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Chemogenetics defines receptor-mediated functions of short chain free fatty acids
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Journal Article
Chemogenetics defines receptor-mediated functions of short chain free fatty acids
2019
Overview
Differentiating actions of short chain fatty acids (SCFAs) at free fatty acid receptor 2 (FFA2) from other free fatty acid-responsive receptors and from non-receptor-mediated effects has been challenging. Using a novel chemogenetic and knock-in strategy, whereby an engineered variant of FFA2 (FFA2-DREADD) that is unresponsive to natural SCFAs but is instead activated by sorbic acid replaced the wild-type receptor, we determined that activation of FFA2 in differentiated adipocytes and colonic crypt enteroendocrine cells of mouse accounts fully for SCFA-regulated lipolysis and release of the incretin glucagon-like peptide-1 (GLP-1), respectively. In vivo studies confirmed the specific role of FFA2 in GLP-1 release and also demonstrated a direct role for FFA2 in accelerating gut transit. Thereby, we establish the general principle that such a chemogenetic knock-in strategy can successfully define novel G-protein-coupled receptor (GPCR) biology and provide both target validation and establish therapeutic potential of a ‘hard to target’ GPCR.
A chemogenomic approach to explore activity of the free fatty acid receptor FFA2 independently of the related FFA3 shows that FFA2 in differentiated adipocytes and colonic crypt cells in mice is responsible for regulated lipolysis and GLP-1 release.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 631/80
/ Animals
/ Chains
/ Chemistry and Materials Science
/ Crypts
/ Fatty Acids, Volatile - metabolism
/ Glucagon
/ Humans
/ Mice
/ Proteins
/ Receptors, Cell Surface - chemistry
/ Receptors, Cell Surface - genetics
/ Receptors, Cell Surface - metabolism
/ Receptors, G-Protein-Coupled - genetics
