ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Signaling
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1645031
Endogenous ligands of bovine FFAR2/GPR43 display distinct pharmacological properties
Provisionally accepted
Tainara Cristina Michelotti1
Valérie Lamothe2Frederic Jean-Alphonse3,4Eric Reiter3,4Muriel Bonnet1
Guillaume Durand1,2*- 1INRAE, Université Clermont Auvergne, VetAgro Sup, UMR Herbivores, Saint Genès Champanelle, France
- 2Bordeaux Sciences Agro, Gradignan, France
- 3INRAE, CNRS, Université de Tours, PRC, Nouzilly, France
- 4Inria, Inria Saclay-Ile-de-France, Palaiseau, France
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Free fatty acids (FFAs) have been identified as ligands for members of the G protein-coupled receptor (GPCR) family, called free fatty acid receptors (FFARs). Among these receptors, there is a particular interest in the physiological roles of FFAR2 and its potential use as a therapeutic target for various health disorders. Despite great progress in other species, pharmacological properties of the bovine FFAR2 (bFFAR2) are not fully understood. The aim of the current study was to evaluate how a selection of FFAs (C2:0 to C8:0, and branched FFAs) activate and regulate bFFAR2 signaling. We used HEK293A cells and BRET assays to measure Gαi/Gαq coupling and signaling, β-arrestin 2 recruitment, and receptor internalization/trafficking. SRE and NFAT-RE dependent transcription was assessed by luciferase reporter assay. Results show that bFFAR2 presents a dual coupling to Gαi and Gαq and recruits β-arrestin 2 when stimulated with short and medium-chain FFAs up to eight carbons. Straight-chain FFAs with 4 to 7 carbons plus 3-methyl-butanoic acid showed the greatest potency to activate bFFAR2 upstream and downstream signaling, while C2:0, C3:0 and 2-methylpropanoic acid (2MP) were the least potent. 2MP had little pharmacological activity towards β-arrestin 2, and although it induced receptor internalization, bFFAR2 trafficking to the early endosome was not observed. Overall, the number of carbons of straight-chain FFAs and methyl position of branched FFAs differentially regulates the activation of bFFAR2.
Keywords: Cell signaling, cell surface receptor, fatty acid, bioluminescence resonance energy transfer, lipid signaling, G protein-coupled receptor, bovine FFAR2
Received: 11 Jun 2025; Accepted: 26 Jul 2025.
Copyright: © 2025 Michelotti, Lamothe, Jean-Alphonse, Reiter, Bonnet and Durand. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Guillaume Durand, Bordeaux Sciences Agro, Gradignan, France
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