Ghrelin: The Hunger Hormone that Isn't

Ghrelin is a 28-amino acid acylated peptide hormone secreted by endocrine cells in the stomach. It was first identified in 1999 and shortly thereafter shown to stimulate appetite when injected into rodents and humans. While ghrelin knockout mice have failed to show a decrease in appetite or bodyweight, the literature -- as well as the lay press -- continues to presume ghrelin levels are a mediator of appetite in vivo. For example, the suppression of ghrelin levels secondary to gastric bypass surgery is frequently invoked as a contributing factor in the resulting weight loss. In the literature, this incongruity has been rationalized as embryonic or neonatal compensation, a claim predicated on a study by Luquet et al. which showed that AgRP/NPY neurons (which express the ghrelin receptor and are thought to be the critical target for appetite stimulation) can be ablated without consequence in neonatal mice, while in adult mice ablation causes a rapid and profound loss of appetite. Widespread acceptance notwithstanding, the hypothesis that a reduction in ghrelin levels decreases appetite in adults has never been tested. We generated a mouse line expressing the simian diphtheria toxin receptor on ghrelin cells. With these mice we are able to rapidly ablate ghrelin cells in adulthood with the injection of diphtheria toxin. Despite an 80-95% loss of circulating ghrelin, our mice show no decrease in appetite or body weight in the short or long term and become obese and hyperinsulinemic in response to high fat feeding. To investigate why ghrelin seems to be sufficient but not necessary for hunger, we injected increasing doses of ghrelin and measured both food intake and the resulting plasma concentration. We found that the threshold dose for an appetite response raised blood concentrations more than 50-fold above physiologic levels -- well above the highest concentration we have observed even during extreme starvation. We show that at physiologic levels ghrelin is neither necessary nor sufficient for hunger and conclude that it is not a key regulator of appetite or weight gain in mice. Ghrelin's only essential role in mice appears to be the maintenance of plasma glucose during periods of starvation.