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Updated: Jul 2, 2026

Measuring the Rate of Lipolysis in Ex Vivo Murine Adipose Tissue and Primary Preadipocytes Differentiated In Vitro
Published on: March 17, 2023
Allosteric ligands with distinct properties uncover tissue-specific physiological regulation mediated by free fatty
Natasja Barki1, Aisha M Hassan Abdelmalik1, Laura Jenkins1
1Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Abstract:
Individual G protein-coupled receptors (GPCRs) are present on many cell types and regulate multiple physiological responses, making it necessary to design ligands that are selective for the targeted GPCR in a tissue-selective manner. Here, we found ligand-selective effects of the GPCR free fatty acid receptor 2 (FFAR2) mediated through differential activation of Gq and Gi family proteins in various tissues. These effects were elucidated with ago-allosteric regulators of FFAR2 that bind to overlapping sites (compound 187 and AZ1729) and to a distinct site (4-CMTB) in tissues from mice expressing a hemagglutinin-tagged human FFAR2 DREADD (designer receptor exclusively activated by designer drugs). The Gq-activating ligand compound 187 stimulated the release of the gut hormones GLP-1 and PYY from colonic crypts and the secretion of insulin from pancreatic islets, effects that 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 synergistically with an orthosteric DREADD agonist, whereas 4-CMTB was ineffective in both of these tissues. In contrast, 4-CMTB, alone or with the orthosteric agonist, produced Gq signaling-dependent effects in colonic crypts and pancreatic islets. These insights into the functional selectivity of allosteric ligands acting on the same GPCR may enable the development of physiologically specific therapeutics.
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