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bioRxiv · 10.1101/2020.03.24.004762

Endosomal free fatty acid receptor 2 signaling is essential for propionate-induced anorectic gut hormone release

Caengprasath, N.·Gonzalez-Abuin, N.·Shchepinova, M.·Ma, Y.·Inoue, A.·Tate, E. W.·Frost, G.·Hanyaloglu, A.
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Abstract

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 Gi and Gq/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 Gi/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.

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Caengprasath, N., Gonzalez-Abuin, N., Shchepinova, M., Ma, Y., Inoue, A., Tate, E. W., Frost, G., Hanyaloglu, A.. 2020-03-25. Endosomal free fatty acid receptor 2 signaling is essential for propionate-induced anorectic gut hormone release. https://doi.org/10.1101/2020.03.24.004762

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