Allosteric FFAR2 ligands reveal tissue-specific Gq/Gi signaling, modulating GLP-1, PYY, and insulin secretion
Background
The free fatty acid receptor 2 (FFAR2), a G protein-coupled receptor (GPCR), is expressed on various cell types and regulates multiple physiological responses. Designing ligands that selectively target GPCRs in a tissue-specific manner is crucial to avoid off-target effects and enhance therapeutic precision. Current approaches often lack this specificity, leading to broad activation profiles. Understanding the nuances of G protein coupling (e.g., Gq vs. Gi) in different tissues is key to developing functionally selective drugs for conditions like metabolic disorders and inflammation where FFAR2 plays a role.
Study Design
Researchers investigated the functional selectivity of FFAR2 allosteric ligands using mice expressing a hemagglutinin-tagged human FFAR2 DREADD. They tested three distinct ago-allosteric regulators: compound 187 and AZ1729 (binding to overlapping sites), and 4-CMTB (binding to a distinct site). The study assessed Gq and Gi family protein activation in various tissues, including colonic crypts, pancreatic islets, bone marrow, and adipose tissue. Primary endpoints included the release of gut hormones (GLP-1, PYY), insulin secretion, neutrophil migration, and antilipolytic effects, often in combination with an orthosteric DREADD agonist.
Results
Ligand-selective effects of FFAR2 were observed, mediated through differential activation of Gq and Gi family proteins across tissues. > Compound 187, a Gq-activating ligand, stimulated the release of GLP-1 and PYY from colonic crypts and insulin secretion from pancreatic islets. These Gq-mediated effects were prevented by the Gi-biased ligand AZ1729. Both compound 187 and AZ1729 promoted Gi-mediated neutrophil migration in bone marrow and antilipolytic effects in adipose tissue, acting synergistically with an orthosteric DREADD agonist. In contrast, 4-CMTB was ineffective in bone marrow and adipose tissue but produced Gq signaling-dependent effects in colonic crypts and pancreatic islets, both alone and with the orthosteric agonist.
Why It Matters
Targeting FFAR2 with functionally selective allosteric ligands could enable precision therapeutics for metabolic and inflammatory conditions. This research demonstrates that different allosteric ligands can bias FFAR2 signaling towards specific G protein pathways (Gq or Gi) in a tissue-dependent manner. This insight is critical for designing drugs that activate desired physiological responses (e.g., GLP-1 release for glucose control) while avoiding unwanted effects in other tissues. It suggests a path towards highly tailored interventions, potentially leading to novel compounds that modulate gut hormones, insulin, or immune responses with unprecedented specificity, moving beyond broad-acting GPCR agonists.