/o but no Gαq/11 signaling in STC-1 cells or colonic crypts•Acute Gαi/o signaling via FFA2 requires endocytosis and mediates GLP-1 release•FFA2 traffics to very early endosomes to control rapid recycling and Gαi/o signals•Propionate-induced internalization of FFA2 drives p38 signaling and GLP-1 releaseCell Biology; Functional Aspects of Cell Biology
