Bolognini, D. et al. (2019) Chemogenetics defines receptor-mediated functions of short chain free fatty acids. Nature Chemical Biology, 15(5), pp. 489-498. (doi: 10.1038/s41589-019-0270-1) (PMID:30992568)
|
Text
183723.pdf - Accepted Version 419kB | |
|
Text
183723Suppl.pdf - Supplemental Material 8MB |
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.
Item Type: | Articles |
---|---|
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Bolognini, Dr Daniele and Moss, Catherine and Molloy, Mr Colin and Bradley, Dr Sophie and Hudson, Dr Brian and Sergeev, Miss Eugenia and Milligan, Professor Graeme and Tobin, Andrew and Barki, Ms Natasja |
Authors: | Bolognini, D., Barki, N., Butcher, A. J., Hudson, B. D., Sergeev, E., Molloy, C., Moss, C. E., Bradley, S. J., Le Gouill, C., Bouvier, M., Tobin, A. B., and Milligan, G. |
College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Medical Veterinary and Life Sciences > School of Life Sciences |
Journal Name: | Nature Chemical Biology |
Publisher: | Nature Research |
ISSN: | 1552-4450 |
ISSN (Online): | 1552-4469 |
Published Online: | 15 April 2019 |
Copyright Holders: | Copyright © 2019 The Authors |
First Published: | First published in Nature Chemical Biology 15(5): 489-498 |
Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
University Staff: Request a correction | Enlighten Editors: Update this record