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Selective FFA2 agonism appears to act via intestinal PYY to reduce transit and food intake but does not improve glucose tolerance in mouse models

journal contribution
posted on 2022-10-31, 03:34 authored by S Forbes, S Stafford, G Coope, H Heffron, K Real, R Newman, R Davenport, M Barnes, J Grosse, Helen CoxHelen Cox
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.

History

Journal

Diabetes

Volume

64

Pagination

3763-3771

Location

United States

ISSN

0012-1797

eISSN

1939-327X

Language

en

Publication classification

C1.1 Refereed article in a scholarly journal

Issue

11

Publisher

American Diabetes Association

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