Science Editor

In the comic book "Asterix in Switzerland," in a send-up of the Red Cross, the Swiss lend medical assistance to the Roman legionnaires they have just vanquished through a unique mixture of magic potion-derived superhuman strength and yodeling.

Incredulous, a Roman asks a Swiss warrior, "First you hit me and then you bandage me up?"

Apparently, the ghrelin gene works something like that.

Discovered in 1999, ghrelin is a peptide hormone that stimulates appetite. Ghrelin, and agonists and antagonists of its receptor, are in clinical development with the goal of variously suppressing appetite (for obesity) or increasing it (for such diseases as AIDS and cancer). (See BioWorld Today, April 28, 2005.)

In the Nov. 11, 2005, issue of Science magazine, researchers from Stanford University reported that they found a second protein coded by the ghrelin gene that exerts effects opposite to those of ghrelin. Senior author Aaron Hsueh, professor of reproductive biology at Stanford, described at a press conference the protein, which he named obestatin, as "a stomach hormone that suppresses food intake."

The simultaneous production of a pro- and an anti-feeding peptide hormone from the same gene is somewhat counterintuitive. As University of Cincinnati obesity researcher Matthias Tschoep phrased it at the press conference, "Mother Nature is stepping on the brakes and the gas pedal at the same time" with the ghrelin gene. The gene seems to have arisen by exon duplication; fish, for example, have only ghrelin, not obestatin.

Regardless of the details of the interaction between ghrelin and obestatin, the discovery could explain several unresolved issues in ghrelin research; for example, knockout mice missing the ghrelin gene do not actually eat much less than their normal counterparts. Tschoep called that observation "much more plausible" in light of the fact that knocking out the ghrelin gene removes a satiety factor as well as a hunger factor. He also called the results "a lesson in the interpretation of data on a genetic level." mRNA data, as well knockout phenotypes, "can only be interpreted when we know more about what's going on at a post-translational level," he said.

The Stanford scientists identified obestatin via bioinformatics methods: They found a conserved stretch of amino acids (suggesting biological function) in the ghrelin precursor protein. Armed with that knowledge, the researchers were able to isolate a protein that fit the bill from rat stomachs. Hsueh's group also identified the obestatin receptor; Tschoep termed the simultaneous discovery of hormone and receptor "spectacular."

Synthetic obestatin suppressed food intake by about 50 percent in normal adult mice, with a concomitant reduction in weight gain of a still-impressive 20 percent over eight weeks, though in mice, a 20 percent reduction in body weight gain works out to less than a gram.

There's plenty of work to do before obestatin pans out in the clinic, if it ever does. Hsueh and his team have studied only effects of administering obestatin in normal weight mice to date, and no data exist on its effects in obese mice, let alone normal or obese humans. Furthermore, while ghrelin levels vary according to whether animals have recently eaten or not, obestatin levels showed no such sensitivity to food. Weight and appetite regulation is a complex system, with dozens of players identified to date. Both ghrelin and obestatin are modified after being translated, so their ultimate interplay in the body may be much more complicated than their derivation from the same protein precursor suggests. Another possibility is that bodyweight regulation is not obestatin's primary function.

Nevertheless, either direct administration of obestatin or screening for drugs that affect its receptors are obvious possibilities for drug development. Hsueh said his group is "working hard" on making a knockout mouse for the obestatin receptor, as well as on what he termed the most obvious question: "Does this work in the obese animal?"

Given the considerable industry interest - New Brunswick, N.J.-based Johnson & Johnson sponsored the research and already has licensed some of the rights to obestatin - we are sure to find out.