Chemogenetics defines receptor-mediated functions of short chain free fatty acids

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)

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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:Milligan, Professor Graeme and Tobin, Andrew and Bolognini, Dr Daniele and Barki, Ms Natasja and Molloy, Mr Colin and Moss, Catherine and Sergeev, Miss Eugenia and Hudson, Dr Brian and Bradley, Dr Sophie
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 > Institute of Molecular Cell and Systems Biology
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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
659371Designer Receptor Exclusively Activated by Designer Drug' to define the role of short chain fatty acids in metabolic disease and inflammation (Fatty acid DREADD)Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/L027887/1RI MOLECULAR CELL & SYSTEMS BIOLOGY
765471Using a Designer Receptor Exclusively Activated by Designer Drug to define the role of short chain fatty acids in metabolic disease and inflammationAndrew TobinBiotechnology and Biological Sciences Research Council (BBSRC)BB/L02781X/2RI MOLECULAR CELL & SYSTEMS BIOLOGY
750711MICA Pharmacological, molecular and cellular mechanisms of muscarinic slowing (modification) of neurodegenerative disease.Andrew TobinMedical Research Council (MRC)MR/P019366/1RI MOLECULAR CELL & SYSTEMS BIOLOGY