title: Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models.
abstract: Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) when activated by short-chain fatty acids (SCFAs). Functionally GLP-1 and PYY inhibit gut transit, increase glucose tolerance, and suppress appetite; thus, FFA2 has therapeutic potential for type 2 diabetes and obesity. However, FFA2-selective agonists have not been characterized in vivo. Compound 1 (Cpd 1), a potent FFA2 agonist, was tested for its activity on the following: GLP-1 release, modulation of intestinal mucosal ion transport and transit in wild-type (WT) and FFA2(-/-) tissue, and food intake and glucose tolerance in lean and diet-induced obese (DIO) mice. Cpd 1 stimulated GLP-1 secretion in vivo, but this effect was only detected with dipeptidyl peptidase IV inhibition, while mucosal responses were PYY, not GLP-1, mediated. Gut transit was faster in FFA2(-/-) mice, while Cpd 1 slowed WT transit and reduced food intake and body weight in DIO mice. Cpd 1 decreased glucose tolerance and suppressed plasma insulin in lean and DIO mice, despite FFA2(-/-) mice displaying impaired glucose tolerance. These results suggest that FFA2 inhibits intestinal functions and suppresses food intake via PYY pathways, with limited GLP-1 contribution. Thus, FFA2 may be an effective therapeutic target for obesity but not for type 2 diabetes.
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College London, London, U.K.
authors.forename: Sarah
authors.initials: S
authors.lastname: Forbes
authors.affiliation: Takeda Cambridge Ltd, Cambridge, U.K. stuart.stafford@takeda.com helen.cox@kcl.ac.uk.
authors.forename: Stuart
authors.initials: S
authors.lastname: Stafford
authors.affiliation: Takeda Cambridge Ltd, Cambridge, U.K.
authors.forename: Gareth
authors.initials: G
authors.lastname: Coope
authors.affiliation: Takeda Cambridge Ltd, Cambridge, U.K.
authors.forename: Helen
authors.initials: H
authors.lastname: Heffron
authors.affiliation: Takeda Cambridge Ltd, Cambridge, U.K.
authors.forename: Katia
authors.initials: K
authors.lastname: Real
authors.affiliation: Takeda Cambridge Ltd, Cambridge, U.K.
authors.forename: Robert
authors.initials: R
authors.lastname: Newman
authors.affiliation: Takeda Cambridge Ltd, Cambridge, U.K.
authors.forename: Richard
authors.initials: R
authors.lastname: Davenport
authors.affiliation: Takeda Cambridge Ltd, Cambridge, U.K.
authors.forename: Matt
authors.initials: M
authors.lastname: Barnes
authors.affiliation: Takeda Cambridge Ltd, Cambridge, U.K.
authors.forename: Johannes
authors.initials: J
authors.lastname: Grosse
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College London, London, U.K. stuart.stafford@takeda.com helen.cox@kcl.ac.uk.
authors.forename: Helen
authors.initials: H
authors.lastname: Cox
mesh_terms: D000818:Animals; D001066:Appetite / Q000187:drug effects; D002478:Cells, Cultured; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D005772:Gastrointestinal Transit / Q000187:drug effects* / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D019894:Peptide YY / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000819:agonists*; D043562:Receptors, G-Protein-Coupled
chemical_list: D052216:Glucagon-Like Peptide 1; D019894:Peptide YY; D011956:Receptors, Cell Surface; C506481:Ffar2 protein, mouse; D043562:Receptors, G-Protein-Coupled