Twin Hormones, Opposite Effects on Appetite

November 16, 2005

Two hormones derived from the same gene appear to affect appetite in opposite ways, according to a new study.

Obestatin, a newly discovered hormone that seems to suppress appetite, is derived from the same gene that generates ghrelin, a hormone that raises appetite, according to Aaron Hsueh, PhD, an endocrinologist and professor of obstetrics and gynecology at Stanford.

Obestatin gets its name from a combination of the Latin ''obedere'' (meaning to devour) and ''statin'' (which denotes suppression).

The study, performed by researchers Zhang et al. at Stanford University, was published in Science and reported by MedPage Today on 11 November 2005.

Discovering that two proteins originate from the same gene, yet have opposing effects was "a big surprise," Dr. Hsueh commented to MedPage Today.

Ghrelin hormone is formed by post-translational processing - that is, the hormone is part of the original gene-product ("proghrelin") and is cleaved off. However, Dr. Hsueh reported that analysis of the proghrelin's structure showed that it had another hormone attached at the end.

Ghrelin and obestatin both require post-translational modification to be biologically active. Ghrelin requires acylation near its amino terminus, whereas the ghrelin-associated peptide (obestatin) requires amidation at its carboxyl terminus.

Zhang et al. were able to synthesize the new hormone and to demonstrate that it is present in rats' brain tissue and stomach, which suggests that it may be involved in the complex interaction between brain and gut that regulates appetite.

Animal models supported this hypothesis. Injections of the synthetic hormone in male rats suppressed food intake, slowed stomach emptying and inhibited jejunum contractions, which researchers speculated may a signal of satiety to the brain.

Moreover, the opposite effects of obestatin and ghrelin may explain why animals whose ghrelin gene was removed showed little or no change in appetite - "most likely because these animals lacked both orexigenic ghrelin and anorexic obestatin," according to Dr Hsueh and colleagues.

Body weight is regulated by several pathways, including those of ghrelin, leptin and melanocortin. The discovery of appetite-related hormones, which started in 1994 with leptin, has inspired hope that drugs may be developed to help control obesity.

"This work [on obestatin] is notable because it reveals a completely new pathway," said Greg Barsh, MD, PhD, a Stanford geneticist who studies melanocortin, but who was not involved in the Obestatin project, according to MedPage Today.

Indeed, the discovery of obestatin and its receptor, G-protein-coupled protein "GPR39", opens up the way for drug-discovery efforts to exploit obestatin's anti-appetite effects. Hsueh et al's project was, in fact, sponsored by Johnson & Johnson Pharmaceutical Research and Development, which retains some licensing rights, according to Stanford university.

Hsueh and colleagues' findings of "the adversarial relationship between ghrelin and obestatin certainly is an important contribution to our understanding of body weight regulation," according to Ruben Nogueiras, MD, of the German Institute of Human Nutrition in Nuthetal, Germany, and Matthias Tschöp, MD, of the University of Cincinnati, in an editorial published in the same issue of Science.

However, they wrote, "the search for a magic bullet against obesity is likely to continue."

Sources:
Twin Hormones Have Opposite Effects on Appetite, MedPage Today, 11 November 2005.
Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake, Zhang JV et al. Science, volume 310 (5750), pages 996-999, 11 November 2005.
Separation of Conjoined Hormones Yields Appetite Rivals, Nogueiras R and Tschöp M. Science, volume 310 (5750), pages 985 - 986, 11 November 2005.

Posted: November 2005


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