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.

  • Hudson B
  • Shimpukade B
  • Mackenzie A
 et al. 
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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.

Author-supplied keywords

  • 3T3-L1 Cells
  • Animals
  • Arrestins
  • Arrestins: physiology
  • Biphenyl Compounds
  • Biphenyl Compounds: pharmacology
  • Calcium
  • Calcium: metabolism
  • Extracellular Signal-Regulated MAP Kinases
  • Extracellular Signal-Regulated MAP Kinases: metabo
  • G-Protein-Coupled
  • G-Protein-Coupled: agonists
  • GTP-Binding Protein alpha Subunits
  • Glucose
  • Glucose: metabolism
  • Gq-G11
  • Gq-G11: physio
  • HEK293 Cells
  • Humans
  • Mice
  • Phenylpropionates
  • Phenylpropionates: pharmacology
  • Phosphorylation
  • Receptors

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Authors

  • Brian D Hudson

  • Bharat Shimpukade

  • Amanda E Mackenzie

  • Adrian J Butcher

  • John D Pediani

  • Elisabeth Christiansen

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