SCIENCE; SELLING THE BIG ISSUE

Is your weight determined by your genes and not what you eat? Hilary Bower reports on the search for an obesity cure

Anyone who has spent their life counting calories knows that obesity is all about figures. But these days the important figures are no longer just the one you see reflected in the mirror, the number of calories in a grapefruit, or how many minutes of sex are needed to cancel out last night's burger, fries and thick chocolate shake.

The crucial figures are the six weight-related genes, half-a-dozen brain proteins, 12 anti-obesity drugs, a doubling in the number of obese people, pounds 2 billion pounds and rising in health costs.

Once to be fat was to be happy and also a sign of health and prosperity. Large men were envied while curvaceous women were celebrated as models of fertility and beauty. Now tubbiness is a time bomb with the fuses already lit and running to all our vital organs.

Based on body-mass index (BMI) - a measurement found by dividing your weight in kilograms by your height in metres squared - the number of British people considered clinically obese has doubled in the last 10 years to 17 per cent of men and 13 per cent of woman, and 50 per cent of us are overweight.

A BMI of 20 to 25 is normal or ideal and over 30 is considered obese, but recent epidemiological [population-based] studies have revealed health risks start to climb even with a small spare tyre.

According to statistics compiled by the Association for the Study of Obesity, a person with a BMI of 27 has double the risk of heart disease, hypertension and gallstones and 14 times the chance of becoming diabetic. With a BMI of over 30 this soars to four times the risk of heart disease, hypertension and gallstones, 30 to 50 times the risk of diabetes and a quadrupling of the chance of degenerative arthritis.

The cost of treating this ill health is huge, conservatively estimated at around pounds 2 billion a year in the UK not counting the impact of work lost, benefits paid and social disruption.

But can we help it? Findings from genetic researchers over the past two years suggest we may have much less control over our expanding waistlines than we've been encouraged to think. Using information gleaned from rats and mice, researchers have discovered that our eating habits are governed by a complex series of switches and relationships that work to keep the body's energy intake and energy usage in balance.

The first clue to the labyrinth was revealed two years ago when US scientist Jeffrey Friedman, and colleagues at the Rockefeller University New York, discovered that a species of chronically obese mice had a defect on what is now known as the obese or ob gene, which resulted in constantly low levels of a protein they named leptin. Mice with the defect grew rapidly to three times the size of a normal mouse, but when they were injected with leptin, lo and behold, they lost weight.

Manufactured by the ob gene, leptin circulates in the blood at levels corresponding to the amount of fat in the body and appears to act as signalling system which guides the brain's control over basic metabolic functions such as heat creation, digestion and energy storage.

When leptin reaches a certain level, the brain registers that enough fat has been taken in, turns off the "I need food" message, and initiates a new message to stimulate energy burning rather than conservation, and tells the ob gene to stop producing leptin. Conversely, when leptin levels in the blood fall, the brain activates the desire to eat and slows metabolic functions to conserve energy. With the arrival of fat, the ob gene switches on and leptin levels start to rise again.

Exactly how all this occurred was a mystery but it looked like the ultimate diet pill. All that was needed was to find a way to artificially increase leptin and trick the brain into thinking the body had eaten enough.

Unfortunately this eureka moment didn't last long. Further research found that though humans have the ob gene, the mouse mutation simply doesn't occur. Not only that, but obese people don't have low levels of leptin, they have high levels - as high or higher than slimmer folk.

While scientists pondered this setback, research findings in rodents continued to add flesh to the skeleton pathways of weight regulation.

The diabetes or db gene cloned in December 1995 by a research team from Cambridge Massachusetts, was found to control the protein receptor that starts up the response to leptin. Diabetic mice with their bad copy of the gene, it appeared, were not receiving the leptin signal and, as a result, ballooned rapidly from infancy.

Mutations on two other genes coded in the past year make mice put on weight more gradually - more like humans. One, the fat gene, controls an enzyme that processes insulin, the hormone which signals to the body that it has been fed. The other, tubby, produced an enzyme unlike any seen before.

