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Research into obese mice and its relationship to humans

NORMAN SWAN: A few weeks ago, the papers and magazines were full of news about obesity research which implied that a new drug for fatness was just around the corner. The talk was of obesity genes in mice, of obesity hormones which told the brain to stop eating, and of the share price of the company which holds the rights to the fruits of the research.

But speaking as someone whose appetite is almost always out of control, I wanted to know what all this really meant for humans rather than mice. So I spoke to an Australian authority on the science of obesity, Dr Greg Cooney, who gave me the story.

GREG COONEY: The key finding appears to be that there is a blood-borne factor which does affect appetite and energy expenditure in experimental animals and in humans.

NORMAN SWAN: What is this factor, and how have they discovered it?

GREG COONEY: Studies from several years ago determined that in two experimental animal models of obesity there was one genetic defect where this protein was not produced, and in another experimental model there appeared to be a genetic defect which stopped this protein, this signal, from being recognised.

NORMAN SWAN: These were these experiments where they actually had mice with a common blood circulation, and one of which was fat and one of which was thin?

GREG COONEY: That's correct.

NORMAN SWAN: And they found that in some mice, the normal mouse could make the fat mouse thin?

GREG COONEY: Yes, that's correct.

NORMAN SWAN: Just by sharing it's blood?

GREG COONEY: Just by sharing its blood. So the assumption was that the fat mouse lacked something that the normal mouse had, which would control its appetite. And when they were connected up, the thin mouse was able to produce the blood-borne factor for the fat mouse, so it then ate less and lost weight.

NORMAN SWAN: And there were some fat mice, when they were joined up, that didn't become thin?

GREG COONEY: Yes, that's right. They were producing an excess of the factor. This had the effect of making the thin mouse that it was joined to, anorexic.

NORMAN SWAN: Because it was producing too much of the thin ....

GREG COONEY: Because it was getting to much from the other animal.

NORMAN SWAN: And the theory was that the fat mouse, which was producing too much of this substance, didn't have the right lock mechanism for the key to fit into, in the so-called receptor?

GREG COONEY: Exactly, yes.

NORMAN SWAN: Now what's been the latest finding that everybody has been making so much fuss about?

GREG COONEY: Well, the thing was that it was known that this must be genetic and, last December, a group in the United States characterised the gene which was producing this factor, and showed that in the ones that didn't produce the factor, that there was a genetic mutation in the gene which could be responsible for it not producing the factor. But because they had the gene sequence for this factor, they were then able to produce it outside the animal, using genetic engineering, and then inject it back into the animals, to see what effect it would have.

NORMAN SWAN: And this is the most recent finding. And they're calling this 'leptin'?

GREG COONEY: They're calling it leptin because the original discoverers of the gene are using the Latin root 'leptos', meaning 'thin'. And they are saying that this protein, when injected into these mice, makes them thin, and therefore they would like it to be called leptin.

NORMAN SWAN: The big question is: Does the research in fat mice equate to fat humans?

GREG COONEY: Perhaps not in the simplest way. What has been found is that there is, I think, 80 per cent homology between the mouse gene and the human gene.

NORMAN SWAN: By 'homology' you mean the code is similar or identical.

GREG COONEY: Yes, it's extremely similar. And so there is probably a very similar protein produced by adipose tissue in humans, as the one produced by adipose tissue in mice.

NORMAN SWAN: But does anybody know yet whether or not there is a failure of production of this in people who are fat, or it's a problem with the receptor?

GREG COONEY: There is one study that has been published so far, in a very small number of people, I think it was six or eight, where they mapped the gene and decided that it did not have a mutation or the same mutation as the particular model of obese mice.

NORMAN SWAN: So the message didn't seem to be the problem?

GREG COONEY: So the message didn't seem to be the problem. And more recently, the presence of the protein has been shown in serum from some humans. So it would appear that perhaps the easiest scenario which is for this protein to be absent in humans and simply by making it and replacing it that you will be able to correct obesity, doesn't seem to be the scenario at the moment.

It seems to be more likely to be a problem with the receptor end of the thing which gets into the brain and the areas of the brain which control appetite, and looking for the receptor in there and what might modify it or what might change it.

NORMAN SWAN: What a blow, particularly for people who might have bought shares in AMGEN, the company that holds the patent on the gene.

GREG COONEY: Well, I think if you've got the shares, you're probably okay, .... whether it comes to anything.

NORMAN SWAN: So in other words, just to summarise: the story may be true for humans, but not all humans who are fat; it may only just be a small subgroup.

GREG COONEY: Well, I think that the general theory applies to humans, that it does seem that human adipose tissue produces a factor similar to that in a mouse, which has been shown to control appetite and food intake. Now the defect that causes people to perhaps overeat or have lower energy expenditure, which might be a major cause of their obesity, is probably not likely to be a simple absence of this protein.

NORMAN SWAN: So don't leap into leptin just yet. Dr Greg Cooney is NHMRC Research Fellow in the Department of Endocrinology at Royal Prince Alfred Hospital in Sydney.