Hydrogen sulfide suppresses ghrelin secretion in vitro and delays postprandial ghrelin secretion while reducing appetite in mice

Ghrelin is a stomach‐derived hormone that regulates several metabolic functions including growth hormone release, appetite, adiposity, and gastric motility. Nutrients, the autonomic nervous system, and other metabolic hormones have all been implicated in the regulation of ghrelin secretion. Despite this, ongoing efforts to develop modulators of ghrelin secretion in human diseases are still underway. Hydrogen sulfide (H(2)S) is a gaseous signaling molecule that is produced both endogenously in many tissues and by the gut microbiome. H(2)S has established roles in cardiovascular and immune health, however, more recently H(2)S has been implicated in the regulation of metabolic hormone secretion. We hypothesized that H(2)S is able to directly regulate ghrelin secretion and in turn, regulate appetite. We first demonstrated that GYY4137 (an H(2)S donor molecule) directly suppresses ghrelin secretion in rat primary gastric culture, in part through the activation of the protein kinase B (AKT) pathway. We then demonstrated the colocalization of ghrelin‐positive gastric cells with the H(2)S producing enzyme cystathionine‐γ‐lyase (CSE). While GYY4137 suppressed ghrelin secretion, inhibition of CSE caused a stimulation in ghrelin secretion in primary gastric culture. In mice, GYY4137 treatment prolonged the postprandial drop of circulating ghrelin and caused reduced food consumption up to 4 h after treatment. These results demonstrate for the first time a role for H(2)S in the regulation of ghrelin and appetite. Modulating H(2)S levels may be a novel approach to regulate ghrelin secretion in the treatment of metabolic diseases.