While researchers do not know how these two defects translate into extra ounces the implications of another gene, RII, reported this summer by Harvard scientists has again sparked excitement. RII appears to be responsible for regulating heat production in cells. Mice bred without this gene can eat extremely high-fat diets but don't put on weight because their fat cells overproduce heat. This wastes food calories and depletes the fat stores: they don't eat or absorb less food they just use more up and seem none the worse for it.

As with ob, none of these mutations have been discovered in the human genome, though the genes themselves are there. Nevertheless, according to British leptin expert Professor Paul Trayburn from the Rowett Research Institute in Aberdeen, the rodent genes have revolutionised the way we think about weight regulation by focusing attention on a finely tuned set of metabolic tripwires that regulate the body's energy intake and expenditure.

"What the ob gene and the others did was to tell us about a normal body system for controlling weight. It showed us where to look. There is good evidence now that leptin affects energy expenditure more than the desire to eat. Ob ob [when the ob genes have been inherited from both parents] mice get fat without increasing their food intake because their energy expenditure is out of balance with their intake.

"What we don't know yet is whether leptin is the big fat controller or just a postman sending messages along about how much fat we have on board. If it is just the postman then it's always good to get the post but it's a completely different role from the chief executive making the decisions."

One of the rival candidates for "chief executive", according to Professor Gareth Williams, an expert in the convoluted links between obesity and diabetes at Fazakerly Hospital Liverpool, is neuropeptide Y (NPY) - a protein found in the hypothalamus, the area of the brain that controls the body's automatic functions like breathing and temperature control.

NPY has long been known to be a potent appetite stimulant. Give it to normal mice and they will overeat in a spectacular fashion, eating when they are full, at the wrong time of day, and even when they have been primed with drugs that should quell appetite.

Work which has broken NPY down into different types of receptor now suggests that one of these - NPY5 - is the switch activated by leptin which sets off the body's regulatory response. If this is so, it prompts two possible explanations for why obese people with their high levels of leptin can't activate it, says Professor Williams. Either there is something wrong with the NPY receptor itself: like the receptor mutation caused by the db gene. Or there is something wrong with the mechanism that transports the leptin across the blood-brain barrier - the sieve-like mechanism that ensures only molecules absolutely necessary for brain function are able to get into the brain's fluids.

This, says Professor Williams, is one of the most exciting lines of biochemical inquiry, not least because evidence of a transport fault has just been found in humans. Research reported this summer discovered heavy people with high levels of leptin in the blood have very low levels of the protein on the other side of the blood-brain barrier, in the cerebrospinal fluid.

"We don't know yet whether the difficulty of getting leptin in to the cerebrospinal fluid comes down to a genetic fault, or whether there is so much leptin around that it sets up a resistance, but it could explain why people with lots of leptin still get fat. The hypothalamus simply isn't seeing all the leptin floating around," according to Professor Williams.

If this is so, then a drug which mimics the tiny transport molecules needed to carry leptin in to the hypothalamus could cure obesity.

But do these discoveries mean we can relax, stop pursuing that illusive diet and put our extra pounds down to genes and malfunctioning energy systems? Not exactly.

Estimates of the degree to which genes regulate obesity range from 20 to 80 per cent depending on your side of the nature-nurture divide. Genetic proponents point to powerful twin studies which show twins reared apart echo the shape of their biological parents not their adoptive ones, regardless of the food in the refrigerator, the frequency of meals, or the level of activity the family indulges in.

The concept of an out-of-balance regulatory system squares with the fact that few people become obese because they can't stop eating, they say, and lays to rest the puritanical view that obesity is a result of a gluttonous lifestyle which can be overcome with willpower and restraint.

But critics like Dr Tim Gill, scientific secretary of the International Obesity Task Force and director of postgraduate nutrition and dietetics at the Rowett Institute, point out that none of this explains why we have ballooned over the last 10 years. Our genes are the same as they were 10, 20, 50 years ago and obesity is five times more prevalent among the poor in developed countries than among the rich. This indicates a strong environmental influence says Dr Gill: "Genes may influence your susceptibility, but you don't become obese without consuming excess calories or failing to burn them up."

