Summary
The 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 glycaemic 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 pathways. 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 via the targeting of FFA2 to very early endosomes. Furthermore, propionate activates an endosomal Gαi/p38 signaling pathway, which is essential for propionate-induced GLP-1 release in enteroendocrine cells and colonic crypts. Our study reveals that intestinal metabolites can engage membrane trafficking pathways and endosomal signaling platforms to orchestrate complex GPCR pathways within the gut.
ABBREVIATIONS
- APPL1
- adaptor protein containing
- PH domain
- PTB domain and leucine zipper motif;
- B2AR
- β2-adrenergic receptor;
- Cmp1
- compound 1;
- DMEM
- Dulbecco’s modified eagles medium;
- EE
- early endosome;
- EEA1
- early endosome antigen 1;
- FFA2
- free fatty acid receptor 2;
- FFA3
- free fatty acid receptor 3;
- GAPDH
- glyceraldehyde 3-phosphate dehydrogenase;
- GPCR
- G protein-coupled receptor;
- LHR
- luteinizing hormone receptor;
- Ptx
- pertussis toxin;
- RIA
- radio-immunoassay;
- SEP
- super ecliptic pHluorin;
- SCFA
- short chain fatty acid;
- TIRFM
- total internal reflection fluorescent microscopy;
- VEE
- very early endosome.