A big, fat leap forward

Remember leptin? The much-publicised "fat-busting" protein? Maybe not. A few years can be a long time in the fad-prone world of obesity and weight loss.

Leptin's big moment came in the mid-Nineties when it was given to a bunch of grossly overweight mice. The flab melted away. The results from human trials were, sadly, less than spectacular.

But that wasn't the end of the story. Earlier this month, the medical news of the day was of a French drug called Rimonabant. Two studies had shown that it not only combated obesity, but also encouraged smokers to quit their habit. It seems to work by blocking the same chemical signals that make cannabis-smokers feel peckish - and these signals are reckoned to be part of a much wider system of appetite and metabolic control: the leptin system.

Back in 1994, Dr Jeffrey Friedman of the Howard Hughes Medical Institute at New York's Rockefeller University uncovered the root of the problems besetting a strain of obese mice. He showed that they had an inherited inability to make a particular protein, leptin. Dosing them with it induced dramatic weight loss. "The work began to offer a molecular and physiological explanation for obesity," says Dr Friedman. Getting fat wasn't solely about self-indulgence after all.

So if mice, why not men? We too have a leptin gene. A course of leptin, even a lifetime of swallowing it, is surely preferable to a thickening waist or an unrequited craving for chocolate.

In a world where many go hungry, tackling obesity with drugs may strike some as decadent. Like most doctors, Professor Steven Bloom of the Imperial College Medical School in London, is not happy about people using a drug in isolation from other methods of weight loss. "You should never do this," he says. "But the reality is that people have difficulty controlling their intake of calories."

In one group of humans, however - children with an inherited inability to produce their own leptin - the drug has lived up to the hype. Steven O'Rahilly, professor of clinical biochemistry at the University of Cambridge, has treated half-a-dozen such patients. "These children are huge, and effectively wheelchair-bound. All show a dramatic response to the replacement of leptin. Over time, their weight goes away."

Drug companies, of course, were more interested in leptin's potential for dealing with more everyday forms of obesity. One company, Amgen Inc, reportedly paid $20m for the rights to exploit the new finding. The results of the first trial, carried out on some 70 obese volunteers, appeared in 1999. They were not impressive.

Dr Friedman was not surprised. "It was what I expected," he recalls. "In the obese, for some reason, the ability to respond to leptin is reduced." This is not unlike the predicament that some people with diabetes face: they make normal amounts of insulin, but their bodies don't respond to it.

"If you look carefully at the trial overall," says Professor O'Rahilly, "there was some weight loss." But it was modest and variable, and certainly not significant enough to suggest that leptin might prove to be a financial blockbuster.

The view from within obesity research was very different. "Whatever the result of that paper, it didn't detract from the scientific importance of leptin," Professor O'Rahilly claims. "It's actually typical of what happens in most discoveries. First there's hope that it's going to cure all human unhappiness. Then we all think it's useless. Eventually, things balance out and we agree that it's useful for this or that subset of patients."

What the earliest work made clear, he adds, is that in the absence of leptin nothing works to control appetite and energy balance. "This realisation transformed the obesity field dramatically. Until then, it had been a backwater with a lot of cranks."

But clear thinking about leptin was still fogged by a misconception about its role in the body. Give leptin to a fat mouse, the fat mouse loses weight. Therefore leptin must be an anti-obesity hormone. QED.

"We were always sceptical about that," says Dr Roger Unger, an obesity researcher at the Southwestern Medical Center in Texas. "There was never any evolutionary pressure to evolve a hormone that would combat obesity. Obesity was a godsend to our ancestors when there was famine once or twice a year. Those were the people who survived." Dr Unger was naturally disappointed when the clinical trial proved to be such a damp squib but, like Dr Friedman, not really surprised.

He and his colleagues had also begun experimenting with leptin. They administered large amounts of it to rats, then analysed the effect it had on the biochemistry of their fats. This reinforced Dr Unger's belief that leptin is not there to prevent obesity but, paradoxically, to allow it.

His reasoning goes like this. Certain parts of the body contain large numbers of cells, called adipocytes, that are specially adapted to store fat. But eat to excess, and even tissues made up of cells that are not designed to deal with fat become loaded with it. These cells may then malfunction. So cells that aren't designed to store fat need to be protected against accumulating too much of it. Leptin, claims Dr Unger, provides that protection. It triggers the breakdown of this hazardous excess.

Adipocytes, by contrast, do need to accumulate fat; it's their purpose. So they have to be able to resist the action of leptin. The dose that Dr Unger gave his animals overwhelmed that resistance. "We clobbered the adipocytes with an excess of leptin," he says, "and before they knew it they'd been converted into fat-wasting cells."

Precisely how leptin achieves this reprogramming is a matter of conjecture. "My own view is that most of leptin's effects are via the brain," says Dr Friedman. Professor O'Rahilly agrees. Dr Unger, however, more speculatively suggests that leptin works directly on each individual cell.

But what all three do agree on is that biologists will one day be able to map the chemical and/or nerve paths that make up the control system. We already know that leptin alone won't fix human obesity - but drugs that interfere with its control system might. The evidence is still scanty, but the new kid on the block, Rimonabant, may be just such a drug. Those fat-storage cells could yet be turned into fat-burners.