Abstract
Obesity is a prevalent disease that also contributes to the incidence and severity of many other chronic diseases and health conditions. Treatment approaches include lifestyle intervention, bariatric surgery, and pharmacological approaches, with glucagon-like peptide 1 (GLP-1) receptor agonists approved specifically for weight loss having changed the treatment landscape significantly in the last 5 years. Targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor may enhance the metabolic benefits of GLP-1 receptor agonism. These beneficial effects are seen with both GIP receptor antagonism and GIP receptor agonism, although the mechanisms underlying this apparent paradox remain unknown. Here, we summarize the physiologic, genetic, and clinical evidence for pursuing GIP receptor antagonism to achieve metabolic and weight benefits. Both global and central nervous system knockout of GIP receptors protects mice fed a high-fat diet from obesity and insulin resistance. Genome-wide association studies in humans support this notion, correlating lower BMI with GIP receptor genetic variants with reduced function. Pharmacologic approaches in mice and monkeys confirm that GIP receptor antagonism enhances GLP-1-induced weight reduction and other metabolic benefits, and a phase 1 study provides proof of principle that beneficial effects extend to humans. GIP receptor antagonism may represent an important new mechanism to expand the treatment options available to individuals living with obesity.