Alex Blakemore - New obesity gene

Kat - More than 30 genes are now known to be involved in obesity and, intriguingly, most of them seem to be active in the brain, controlling eating behaviour and hormones. Researchers at Imperial College in London, led by Alex Blakemore, have used DNA sequencing technology to pin down the cause of one young woman's severe obesity to a faulty version of a gene called carboxypeptidase E, or CPE, publishing their findings in the journal PLoS ONE. 

Alex - The earliest studies of genes causing human obesity followed on from looking at mouse models of obesity. So, you have certain strains from mice that, just hanging around in their cage with other mice, had a tendency to eat very much more than the others and became very, very fat. Those mice weren't doing that because they were mice with weak personality or rubbish life. They were just mice along with the other mice. And so, by looking at those mice, we found a way into understanding what controls eating behaviour. The first mouse that was investigated in that way was called the 'obese' mouse, and that began to be understood in about the early 1990s. But since 1974, there's been another mouse that became obese which is known as the 'fat'  mouse. That mouse had a defect in a gene that processes the hormones that control appetite and the regulators in the brain that control appetite. But there had never been a human person found with problems with that gene.

Kat - Until now.

Alex - Until now. This is the first case of what's called carboxypeptidase E deficiency found in humans although we've had the mouse models for some time. The mouse has eating behaviour problems becomes very obese. It has obesity, it has fertility problems, and it has memory problems. And so, this woman that we found was a woman of 20 years of age who has problem with the same gene. She also have that same constellations of features. So, she has severe obesity since she was a child. At the age of 20, she weighs twice what her maximum recommended weight would be. She has reproductive issues, some intellectual disability and hasn't been able to learn to read despite schooling. She also has type 2 diabetes.

Kat - And how did you actually find out that this woman had this faulty gene?

Alex - She was referred to us by the consultant endocrinologist, Tony Goldstone, who was looking after her. And so, we included this family in a sequencing study looking at the sequence of their genes. And we first looked for problems with some of the already known obesity genes, but we drew a blank there. So then we started to look at other genes that had been implicated in obesity but not found in humans and big among those among those was the fat mouse. So, we looked at that gene and we were surprised to be that this young woman had two broken copies of the gene so she couldn't make carboxypeptidase E at all.

Kat - Given that you found this one woman, this one family where it seems to be this gene fault, do you think that there may be other people out there with this faulty gene? Do you think that it might lie at the heart of many cases of severe obesity?

Alex - It's very difficult to tell right now. While we were writing the paper about this, we saw that in an online database of genome sequences from around the world, two other people have been seen who carry exactly the same mutation. So, it could be that it's more common than we anticipate but has been missed.

Kat - So, is it fair to say that obesity is really in the genes, but then what can we do about it?

Alex - I think we have to stop thinking of obesity as a single disorder. Everybody is obese for a different reason. For some people, it might be almost totally environmental and for others, it's almost totally genetic. One of the useful things we can do is try to find ways of seeing which is which, looking at people to say, "Okay, is this a genetic condition for you or is it an environmental condition for you" because the way we manage people might be different, depending on the different causes.

Kat - So, it's not as simple as saying, "It's just all in my genes. There's nothing I can do. Pass me the cake."

Alex - No, absolutely not. That's a very funny idea that people have got that because you might tell somebody that they've got a genetic condition then they won't be motivated to do something about it. In our experience, the opposite might be true. It's very, very helpful for people to have a diagnosis and be told, "You have an actual disorder which we can describe. It's not your fault. It's not a character flaw, but it is a battle you're going to have to fight for the rest of your life." In our experience, it doesn't make people throw in the towel. It gives them renewed vigour because what really saps people's energy is the sense of guilt and shame about their obesity and the feeling that there's nothing they could do about it because of that. So, to say something genetic, it doesn't mean it's cast in stone or that you shouldn't fight against it. It just lets you know that you're likely to have a harder fight than the general person in the street.

Kat - That was Alex Blakemore, from Imperial College.