Everyone is familiar with the complaints of a hungry stomach. For years, scientists attributed the gnawing increase in appetite before a meal to ghrelin, a hormone which is secreted in the gut and circulates in the blood, playing a role in food intake and storage. Researchers have found that levels of ghrelin, dubbed the “hunger hormone,” peak before meals and recede after eating.

Given its association with appetite, ghrelin is a tempting drug target for potential obesity treatments—but findings thus far have not lived up to expectations. Experiments that knock out the genes coding for ghrelin and its single receptor, GHSR (growth hormone secretagogue receptor), have been inconclusive: Remove the hormone or receptor, and rodents used in the experiments do not necessarily lose their drive to eat.

Now a team of researchers at the French Institute of Health and Medical Research (INSERM) in Paris believe that scientists have had it wrong all along. In a study published this week in Science Signaling, they report that ghrelin does not enhance appetite in rats but rather increases weight gain and fat buildup.

Unlike in earlier work, in the new study the researchers used a novel genetic method that kept the ghrelin receptor functional but modified it to have greater signaling in response to ghrelin—in other words, the receptor would enhance the hormone’s effects. The team then performed a series of experiments, first in isolated cells and then in rats. As expected, exposing ghrelin to modified receptors prompted a more potent response compared with the unaltered GHSR.

In one of these experiments, the researchers induced higher ghrelin levels in rodents by restricting the animals’ caloric intake. Ghrelin increased, and the receptors in modified rats showed a more intense response. In addition, the scientists found that the rats with the mutation causing ghrelin sensitivity were able to maintain their body weight much better than normal counterparts who quickly lost fat mass—an observation that suggests ghrelin plays a role in metabolizing and storing energy.

Finally, the researchers examined the consequences of the GHSR mutation when the rats had normal access to food. The rats with enhanced sensitivity to ghrelin gained more weight than ordinary rats—even though these modified rodents did not eat more food (proportionally) than the control group. “This was a surprising observation,” says Jacques Pantel, a biomedical researcher at INSERM and the paper’s lead author. The finding suggests that, unlike in previous hypotheses, ghrelin regulates fat storage and not appetite. Moreover, the rats with the GHSR modification also exhibited decreased glucose tolerance, a change associated with diabetes and obesity in many animals. “So overall, these animals are in a pre-obesity state, but without the increased food intake,” Pantel adds.

Matthias Tschöp, the director of the Helmholtz Diabetes Center in Munich, was among the researchers who discovered ghrelin’s effects on food intake and body weight in 2000. “We have struggled for more than 15 years to understand [ghrelin’s] endogenous biological actions,” says Tschöp, who did not participate in the current study. “This paper shows with elegant genetic tools that natural ghrelin may play a role in the regulation of energy balance.”

Pantel is optimistic these findings can now be used to identify drugs that would be more effective in targeting the ghrelin receptor to treat obesity. “We have demonstrated one mechanism that might induce a predisposition to obesity,” he says. Finding compounds that reduce the receptor’s ghrelin signaling could therefore modulate fat storage and potentially protect against that predisposition. “The outcome in these animals, which are hypersensitive to ghrelin, should be decreased body weight and increased glucose tolerance,” Pantel says.

Similarly, modifications which strengthen the receptor’s response to ghrelin may be beneficial in treating conditions that involve severe weight loss or caloric restriction, such as anorexia. The researchers intend to explore this idea in greater depth.

Pantel is also excited about investigating other functions of ghrelin and its receptor, beyond the metabolic consequences examined in this study. The receptor is expressed in many brain regions—not only in those associated with energy storage and food intake. It is also implicated, for instance, in learning and memory as well as the reward system. “We’re particularly interested in exploring the consequences of this mutation on those functions,” Pantel says.