In search of the lean gene

With an abundance of food in the West, it's no surprise that people are getting fatter. But why do some remain slim? Experts believe the answer could lie deep in our DNA. Jeremy Laurance investigates

(AP)

Seven years ago, the death of a three-year-old girl in east London, who was so grossly overweight she was said to have been "choked to death" by her own fat, created a media storm. She was presented as the youngest casualty of the obesity epidemic in a report by the Commons Health Committee, and although she was mentioned only in a single paragraph at the beginning of its 146-page document, and unidentified, she made headlines around the world.

The MPs wanted her case to serve as a warning of how overeating would soon kill more people than smoking, and how today's children would become the "first generation to die before their parents". She became, as Professor Stephen O'Rahilly, an obesity expert at the University of Cambridge, observed at the time, the "poster girl" for the obesity epidemic.

What the committee did not know was that blood samples from the girl had been sent from the Royal London Hospital, where she had been treated, to specialists at Addenbrooke's Hospital, Cambridge, to assist with a diagnosis. They found that the girl had a genetic defect that gave her an insatiable appetite and that it was "completely scientifically inappropriate" to link her case with the problem of childhood obesity.

Professor O'Rahilly, who heads the obesity research laboratory at Addenbrooke's, decided to speak out about the case because, he said, it seemed "rather cruel" to expose a child on the front pages of the newspapers as an example of how parents were "stuffing their children" in a way that made them liable to charges of child neglect. "It was a terrible indictment of the parents when we knew there was a genetic defect in this child and we knew 100 per cent that was the cause of her obesity," he says.

The dispute reflected a wider confusion about the relative contribution of genes and environment to the global problem of obesity. Which determines how fat we are? Many would like to claim that, like the three-year-old girl, they are victims of their genetic make-up, powerless to counteract the legacy of their inheritance.

But we are also products of our world. We lead an increasingly urbanised, office-based lifestyle with a surfeit of cheap, readily available, calorie-dense food. This is the so-called "obesogenic" environment – one that encourages overeating and sedentary behaviour. We are all exposed to it – so why are we not all fat?

In a lecture at the Cambridge Science Festival this week, Professor O'Rahilly will seek to answer this question. People who are fat, he says, are often dismissed by their leaner peers as greedy, lazy and stupid. "Eat less and move more," they are told. But this ignores the influence of their genes.

The key question, he says, is not why so many people are fat – almost one in four adults in the UK is obese, and the numbers have tripled in the past 30 years – but why some remain lean. How do they do it?

Most lean people are naturally lean. They do not have to struggle to be that way. That points to a genetic explanation – they naturally have smaller appetites or burn off calories more readily and thus can eat freely without thinking. "We know for sure that a propensity for obesity – or its opposite, a propensity for leanness – is rooted in the genes. Some 70 per cent of the variation between people in terms of their amount of body fat is explained by inherited differences that are built into our genetic make-up and passed from generation to generation," he says. "What our work has shown is that, rather unexpectedly, a lot of these genes primarily influence appetite and satiety – in other words, how hungry we get and/or how satisfied by a particular amount of food we are – rather than how fast or slowly we burn off calories."

There are around 32 common genetic variants so far identified that influence whether an individual will be fat or lean, based on twin and adoption studies in 250,000 people. Separately, they have small effects – the most powerful add perhaps 3kg to a person's body weight. But when taken together with other, still unidentified, genetic factors, the overall effect is large. Some people, in other words, are born lean.

How, then, can the obesity explosion in the past 50 years be explained? It is too short a period to be accounted for by genetic selection, which takes place over thousands, or millions, of years. White skin was selected in northern populations, for example, as they moved away from the Equator. With less sunlight it was advantageous to make extra vitamin D from what sun was available, and thus pale skin became the norm.

Fat, like vitamin D, also confers a survival advantage. In the 1960s, the American geneticist James Neel developed what became known as the "thrifty gene" theory to explain the increase in obesity. According to his hypothesis, the "thrifty" genotype would have been advantageous for early humans, allowing them to store fat in times of abundance and survive in times of food scarcity, through periods of famine.

