Free Fatty Acid Receptor Antibodies

The free fatty acid receptor family comprises four class A G protein-coupled receptors, FFA1 (GPR40), FFA2 (GPR43), FFA3 (GPR41), and FFA4 (GPR120). FFA1 and FFA4 respond to medium- and/or long-chain fatty acids, whereas FFA2 and FFA3 respond to short-chain fatty acids such as acetate, propionate, and butyrate, which are produced by gut microbial fermentation. FFA1 and FFA4 commonly signal through Gq/11, FFA3 couples predominantly to Gi/o, and FFA2 can engage both pathways. FFA1 is expressed in pancreatic β-cells, where it amplifies glucose-stimulated insulin secretion, and in enteroendocrine cells, where it contributes to gut hormone release. FFA2 is expressed on immune cells, including neutrophils, and in the intestinal epithelium, while FFA3 is found in enteroendocrine cells and peripheral neurons. FFA4 is expressed in intestinal cells, adipocytes, and macrophages and has been implicated in nutrient sensing, glucose homeostasis, and the regulation of inflammation. Agonist-induced phosphorylation, β-arrestin recruitment, and internalization can regulate receptor responsiveness, with FFA4 providing a well-characterized example of ligand- and splice variant-dependent signaling. The FFA1 agonist fasiglifam reached phase 3 trials for type 2 diabetes, but its development was discontinued because of liver safety concerns. The FFA2 antagonist GLPG0974 was evaluated in patients with ulcerative colitis, and no drug selectively targeting FFA1–FFA4 is currently approved for therapeutic use.