PT  - JOURNAL ARTICLE
AU  - Brian D. Hudson
AU  - Bharat Shimpukade
AU  - Amanda E. Mackenzie
AU  - Adrian J. Butcher
AU  - John D. Pediani
AU  - Elisabeth Christiansen
AU  - Helen Heathcote
AU  - Andrew B. Tobin
AU  - Trond Ulven
AU  - Graeme Milligan
TI  - The Pharmacology of TUG-891, a Potent and Selective Agonist of the Free Fatty Acid Receptor 4 (FFA4/GPR120), Demonstrates Both Potential Opportunity and Possible Challenges to Therapeutic Agonism
AID  - 10.1124/mol.113.087783
DP  - 2013 Nov 01
TA  - Molecular Pharmacology
PG  - 710--725
VI  - 84
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/84/5/710.short
4100  - http://molpharm.aspetjournals.org/content/84/5/710.full
SO  - Mol Pharmacol2013 Nov 01; 84
AB  - TUG-891 [3-(4-((4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein–coupled receptor 120, or GPR120). Herein, we have used TUG-891 to further define the function of FFA4 and used this compound in proof of principle studies to indicate the therapeutic potential of this receptor. TUG-891 displayed similar signaling properties to the LCFA α-linolenic acid at human FFA4 across various assay end points, including stimulation of Ca2+ mobilization, β-arrestin-1 and β-arrestin-2 recruitment, and extracellular signal-regulated kinase phosphorylation. Activation of human FFA4 by TUG-891 also resulted in rapid phosphorylation and internalization of the receptor. While these latter events were associated with desensitization of the FFA4 signaling response, removal of TUG-891 allowed both rapid recycling of FFA4 back to the cell surface and resensitization of the FFA4 Ca2+ signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species. Pharmacologic dissection of responses to TUG-891 in model murine cell systems indicated that activation of FFA4 was able to mimic many potentially beneficial therapeutic properties previously reported for LCFAs, including stimulating glucagon-like peptide-1 secretion from enteroendocrine cells, enhancing glucose uptake in 3T3-L1 adipocytes, and inhibiting release of proinflammatory mediators from RAW264.7 macrophages, which suggests promise for FFA4 as a therapeutic target for type 2 diabetes and obesity. Together, these results demonstrate both potential but also significant challenges that still need to be overcome to therapeutically target FFA4.