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. 2015 Nov;64(11):3763-71. doi: 10.2337/db15-0481. Epub 2015 Aug 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Appetite / drug effects
  • Cells, Cultured
  • Eating / drug effects*
  • Eating / physiology
  • Gastrointestinal Transit / drug effects*
  • Gastrointestinal Transit / physiology
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose Intolerance / metabolism*
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects*
  • Mice
  • Mice, Obese
  • Obesity / metabolism
  • Peptide YY / metabolism*
  • Receptors, Cell Surface / agonists*


  • Receptors, Cell Surface
  • free fatty acid 2 receptor, mouse
  • Peptide YY
  • Glucagon-Like Peptide 1