An antibody that works against the gastric hormone ghrelin has been identified by scientists at The Scripps Research. Ghrelin has been linked to weight gain and fat storage through its metabolic actions.
Research leaders Kim Janda and Eric P. Zorrilla say that their findings point towards a potentially novel treatment for obesity that would interfere directly with the some of the biological mechanisms determining weight.
The researchers observed during the study that the antibody catalyst GHR-11E11 led to a higher metabolic rate in fasting mice, and suppressed feeding following 24-hour food deprivation.
"Our study showed that this novel catalytic ghrelin antibody could specifically seek out and degrade ghrelin," said Janda, who is Ely R. Callaway, Jr. Professor of Chemistry, member of The Skaggs Institute for Chemical Biology, and director, Worm Institute of Research and Medicine (WIRM), at Scripps Research.
"While this antibody lacks a high level of catalytic efficiency, our study clearly demonstrates that even a basal level of catalysis can effectively modulate feeding behavior. These findings not only validate antibody-based therapeutics, but strongly suggest that catalytic anti-ghrelin antibodies might help patients reach and maintain their weight loss goals," Janda added.
Ghrelin is a gastric endocrine hormone produced primarily in the stomach, which encourage eating during periods of calorie restriction. It promotes weight gain and fat storage through its metabolic actions, decreasing the break down of stored fat for energy as well as energy expenditure itself.
The new study suggests the possibility that passive immunopharmacotherapy with the catalytic anti-ghrelin antibody such as GHR-11E11 could decrease the level of serum ghrelin, and modulate energy homeostasis.
"The reason we looked at passive immunopharmacotherapy to treat obesity was because agonist/antagonist types of drugs have been remarkably unsuccessful," Janda said.
"They are effective only while treatment is maintained and when treatment stops, weight returns. For obesity treatments to work, they must affect food intake and energy expenditure or storage-which is what this new catalytic antibody does by degrading ghrelin. Some people have the idea that because ghrelin is an endogenous hormone there might be too many adverse side effects if you eliminate it, but there is new evidence that the body itself produces antibodies against ghrelin," the researcher added.
Since immunoneutralization would occur outside the central nervous system, the researchers believe that their approach might eliminate potential side effects that might occur with blood-brain barrier-penetrating small molecule antagonists.
Given the complex nature of obesity, any antibody-based strategy would most likely be used in combination with other available drugs, and as part of a comprehensive treatment approach that included nutritional, exercise, educational, and psychosocial components, Janda said.
He, however, conceded that more research was needed and, in addition to the development of more effective ghrelin antibodies, scientists needed to better understand issues like the effect of the antibodies over the long-term and their impact on individuals with varying body weights.
The study has been published in the online edition of the journal Proceedings of the National Academy of Sciences (PNAS).