title: 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.
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.
authors: 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.).
authors: Brian D
authors: BD
authors: Hudson
authors: Bharat
authors: B
authors: Shimpukade
authors: Amanda E
authors: AE
authors: Mackenzie
authors: Adrian J
authors: AJ
authors: Butcher
authors: John D
authors: JD
authors: Pediani
authors: Elisabeth
authors: E
authors: Christiansen
authors: Helen
authors: H
authors: Heathcote
authors: Andrew B
authors: AB
authors: Tobin
authors: Trond
authors: T
authors: Ulven
authors: Graeme
authors: G
authors: Milligan
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D019390:Arrestins / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010666:Phenylpropionates / Q000494:pharmacology*; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C585065:3-(4-((4-fluoro-4'-methyl-(1,1'-biphenyl)-2-yl)methoxy)phenyl)propanoic acid; C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D001713:Biphenyl Compounds; C519853:FFAR4 protein, human; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D048049:Extracellular Signal-Regulated MAP Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005947:Glucose; D002118:Calcium
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