By Dean A. Haycock

Special To BioWorld Today

There is more than one way to create an overweight mouse.

Any of a handful of genetic mutations will do the job. Although we know more about the genetics of obesity in mice than in humans, mouse models continue to point to regulatory pathways that provide therapeutic targets for the treatment of obesity in humans.

The latest advance in this area links, curiously, hair color and body weight in mice. The association of these two seemingly disparate traits might be traced in an evolutionary sense back to frogs.

"You might speculate that at one time it was important for a cold-blooded vertebrate to regulate both its heat conservation by altering its surface pigmentation and its conservation of energy," Gregory Barsh, associate professor of pediatrics and genetics at Stanford University, in Palo Alto, Calif., told BioWorld Today. Barsh also is an associate investigator of the Howard Hughes Medical Institute.

Frogs, like mice, have melanocortin receptors that respond to a protein called agouti. Normally, agouti is confined to the skin, where it affects pigmentation through its interaction with a subtype of melanocortin receptor designated Mc1. But in mice with mutations like "lethal yellow" and "viable yellow," agouti is expressed far more widely throughout the body. These mice display yellow coats, increased body length and obesity. Determining why excess agouti protein affects energy expenditure in mammals could provide viable targets for weight control drugs.

A paper in the Oct. 3 Science, "Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein," helps explain agouti's mechanism of action when it is expressed outside the confines of the skin.

Barsh and his co-authors began by isolating a gene from mice and humans that encodes a molecule that looks very much like agouti. Agouti-related protein (AGRP) is about the same size and has about the same structure as agouti but is distributed differently in the body. While agouti is normally localized in the skin, AGRP is found in the adrenal gland and the hypothalamus.

To find out if agouti and AGRP have similar effects on weight regulation, the researchers made transgenic mice that ubiquitously expressed human AGRP protein. The transgenic animals did show increased body length and weight but did not develop the pigmentation typically seen in lethal yellow animals.

Furthermore, AGRP levels were found to be eightfold higher in another a strain of obese mice. These ob/ob mutants lack leptin, a hormone implicated in weight control.

The authors suggest that just as agouti regulates pigmentation via the Mc1 receptor, the neuropeptide AGRP regulates body weight by interacting with other melanocortin receptors in the brain downstream of leptin signaling. Data suggest these receptors are the melanocortin receptor subtypes designated Mc3 and Mc4, which are expressed in the brain. The results indicate that recombinant AGRP acts as a potent, selective antagonist of both Mc3 and Mc4.

This work provides an explanation for why excess agouti protein produces effects in addition to changes in pigmentation: When agouti protein is present in the brain as it is in lethal yellow mice, it mimics the activity of AGRP by interacting with Mc4, a receptor normally seen by AGRP but not by agouti protein. It therefore has the opportunity to mimic the activity of AGRP.

Jef Flier, professor of medicine at Harvard Medical School, told BioWorld Today, "It (AGRP) is very likely to be an important molecule that regulates energy balance and body weight in the hypothalamus. Over-production causes obesity. It is an important potential molecular basis for disease and the pathway that it operates on may be an important one to interfere with obesity.

Barsh and his colleagues now are turning their attention to the biochemical interactions between these two closely related molecules and their receptors.

Flier said, "It looks like the molecular mechanism by which it acts is likely to be a previously identified molecule, the Mc4 receptor that is already viewed as a target. If that is the case, it doesn't give you a new target. It just tells you that this target is even more likely to be valid. But it could be that it has mechanisms of action that are not exactly related to that one target. That needs to be further identified."

Barsh agreed. "I think it is quite possible that these molecules, agouti and AGRP, have additional signaling mechanisms besides inhibition of melanocortin binding," he said.

More Study Needed To Define Roles

One possibility is that they bind to other receptors besides melanocortin receptors. Another is that they cause melanocortin receptors to signal themselves.

"It could be that a melanocortin receptor bound by MSH [melanocyte-stimulating hormone] causes one type of signal but when bound by agouti or AGRP, it causes a different kind of signal," Barsh said.

Both molecules are much larger than MSH, Barsh pointed out, and are likely to interact with an extracellular portion of a melanocortin receptor. There is some evidence in the literature, Barsh recalled, to suggest that MSH binding to melanocortin receptors involves some interaction with part of the receptor that spans the membrane.

"One would not expect that agouti or AGRP would be able to do that because they're tightly folded and much larger than MSH," Barsh said.

It is still not known whether AGRP plays a role in normal regulation of body weight, but the data suggest that future study of knockout mice lacking the AGRP gene could definitely establish a role for the peptide in feeding behavior, according to the authors.

Scientists at Millennium Pharmaceuticals Inc., in Cambridge, Mass., found that mice lacking Mc4 receptors developed obesity. This suggests that Mc4 antagonists might stimulate weight gain while Mc4 agonists might induce weight loss.

"The recognition that AGRP is likely to be the normal ligand for the Mc4 and/or the Mc3 receptors suggests that drugs that modulate the production or the activity of AGRP are likely to be useful," Barsh told BioWorld Today. *

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