Glucagon-like peptide-1 regulates lipid metabolism through actions in the gut and liver

The two incretins, known as glucagon-like peptide-1 (GLP-1) and glucose‑dependent insulinotropic polypeptide (GIP), were initially identified for their function in enhancing glucose-dependent insulin secretion from pancreatic β-cells. Over the past two decades, pharmaceutical agents including exenatide, liraglutide, semaglutide, and tirzepatide, were developed for the treatment of type 2 diabetes (T2D). Some of these agents have subsequently been approved for the treatment of obesity and body weight management, and their applications have been further expanded into other metabolic disorders including metabolic dysfunction-associated steatotic liver disease. Studies conducted by our teams and others demonstrated the effect of GLP-1 and GLP-1 medicine on lipid metabolism, a feature that is beyond the definition of incretin. Here we present a brief historical review of the discovery of GIP and GLP-1. We then discuss literature on the role of GLP-1 and GLP-1 medicine in regulating lipid metabolism, particularly their actions in the intestine. This is followed by presenting the identification of the GLP-1-fibroblast growth factor 21 (FGF21) axis in mediating hepatic function of GLP-1, and our closing remarks on knowledge gaps that remain to be filled in the future.