| First Author | Forbes S | Year | 2015 |
| Journal | Diabetes | Volume | 64 |
| Issue | 11 | Pages | 3763-71 |
| PubMed ID | 26239054 | Mgi Jnum | J:249446 |
| Mgi Id | MGI:5922393 | Doi | 10.2337/db15-0481 |
| Citation | Forbes S, et al. (2015) Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models. Diabetes 64(11):3763-71 |
| abstractText | 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. |