It was thus preferentially selected through millions of years of evolution. But what used to be an advantage – the ability to store fat – has become a disadvantage in modern societies with an abundance of food. This genotype prepares individuals for a famine that never comes. The result is obesity and diabetes.

The "thrifty gene" argument begs the question: why isn't everyone fat? If everyone has it, everyone should have the same tendency to put on weight in the presence of an abundance of readily available food. "One theory is that we do all have it – and it is just our lack of moral fibre and the willpower to control our appetite that makes many of us fat. That doesn't seem right to me – perhaps because I am chunky myself," Professor O'Rahilly says.

"The biologist John Speakman from the University of Aberdeen has re-examined the 'thrifty gene' theory and suggested that it doesn't necessarily add up. He has suggested that famines weren't a huge threat before the advent of farming – about 15,000 years ago – and could not have had sufficient differential impact on survival of the lean and obese as to have had such a powerful selective effect."

Speakman's alternative theory, nicknamed the "drifty gene" hypothesis, is that the modern distribution of obesity stems from a genetic drift in the genes that control the upper limit on our body fatness.

Until around two million years ago, it was important for humans to remain lean in order to have the best chance of escape from predators. But once they started living in groups and discovered fire, they became less vulnerable. So being fat mattered less. Random mutations in genes that caused weight to drift upwards would then not have been selected against. "It is like having a thermostat in the brain that controls where on the fat spectrum you are going to be," he explains. "Some would stay the same, some would drift down, but quite a few would drift up.

"The explanation for the modern obesity explosion is that only in the last 50 years have humans had enough calories available without expending vast amounts of energy to get them. Obesity used to be a disorder of the rich – now, it affects everybody. The 'drifty gene' theory provides a more satisfying explanation of why, even in places where obesity is very common, a large proportion of the population remains lean. We have all drifted naturally to our set level of obesity. Lean people are mostly naturally lean."

Genes can still dictate 70 per cent of the variation, even as average weight rises as a result of modern environmental influences – fast-food outlets encouraging us to eat more and motorised transport helping us to do less. Such influences shift the whole distribution towards the heavier end of the scale.

Professor O'Rahilly insists he is not nihilistic about the future. Controlling obesity will, he says, require sustained pressure on the environmental side – tackling food marketing and quality – but may also require intervention on the biological side. "We study the genetics to understand the wiring under the car bonnet. If we can understand it, maybe we can tweak it."

He draws a parallel with high blood pressure – once a frightening condition that put people in hospital in the 1930s and led to their undergoing heroic surgery, which often left them more disabled. Today, high blood pressure is controlled by altering the diet, reducing salt and by cheap drugs with few side effects, taken by millions of people.

Obesity, he acknowledges, presents a tougher target because the control systems for body weight are in the brain, not in the blood vessels. But the success of bariatric surgery points the way, he says. "We know bariatric surgery works. It is more than shrinking the stomach – it changes the hormones that are released, so people feel less hungry. If we could obtain the same effect in a cleverer way than with a surgeon's knife, that is what we want. I remain optimistic – but we are in [it] for the long haul."

The Cambridge Science Festival takes place until 27 March. Go to www.cam.ac.uk/sciencefestival or phone 01223 766766.

Drugs to treat obesity

The newest kid on the block is a drug developed by US pharmaceutical company Zafgen.

Results of an early phase-1 trial of its compound ZGN-433, released in January,showed it produced dramatic weight loss of 1kg a week in severely obese patients, equivalent to 20-40 per cent of total weight over a normal treatment period of six to nine months.

The drug has created a buzz of anticipation in the obesity world, even though trials are still at the earliest stage, because of the scale of weight loss it has apparently achieved. But its long-term safety and tolerability have yet to be established.

The record with previous drugs has not been good. Rimonabant and sibutramine were both hailed as major advances in the battle against obesity in their time, but both have since been withdrawn over safety fears relating to depression and suicide associated with the first and cardiovascular effects with the second. That leaves orlistat as the only drug treatment for obesity currently on the market.

One drug with immediate promise is liraglutide, currently marketed for people with type 2 diabetes, but which has been shown to promote significant weight loss. Studies are under way that are expected to lead to its being granted a licence for the treatment of obesity.