From Sideshow to Center Stage: Targeting the Ghrelin System Belongs in the Big Tent of Obesity Therapeutics

In this issue of Diabetes, Holm et al. (1) provide a compelling illustration of why the ghrelin system, comprised of the hormones ghrelin and LEAP2 (liver-expressed antimicrobial peptide 2), their receptor GHSR (growth hormone secretagogue receptor), and the enzyme GOAT (which posttranslationally acylates ghrelin, allowing it to bind to GHSR), has captivated scientists and drug developers alike. Discovered as the endogenous agonist for GHSR in 1999 (2), ghrelin quickly earned a reputation for its potent effects to stimulate appetite, reduce energy expenditure, and promote adiposity. Preclinical and clinical studies demonstrated that ghrelin increases food intake, body weight, reward-based eating behaviors, and blood glucose while also reducing energy expenditure and promoting fat storage (reviewed in Müller et al. [3]). These findings led to the hypothesis that blocking ghrelin signaling via ghrelin reduction, GHSR inhibition, or GOAT inactivation could offer a promising strategy for treating obesity and diabetes. A wealth of experimental evidence supported this concept. For example, pharmacologic studies in mice showed that disrupting ghrelin signaling via ghrelin neutralization or GHSR or GOAT antagonism can reduce food intake and limit weight gain (4–6).