Biased agonism at free-fatty acid receptor-4 (FFA4/GPR120)

Free-fatty acid receptor-4 (FFA4), previously known as GPR120, is a G protein-coupled receptor (GPCR) activated by medium-to-long chain free fatty acids (FFAs), including saturated, monounsaturated, and polyunsaturated fats, many of which (e.g., omega-3 fatty acids) are critical contributors to human health and disease. FFA4 is widely expressed across human tissues, and its activation supports a range of physiological functions, including the release of gastrointestinal incretin hormones like glucagon-like peptide-1 (GLP-1), regulation of pancreatic hormone secretion, peripheral glucose uptake, adipose regulation, and anti-inflammatory responses in macrophages. Due to its pivotal role in energy metabolism and inflammation, FFA4 has emerged as a major target in drug discovery. Historically, FFA4 signaling was linked to the Gαq/11 family of intracellular heterotrimeric G proteins, which mediate its GLP-1 releasing effects. However, emerging evidence indicates that FFA4 can signal through other Gα proteins in various cellular contexts. Notably, its anti-inflammatory effects are also dependent on interactions with β-arrestin proteins, further broadening the receptor's signaling versatility. This review explores the concept of biased agonism at FFA4, emphasizing how this receptor selectively signals through distinct transduction pathways, including Gα proteins and β-arrestins. We also examine the key structural elements of FFA4 that govern its interactions with different signaling partners, the elucidation of which has laid the groundwork for the development of biased agonists aimed at selectively modulating these FFA4-mediated pathways for therapeutic application.