Science Interviews

Interview

Tue, 14th Jul 2015

Alex Blakemore - New obesity gene

Alex Blakemore - Imperial College London

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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.

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It's my excuse, anyway. alancalverd, Tue, 14th Jul 2015

"Call it the Amish paradox. An exercise science professor has discovered that a pocket of Old Order Amish folks in Ontario, Canada, has stunningly low obesity levels, despite a diet high in fat, calories and refined sugar -- exactly the stuff doctors tell us not to eat.

They're at a paltry 4% obesity rate, compared to a whopping 31% in the general U.S. population, which, as we all know, is getting fatter by the minute. This group of Amish manages to keep its overweight levels low despite a diet that includes meat, potatoes, gravy, cakes, pies and eggs. So what's their secret? Exercise, people. Exercise.

For starters, of the 98 Amish pedometer-wearing adults surveyed over a week, men averaged about 18,000 steps a day, women about 14,000. Most Americans do not come anywhere close to that, struggling to get in the recommended 10,000 steps a day." (1.)

The old order Amish call outsiders "English". Maybe you shouldn't be so "English".

Genetics, Hah! If you walk 18000 steps per day, it is highly unlikely you will be fat. I lost 20 pounds walking the Camino de Santiago from Seville to Santiago de Compostela. Good for the body, good for the soul.


(1.) http://articles.latimes.com/2004/jan/12/health/he-amish12 Pecos_Bill, Tue, 14th Jul 2015

Is being fat in our genes?

It is if you're overweight and happen to be wearing a pair of Levi's.

Sorry folks, I just couldn't help myself........................ Ethos_, Tue, 14th Jul 2015

Exercise is unimportant compared with wind chill.

The maximum useful work output of a manual labourer is less than 3 megajoule/day, but you need about 6.5MJ/day from food to maintain your body weight when resting in a 20 degree environment. For an office worker, we are talking about 75 - 80% of your calorie intake being used simply to keep warm and maintain heart and brain function.

In an arctic environment, unless you are wearing full Eskimo kit, you can burn 30 MJ/day just to stay alive.

So here's what distinguishes the Amish and our grandparents (who, in the UK, ate 10 - 20% more calories than the present population): no central heating, and a fair amount of time outdoors in all weathers. 

I've often thought about opening a "gourmet cold camp" in Norway or Greenland, where you can eat well and lose weight, or end your life pleasantly by hypothermia. alancalverd, Wed, 15th Jul 2015



Your point that exercise is they key to avoiding obesity may very well be true , but using the Amish data doesn't prove obesity isn't genetic as Amish are genetically isolated. They are not a representative-sample of the general population : gene(s) to avoid obesity could be over-represented in the Amish gene-pool. RD, Wed, 15th Jul 2015

The chances of the Amish being of some genetically distinct clade of the human race cannot be dismissed nor can it be dismissed that they aren't obese because God loves them more than the other people. However - by Occam's razor - they are lean because they engage in strenuous farm labor six days a week and all year long.

When I went to Russia to teach English in 2003,  there were <<no>> fat people.  I, in fact, lost 30 pounds sharing their lives that winter. Now when the Russian students would return to Tomsk after a year's exchange in Vermont, they would all have blown up like a bull moose...until returning to quotidian Siberian life they thinned down again. Was that genetic? I think not.

I will put you another case. The Pima Indians living in southern California live a pretty normal sedentary American life. They suffer pronounced rates of obesity and type II diabetes. The Pima indians living across the border are dirt poor. They spend their lives eking out a bare living in daily toil growing corn and squash-- which is the major part of their diet. THESE Pima Indians are lean as whippets and Diabetes type II is virtually unheard off.

Same genes- different lifestyles and certainly different health risks.
Pecos_Bill, Wed, 15th Jul 2015

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