Obesity And The Genetic Basis of Appetite

08 January 2006

Interview with

Prof. Steve O'Rahilly, University of Cambridge


Kat - Why is it that you get some people who seem to eat chips and lots of other stuff and they're still skinny as rakes, and I just have to look at chocolate and become a porker?! What's going on?

Steve - Like everything in science, you have to work out whether your premises are correct or not. I have to say that the evidence you just said then is actually very poor. When you take people who are predisposed to obesity and put them under controlled settings and monitor what they eat, in general, obese people eat more than thin people. Although we all think we have friends and colleagues who can eat like pigs and not put on weight, when you put them under experimental conditions, it's very hard to prove that that actually happens, or at least happens on a regular basis. There's no doubt that people with some conditions, such as when your thyroid is over-active and your metabolism is extremely stimulated, will eat lots and still lose weight. However under normal circumstances, the cause of obesity is eating that little bit too much for your metabolic rate. That's not a blame issue. It's an issue that some people really are driven to eat rather more than others. We've looked into that over the last ten years or more, looking at children for example that are particularly prone to obesity at an early age. We've found that many of them have genetic defects causing then to fail to notice fullness, so they continue to eat even when others have stopped. Our particular interest is in the genetic basis of appetite. Going back to your initial question, what you've suggested as a common scenario isn't actually that common. That's one of the great things about science; sometimes things that seem common sense turn out not to be true.

Chris - What do we now understand about how appetite is controlled in the nervous system and in the stomach.

Steve - Firstly, we're beginning to know that it is controlled to some extent, but for many years people were of the opinion that we're at the mercy of our exogenous environment. It's only in the past few years that we've discovered that there are signals sent out to the brain that at least provides the brain with information about how many nutrients are being stored. In the absence of those signals, your brain is ravenously hungry. One of those signals is called leptin, and if you don't have that, you are ravenously hungry all the time.

Chris - Where does it come from?

Steve - It comes from fat cells, so the cells you use to store excess energy. We have these so that in times of starvation, we can use it. Very cleverly, these cells produce this peptide hormone called leptin which travels to the brain and keeps the brain informed about how much stored energy we have on board.

Chris - So how do the fat cells know how much leptin to produce? Presumably if the brain can see a certain amount of leptin, it knows there must a certain amount of fat on the body. It must then know how hungry it should feel. Is that how it works?

Steve - It sort of works like that but it has a slightly different mechanism and isn't quite as simple as we'd like it to be. If it was very precise, we'd all be the same weight and would all be able to readily control our weight. Leptin works best at the very very low end, in other words, when you are very thin. The leptin levels become very low and your brain tells you that you are starving and must go and find food. It dominates your life and also switches off reproduction, which you can see when girls with anorexia nervosa stop having periods. At that very low end, leptin works. The problem is that when leptin levels get higher, the brain gets bored and stops taking any notice.

Chris - So does this mean that if you get a bit too big, you get too high levels of this protein and the brain goes deaf to the signal?

Steve - Yes, so-called leptin resistance comes in.

Chris - So if you take an animal and you inject it artificially, does it think it's full up and not eat even though it's eaten nothing?

Steve - Absolutely. You can give it to a rat and it remains a perfectly fit and well rat but without any body fat. It's also been given to humans, and in normal human beings, they lose fat.

Chris - What about in fat people?

Steve - Due to leptin resistance in fat people, injecting leptin is less effective. It probably isn't ineffective, but we can't get enough of it in because the body is so leptin resistant. A lot of research now is going into why people are leptin resistant and what's downstream of leptin in the brain. This is where lots of the exciting current research is.

Kat - How close are we to finding the wonder pill that people can take, or is that not really the answer?

Steve - I don't think that there will be one wonder pill, but I'm not as anti-pill as many people are with respect to obesity. If we go back 50 years and look at high blood pressure, everyone thought it was down to stress and lifestyle and that it wasn't really a disease. People were a bit uncomfortable about giving people a pill for something to do with stress. Now we treat high blood pressure extremely well and stroke rates in this country have come down and people are living longer due to good hypertensive therapy. We sometimes have to use two, three or four drugs to cure people but doctors prescribe them and we pay for them as a nation. In twenty or thirty year's time, we'll probably have the same attitude towards obesity, and we'll see that people with obesity are at serious risk and we'll see nothing wrong with helping them with therapies to go along with lifestyle, exercise and diet.

Chris - What is the potential cost to the UK at the moment of the roughly one person in five who's obese?

Steve - I'm not a health economist but it's billions in terms of lost work days and secondary illnesses associated with obesity such as diabetes. It's an enormous cost.

Len - It's about 8.3 billion per year.


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