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Los ligandos endógenos de FFAR2/GPR43 bovino presentan propiedades farmacológicas distintas

Tainara Cristina Michelotti¹, Valérie Lamothe², Frédéric Jean-Alphonse^3,4

¹INRAE, Université Clermont Auvergne, VetAgro Sup, UMR Herbivores, Saint-Genès-Champanelle, France.

Frontiers in cell and developmental biology

|September 5, 2025

Resumen

La señalización del receptor de ácidos grasos libres bovina 2 (bFFAR2) está activada por los ácidos grasos de cadena corta y media. La estructura de los ácidos grasos, específicamente la longitud del carbono y la ramificación, influye en la potencia de bFFAR2 y los efectos posteriores.

Área de la Ciencia:

Farmacología y Biología Molecular
La señalización de los receptores acoplados a proteínas G (GPCR)
Metabolismo y señalización de lípidos

Sus antecedentes:

Los ácidos grasos libres son ligandos endógenos para los receptores de ácidos grasos libres (FFAR), una subfamilia de GPCR.
FFAR2 juega un papel en varios procesos fisiológicos, por lo que es un objetivo terapéutico potencial.
La caracterización farmacológica del FFAR2 bovino (bFFAR2) sigue siendo incompleta.

Objetivo del estudio:

Investigar la activación y regulación de la señalización bFFAR2 por una gama de FFAs.
Para aclarar las relaciones estructura-actividad de los AGF de cadena corta y media en bFFAR2.

Principales métodos:

Se utilizaron células HEK293A para evaluar la actividad de bFFAR2.
Se utilizaron ensayos de transferencia de energía por resonancia de bioluminiscencia (BRET) para medir el acoplamiento de la proteína G (Gαi/Gαq) y el reclutamiento de la β-arrestina 2.
Para evaluar la activación transcripcional se utilizaron ensayos de reportería de luciferasa (SRE y NFAT-RE).

Principales resultados:

bFFAR2 exhibe doble acoplamiento a Gαi y Gαq y recluta β-arrestina 2 tras la estimulación con FFAs hasta C8: 0.
Los AGF con 4-7 carbonos y el ácido 3-metil-butanoico demostraron la mayor potencia en la activación de bFFAR2.
El ácido 2-metilpropanoico (2MP) mostró una actividad mínima de la β-arrestina 2 y una internalización limitada de los receptores sin tráfico endosómico temprano.

Conclusiones:

La activación y la señalización de bFFAR2 están moduladas diferencialmente por la longitud de la cadena de carbono de los AGF de cadena recta y la posición del grupo metilo en los AGF ramificados.
Comprender estas relaciones estructura-actividad es crucial para desarrollar terapias dirigidas que modulen bFFAR2.
Se necesitan más investigaciones para delinear completamente las consecuencias posteriores de la activación de bFFAR2 por varios FFAs.

Palabras clave:

Receptor acoplado a la proteína G Transferencia de energía de resonancia de bioluminiscencia Receptores de ácidos grasos libres de origen bovino 2 señalización celular receptor de la superficie celular Ácido graso La señalización lipídica

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