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

Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models.

Author information

1
Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College London, London, U.K.
2
Takeda Cambridge Ltd, Cambridge, U.K. stuart.stafford@takeda.com helen.cox@kcl.ac.uk.
3
Takeda Cambridge Ltd, Cambridge, U.K.
4
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.

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.

PMID:
26239054
DOI:
10.2337/db15-0481
[Indexed for MEDLINE]
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