Thirty years ago people ate between a quarter and a third more calories, but did the equivalent of a marathon a week in extra physical activity. Cars, central heating and supermarkets have all massively reduced the amount of energy we need to expend to survive while increasing the pace of life so dramatically that all we feel like doing at the end of the day is collapsing in front of the TV, explains Dr Gill.

Our environment is obesogenic. The level of physical activity it encourages is extremely low, so we don't burn as much energy. Parents are loathe to allow their children to play outside because it's dangerous, riding a bike is suicidal and trying to find the stairs in a building is an exercise only in ingenuity. On the other side of the equation our food supply has gone from low energy, high roughage to being dominated by fat.

Today around 40 per cent of our calories come from fats. The problem is that our metabolism copes with them less efficiently than with carbohydrates and proteins. Eat a plate of pasta and your body will throw its carbohydrate combustion rapidly into high gear and burn it off, but eat a fat dripping hamburger and your fat oxidation rate will hardly budge. In addition the signals which tell us when we've consumed enough seem to respond quickly to carbohydrates and proteins but slowly to fat - too slowly to stop us eating far too much of a high-fat meal.

It is at this point that the nature and nurture arguments may begin to dovetail with unburnt fat offering a potential cause for excess leptin.

If the secret of slenderness is hidden in our biology, can we find a drug to unlock it? Unimaginable riches await the company that delivers a slim, fat-free figure with a pill, not only because obesity is common, but because it's likely the drug will have to be taken indefinitely.

Recent progress in untangling the biological loops that control body fat has created a plethora of new targets for drug therapy. According to a report in Scientific American, at least 12 types of treatment are under trial with some companies predicting product launches within two years.

Some drugs act on "feel good" chemicals in the brain to give a mood boost without food. Dexfenfluramine - the only drug licensed for weight loss in the UK - works on serotonin, which appears to switch off appetite just as neuropeptide Y turns it on. Other drugs target dopamine which affects blood sugar and fat processing in the liver, and noradrenaline which seems to quell hunger as part of the "fight or flight" response.

The so-called "fat magnets", which inhibit absorption of fats, have succeeded in causing up to a third to pass through the body undigested in human trials. Other trial concoctions stimulate muscle cells to burn fat rather than sugars or focus at stomach level with drugs that slow gastric emptying, mimic the systems that make us feel full, or boost levels of insulin.

Drug therapy may not be the answer if you want to shift a few kilos off the hips. Nor can it be first-line prevention for those who seek to indulge without penalty. But as knowledge increases of the genetic and biochemical loops behind our battles with the bulge, many obesity experts now believe that for those who have tried every diet, the medical approach may be the only way to avert an epidemic of ill health. !

WEIGHTY MATTERS

LAST WEEK the Scottish Intercollegiate Guidelines Network (SIGN) and the Royal College of Physicians of Edinburgh launched a radical approach to weight management, including controversial backing for increased use of appetite-suppressant drugs.

The guidelines call for a "revolution" in the way the public and the medical profession view the trial of losing fat. No more should the bulky be encouraged to reduce to an "ideal" svelte weight - Scottish experts say this primes us for disappointment and batters our self-esteem. Instead the aim should be first and foremost not to put on more weight, and second to lose modest amounts in three-months dieting sessions, followed by a period of weight maintenance to allow the body to stabilise its energy use.

It is persistent weight gain that is the bogey man of health, say the SIGN investigators. Even a water-cracker's worth of energy imbalance can lead to a 2kg weight gain annually. Yet small reductions of 5kg to 10kg can make a dramatic difference to health risks regardless of what the individual's starting BMI is, reducing, for example, premature death by 20 per cent and deaths through diabetes by 30 per cent.

But it's no good waiting until we all have love handles: we have to catch that fat before it goes on. The guidelines say identifying those prone to putting on weight, even as early as childhood, should be a priority for health professionals who can then target advice.

But for those who simply can't keep off the pounds, obesity must be treated like any other chronic medical condition - with long-term drug therapy, say the investigators.