| Literature DB >> 30992568 |
Daniele Bolognini1, Natasja Barki1, Adrian J Butcher2, Brian D Hudson1, Eugenia Sergeev1, Colin Molloy1, Catherine E Moss1, Sophie J Bradley1, Christian Le Gouill3, Michel Bouvier3, Andrew B Tobin4, Graeme Milligan5.
Abstract
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.Entities:
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Year: 2019 PMID： 30992568 DOI： 10.1038/s41589-019-0270-1
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040