“Hunger Hormone” No More?

But attempts to investigate how the hormone and receptor exert these effects have only confused matters, said Jacques Pantel of INSERM’s Center for Psychiatry and Neuroscience in Paris who led the new study. Genetic deletions of ghrelin, or GHSR, for example, did not produce the expected results. “The animals were not anorexic,” Pantel said, which was “a big disappointment.”

Because eating is so essential for survival, it’s possible that the complete removal of ghrelin or GHSR from these animals may have promoted compensatory genes and pathways to kick in, said Pantel. So to avoid possible confounding effects of compensation, Pantel and his colleagues used transgenic rats that lacked only a tiny fraction of GHSR—the distal tip—rather than the whole protein. They showed that in cultured cells and transgenic animals, this mutant receptor had increased activity in response to ghrelin compared with the wild-type receptor.

Specifically, the gain-of-function mutation increased GHSR signaling in response to ghrelin in cultured human cells, and increased the receptor’s sensitivity to injected ghrelin in the transgenic animals: growth hormone release and food intake were stimulated by lower doses of ghrelin in the transgenic animals than in wild-type animals. Aside from increased activity, however, the response to injected ghrelin was similar.

The response to endogenous ghrelin, on the other hand, puzzled the team. While GHSR transgenic animals fed a standard diet gained more weight than control animals (which would be expected with a more active ghrelin-GHSR pathway), this was not the result of increased food intake. “Quite surprisingly, for a so-called orexigenic hormone, these animals were not eating more proportionally compared to their wild-type counterparts,” Pantel said.

Instead, Pantel thinks the weight gain, which was specifically due to increased body fat, might be because “the hormone is playing more of a role in fat storage,” he said. With this in mind, he suggested that the observed peak in ghrelin prior to meals might not be driving the search for food, but instead “preparing an organism to metabolize and store the [incoming] energy.”

Why, then, would injected but not endogenous ghrelin boost appetite? It’s far from clear, said Pantel, but one possibility is that injection provides such a sudden large dose of the hormone that it activates GHSR receptors in certain parts of the brain that normal endogenous fluctuations would not. Such atypical stimulation might then somehow trigger appetite.

Neuroscientist Sebastien Bouret of the University of Southern California who was not involved in the study said he doubts that endogenous ghrelin does not affect food intake, however. He said he thinks it is still possible a compensatory mechanism, albeit one that reduces the expected overeating, could be at work in the transgenic animals. “The ideal experiment would be to have this gain of function exclusively during adult life. . . so that we won’t have the compensatory mechanism,” he said. “Then we would be able to make a very strong conclusion.”

Y. Chebani et al., “Enhanced responsiveness of GhsrQ343X rats to ghrelin results in enhanced adiposity without increased appetite,” Science Signaling, 9, ra39, 2016.