Sibling hormone rivalry

New appetite-suppressing hormone derives from the same gene as 'hunger hormone' ghrelin

By | November 11, 2005

Researchers have identified a new appetite-suppressing hormone – aptly named obestatin -- and its receptor in mammals. Stanford University biologists report this week in Science that obestatin is produced by posttranslational modification of a protein precursor that also gives rise to ghrelin, a peptide dubbed 'the hunger hormone' for its stimulatory effects on appetite. The authors suggest this work may provide new targets for the control of obesity, as well as clear up some mysteries concerning the function of its sibling and physiological opponent, ghrelin.

"It's an enormous data set, an elegant study, and beautiful data," Matthias Tschöp of the Obesity Research Center at the University of Cincinnati, Ohio, who co-wrote an accompanying perspective, told The Scientist. David E. Cummings of the University of Washington, who was not involved in the research, described the work as a "major new find."

The study was led by Aaron Hsueh at Stanford University's School of Medicine, whose lab usually works on reproductive endocrinology. Hsueh's team predicted the existence of obestatin through a bioinformatic search for hormones derived from the protein precursors of known peptide hormones. The exercise yielded a 23-amino-acid region of preproghrelin that is highly conserved across a range of mammalian species.

The authors confirmed the prediction when they isolated obestatin from rat stomach extracts and blood. They showed that, in contrast to ghrelin, synthetic obestatin administered to rodents peripherally and centrally resulted in reductions in appetite, weight gain and the rate of gastric emptying.

While ghrelin requires posttranslational acylation of the amino terminus of its precursor, obestatin is the product of amidation of preproghrelin's carboxyl terminus, the researchers note. By screening orphan mammalian receptors, Hsueh's team found that obestatin binds to GPR39, a ghrelin receptor-family member expressed in the stomach, intestine and hypothalamus.

Hsueh said he is hopeful that obestatin or other compounds that activate the same receptor could one day serve as appetite-suppressing drugs. Tschöp, however, said he is more cautious about the prospects of obestatin as an obesity drug, given that its effects on weight gain were modest and that the hormone has yet to be tested in obese animal models. For instance, leptin is an appetite suppressor, but it is nevertheless high in obese subjects. Tschöp said he considers it "not an unlikely possibility" that obestatin will show a similar relationship with body weight.

It's also not clear whether the lower weight gain observed following obestatin administration is due to reductions in fat mass, muscle mass or water content – or even illness, Tschöp noted. Hsueh told The Scientist that preliminary data suggest illness is not a side effect of obestatin, but Tschöp pointed to PYY3-36, whose appetite-suppressing effects are, according to a recent report, at least in part due to the nausea induced by its administration. "It's important to test that before everybody gets really excited," Tschöp told The Scientist.

Cummings agreed that obestatin sheds new light on some troublesome observations that have "taken some of the wind out of ghrelin's sails" as an anti-obesity target. For example, ghrelin has potent stimulatory effects on appetite in rodents, but ghrelin-null mice are not much leaner than wild-type animals. Given that obestatin and ghrelin derive from the same gene, Hsueh's team write, ghrelin-null mice would also lack obestatin, counterbalancing ghrelin's absence.

Still, Tschöp suggested that the relationship between ghrelin and obestatin might not be so simple. Mice lacking the ghrelin receptor are also not particularly lean, he noted, even though obestatin's effects should be unimpaired. "There is too much we don't know yet," he said.

Cummings observed that the family ties between the obestatin and ghrelin receptors might explain why certain ghrelin receptor blockers mysteriously increase food intake. "Maybe some of these products inadvertently affect the obestatin more than they do the ghrelin receptor," he said. An important next step, said Cummings, is to work out how the body independently regulates posttranslational modification of both obestatin and ghrelin from a single precursor. "It would make no sense to turn them both on at once," he told The Scientist.

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