| GPR120, also known as free fatty acid receptor 4 (FFAR4), is a class A rhodopsin-like G protein-coupled receptor that functions as a nutrient sensor for unsaturated long-chain free fatty acids and links dietary lipid signals to hormonal secretion and anti-inflammatory pathways relevant to metabolic homeostasis. GPR120 is abundantly expressed in enteroendocrine L cells of the distal intestine, where its seven-transmembrane architecture and intracellular loops couple to G proteins and β-arrestin; stimulation by omega-3 and other unsaturated long-chain fatty acids raises intracellular calcium and activates downstream kinases, leading to depolarization and exocytosis of dense-core granules containing the incretin hormone glucagon-like peptide-1 (GLP-1), which enhances glucose-dependent insulin secretion and supports postprandial glycemic control in vivo. GPR120 localizes to GLP-1-producing L cells and selective activation by fatty acids or synthetic agonists triggers robust GLP-1 release, increases circulating insulin, and lowers blood glucose, establishing a direct mechanistic link between luminal lipid sensing, GPR120 signaling, and incretin output. High GPR120 expression in K cells of the upper small intestine contributes to fat-induced secretion of glucose-dependent insulinotropic polypeptide (GIP), indicating a broader role in coordinated incretin regulation after fat ingestion. At the signaling level, GPR120 engages both G protein-dependent and β-arrestin-biased pathways: coupling to Gq/11 stimulates phospholipase C, inositol trisphosphate production, and calcium mobilization that support hormone exocytosis, while β-arrestin-2 recruitment scaffolds kinases such as ERK and also underlies anti-inflammatory signaling in macrophages and intestinal epithelial cells, where GPR120 activation can interfere with TLR-driven NF-κB pathways and reduce production of proinflammatory mediators. Human GPR120 exists as two splice variants, a short isoform (GPR120S) and a long isoform (GPR120L) that differ by a 16–amino acid insertion in the third intracellular loop, and these isoforms display distinct signaling and trafficking behavior: GPR120S couples efficiently to G protein–dependent calcium and dynamic mass redistribution responses, while GPR120L fails to trigger these G protein–mediated readouts but still recruits β-arrestin2 and internalizes to lysosomes after agonist stimulation, marking the long isoform as a naturally more β-arrestin-biased receptor. Both splice variants share the same seven-transmembrane helical bundle and ligand-binding pocket characteristic of class A GPCRs, and both are activated by unsaturated long-chain fatty acids. Expression in pancreatic islets, adipose tissue, and immune cells modulates islet hormone secretion and insulin sensitivity and contributes to the integration of nutrient status with energy storage and inflammatory tone. GPR120 is among the genes linked to type 2 diabetes risk, and loss or dysfunction of GPR120 signaling in mice impairs metabolic responses to dietary fat. |
