By David N. Leff

¿Munchies¿ was the word coined by marijuana users long ago for the snacks they craved between smokes. But you don¿t have to be a joint junkie to feel an irresistible urge to eat ¿ at meals and in between.

In some people, this ¿munchies¿ habit amounts to an addiction, leading to obesity. The ¿O¿ word means tipping the scales at 20 percent or more above your statistically normal body weight. One plausible alibi for an uncontrollable, outsize appetite is, ¿My genes make me do it.¿

What gives that cop-out some substance is that obese strains of mice get that way because of their genetic profile. Obesity research in recent years has pinpointed the genes that make mice overeat, and turn their food intake into excess body fat. And leptin, produced by rodents and humans, has become the celebratory research molecule for slimming.

But leptin isn¿t the last word on obesity control. The latest word takes the form of two back-to-back papers in today¿s Nature, dated March 11, 1999. One, by scientists at Millennium Pharmaceuticals Inc., in Cambridge, Mass., bears the title: ¿The mahogany protein is a receptor involved in suppression of obesity.¿ The other, by molecular geneticist Gregory Barsh, at Stanford University, is titled: ¿The mouse mahogany locus encodes a transmembrane form of human attractin.¿ The Millennium paper¿s senior author is molecular geneticist Karen Moore, the company¿s director of genetic systems.

¿The mahogany mouse owes its name,¿ she told BioWorld Today, ¿to the dark, brownish-black color of its coat. It was originally observed that this mouse gene was capable of making animals dark in coat pigmentation. And the original mahogany mutant has been around for a very long time. It goes back to the 1960s.

¿We knew a little bit about how pigmentation works,¿ Moore said, ¿and that some of the molecules involved in the pigmentation pathway are very similar to molecules involved in obesity. So, we asked, in a simple experiment, whether the mutation in the mahogany gene carried by this mouse could affect not only pigmentation but also obesity.

¿We undertook those experiments a few years ago,¿ she went on, ¿and found initially that when we combined the mahogany mutant mouse with the agouti-yellow obese mouse, it rescued that agouti from obesity. (See BioWorld Today, Oct. 7, 1997, p. 1.)

¿So we took those experiments further,¿ Moore recounted, ¿to try to understand whether the mahogany mutant was capable of suppressing all forms of obesity. We did the appropriate genetic crosses to see if it could suppress the genetically induced obesity of the mutants of other obese mouse strains ¿ ob (leptin), db (leptin receptor), fat and tubby. It couldn¿t. The final experiment that we did, as reported in Nature, was to put the animals onto a high-fat diet. Normal mice on such a regimen gain upward of 50 percent over their starting body weight within a couple of months. Mutant mahogany mice did not. This was probably the most exciting observation that spurred us on to finish cloning the mahogany gene.¿

Name Of The Game: Positional Cloning

Some 2,347 mice later, she and her co-authors finished the tedious task of cornering that gene on murine chromosome 2, and the short arm of human chromosome 20.

¿Early studies,¿ Moore related, ¿long before mahogany was even conceived of, had placed its gene somewhere on murine chromosome 2. That crude area of the genome was all very well and good. What we needed to do was constantly refine that mapping, relying on genetic recombinations. As the map become finer and finer, it took more and more animals to look for those rare recombinants. That¿s all part of positional cloning ¿ narrowing down exactly where in the genome the gene is located. And, once we¿d got it down to a very small region, we could start building physical maps, sequence across them, and discover the mahogany gene.

¿What we discovered,¿ she recalled, ¿was one of the most complex genes known to mouse ¿ or man. Ditto the protein it expresses. That product pokes the head of its 1,400 amino-acid sequence out through the cell membrane and its tail into the cell¿s cytoplasm.¿

As to what that protein is up to ¿ its mode of action, Moore said: ¿We have two thoughts. One is a simple answer, but we don¿t yet understand its consequences. If it is a receptor, capable of sending its own signal into the cell, we don¿t know what that signal would be. And we don¿t know what the downstream molecules that would be receiving that signal within the cell will be.

¿An easier way to explain this complicated mechanism,¿ she said, ¿is that it involves an accessory receptor. This molecule works in combination with melanocortin receptors. One melanocortin version is found in the brain¿s hypothalamus, which plays a key role in body-weight regulation and in feeding behavior. And that melanocortin may well be acting together with the agouti gene product, which is actually an inhibitor of the melanocortins.¿

Moore emphasized that ¿neither of these molecules is good,¿ nor are they bad.¿ Body-weight regulation is tweaking those pathways ¿ be it the agouti pathway or the leptin pathway ¿ and mahogany is one of those fine regulators.

En Route To An Anti-Obesity Pill

¿We have yet to really delve deeply into this on/off control system,¿ Moore said, ¿but I think the important points, from a therapeutic-intervention standpoint, are twofold: One is that, as a receptor, with part of the molecule outside the cell, one can potentially inhibit this protein, by designing a small, orally available molecule to interface with it.

¿The other thing we know from the genetics is that if we down-regulate or block its function, we get the desired effect,¿ she said. ¿That is, reduction of obesity. That¿s always a better situation to be in, if your therapeutic intervention means trying to down-regulate something. Trying to make it more active rather than less is much more difficult. So, I think we¿ve got some definitely strong advantages in the type of molecule these genes reveal for us, in going down the road toward therapeutics.¿

The companion article in Nature, by Stanford¿s Barsh, also reports cloning the mahogany gene, and that it encodes a large membrane-spanning protein. Both papers note the similarity of this gene to a human gene called attractin. n

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