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Molecular Pharmacology

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Research ArticleArticle

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

Brian D. Hudson, Bharat Shimpukade, Amanda E. Mackenzie, Adrian J. Butcher, John D. Pediani, Elisabeth Christiansen, Helen Heathcote, Andrew B. Tobin, Trond Ulven and Graeme Milligan
Molecular Pharmacology November 2013, 84 (5) 710-725; DOI: https://doi.org/10.1124/mol.113.087783
Brian D. Hudson
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Bharat Shimpukade
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Amanda E. Mackenzie
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Adrian J. Butcher
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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John D. Pediani
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Elisabeth Christiansen
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Helen Heathcote
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Andrew B. Tobin
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Trond Ulven
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Graeme Milligan
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.)
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Abstract

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.

Footnotes

    • Received June 7, 2013.
    • Accepted August 26, 2013.
  • This work was funded in part by grants from the Biotechnology and Biosciences Research Council [BB/K019864/1] (to G.M.), and [BB/K019856/1] (to A.B.T.); core funding from the MRC Toxicology Unit (to A.B.T.); the Danish Council for Strategic Research 11-116196 (to T.U. and G.M.); and the Canadian Institutes of Health Research (fellowship to B.D.H.).

  • dx.doi.org/10.1124/mol.113.087783.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (5)
Molecular Pharmacology
Vol. 84, Issue 5
1 Nov 2013
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Research ArticleArticle

The Therapeutic Potential of FFA4

Brian D. Hudson, Bharat Shimpukade, Amanda E. Mackenzie, Adrian J. Butcher, John D. Pediani, Elisabeth Christiansen, Helen Heathcote, Andrew B. Tobin, Trond Ulven and Graeme Milligan
Molecular Pharmacology November 1, 2013, 84 (5) 710-725; DOI: https://doi.org/10.1124/mol.113.087783

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Research ArticleArticle

The Therapeutic Potential of FFA4

Brian D. Hudson, Bharat Shimpukade, Amanda E. Mackenzie, Adrian J. Butcher, John D. Pediani, Elisabeth Christiansen, Helen Heathcote, Andrew B. Tobin, Trond Ulven and Graeme Milligan
Molecular Pharmacology November 1, 2013, 84 (5) 710-725; DOI: https://doi.org/10.1124/mol.113.087783
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