Arlington, Virginia
THERE IT sits, a quarter pound of perfectly cooked minced beef crowned with a slab of partially melted cheese, topped off with fresh lettuce, tomato and onion, all nestling between two halves of a hot bun. A smile lights up your face. You reach toward the plate, and鈥�
Hold on! Do you really want that plateful settling on your waist, thighs or bum?
If you decide, no way, you traditionally had two options: don鈥檛 eat, or do (a lot) more exercise-two public health strategies that have been spectacularly unsuccessful in halting galloping obesity in the affluent West. Now all that is changing, however, as pharmaceutical companies design a new generation of drugs that, for the first time ever, are based on a detailed understanding of the mechanisms our bodies use to control weight.
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鈥淧eople will always have to do some watching what they eat, but in the future we鈥檙e going to get more powerful drugs that will help them do the job,鈥� says Xavier Pi-Sunyer, director of the obesity research centre at St Luke鈥檚-Roosevelt Hospital in New York City. Those drugs, which will initially be targeted at the very obese, will have the power to change your relationship with that cheeseburger. To see how, follow the burger on its final journey.
How hungry you feel for the cheeseburger is going to depend on the mix of signals coming from your stomach, intestines, bloodstream and fat deposits, all integrated at the hypothalamus, the cherry-sized part of the brain that deals with instinctive drives. After blood sugar levels drop, the hypothalamus whispers to the parts of the brain that deal with conscious thought: 鈥淓at.鈥� Depending on other cues-how close it is to lunch time, how good the cheeseburger smells, and how guilty you feel about breaking your diet-you may listen to your hypothalamus, or pay it no heed. If you ignore it, the voice may go away for a while, but it will be back, shouting: 鈥淓AT!鈥�
Until recently, there has been little to put between you and that inner voice. The most common appetite suppressants available in the US (but not Britain) have been scaled-down amphetamines such as phenylpropanolamine hydrochloride. Like bungee-jumping, they give the brain a rush of the neurotransmitter dopamine which, supposedly by reinforcing the satiating effects of food, makes hunger fade. These drugs don鈥檛 have the bad side effects of amphetamines, but they are not very effective either, and the few pounds extra lost during a diet come right back.
So weight researchers have shifted their attention to another neurotransmitter-serotonin, the chemical which is boosted by feel-good drugs such as Prozac. Another drug that boosts serotonin is dexfenfluramine, the active ingredient in what last year became the first diet pill in 20 years to be approved by the Food and Drug Administration (FDA) for sale in the US. 鈥淒exfen鈥� has been available in Europe for several years.
Unlike the amphetamines, serotonin-increasing drugs don鈥檛 stop you picking up that cheeseburger, but they do seem to make you feel sated quicker-more likely to leave a bit of burger on the side of your plate. In clinical trials, that chemical restraint translated into an additional weight loss of up to 10 kilograms (a stone and a half) in obese dieters. (Definitions vary, but a person is usually considered obese if they are more than 20 per cent over their ideal weight.) Serotonin levels in the hypothalamus increase when an animal eats, so the best guess is that dexfen is having its effect by doing the same thing.
Stuffed
But dexfen has its problems: in rare cases it has been linked to pulmonary hypertension, an often fatal lung disease. And there are suspicions that dexfen, and its close cousin, fenfluramine, may damage neurons (This Week, 28 June, p10). Then, just last month, fenfluramine hit the front pages when researchers at the Mayo Clinic in Rochester, Minnesota, reported 24 cases of a severe type of heart disease in women in the US who had used it in combination with a dopamine-booster called phentermine.
The adverse news, however, is doing little to slow the coming of the new generation of drugs that interfere with brain chemistry. The next drug which is likely to hit the marketplace in the US is sibutramine, developed by Knoll Pharmaceuticals in Whippany, New Jersey. It鈥檚 a two-for-one drug that boosts both serotonin and noradrenaline, a second neurotransmitter involved in creating a full feeling. It may also increase the amounts of noradrenaline at nerve endings in the body. Noradrenaline is released by the sympathetic nerves that serve most organs. It signals the fat cells to burn energy as heat and makes skeletal muscle less efficient. It also makes the skeletal muscles less efficient so they use up more calories. Like dexfen, sibutramine can help an obese dieter lose up to 10 kilograms.
But no one expects dexfen or sibutramine to be a complete answer. After all, a loss of 10 kilograms tends not to show on somebody who is seriously obese.
So let鈥檚 suppose that, oblivious to the chemicals floating around your brain, you鈥檝e decided to eat the cheeseburger-the whole, fat-laden thing. There are still plenty of opportunities to stop the calories.
Chewing the burger breaks it into tiny pieces and mixes them with saliva rich in amylase, an enzyme that breaks long starch molecules into manageable pieces. Swallowing pushes the whole stew down the oesophagus and into the stomach. Here, the cheeseburger bits are bathed in hydrochloric acid and processed by more enzymes. The stomach churns the mixture for hours, gradually releasing it into the small intestine.
Blow-out
And as the stomach and intestine mash that cheeseburger, they send signals to other parts of the body to let them know what鈥檚 going on. The vagus nerve, for example, tells the hypothalamus that the stomach is being stretched by food. 鈥淓ight or nine years ago, doctors would put balloons in people鈥檚 stomachs to try to make them feel full,鈥� says psychiatrist Timothy Moran at Johns Hopkins University in Baltimore. 鈥淚t became the most commonly done gastrointestinal procedure.鈥�
The procedure did make patients eat less, although not a lot. But the balloons had an unfortunate tendency to deflate and slip into the intestine, blocking it and killing some people. 鈥淭he procedure very quickly stopped being done,鈥� says Moran. The new approach is to create that just-stretched feeling with a drug instead of a balloon.
Those cheeseburger bits stimulate cells in the upper intestine to release a chemical called cholecystokinin. CCK signals the pancreas to release enzymes that chop proteins into one, two, and three amino acid pieces, and carbohydrates into glucose. CCK also tells the gall bladder to send bile acids to help break fat into fatty acids and glycerol.
But CCK has another mission. It tells the vagus nerve to send the full signal to the brain. Since the mid-1970s, researchers have known that CCK reduces appetite sharply when injected into laboratory animals. Later trials showed that it also works in humans. But CCK does not survive long enough in the body to be taken orally, so the trick was to find a chemical that could get to the CCK receptors on the tips of the vagus before it was broken down.
In 1991, scientists at Glaxo Wellcome in Research Triangle Park, North Carolina, began screening the thousands of compounds in the Glaxo database, looking for those that had the same effects as CCK, so-called CCK agonists. At one time, 120 chemists, pharmacologists, cellular biochemists and others were in on the hunt-an indication not only of the difficulty of discovering such drugs, but also of the potential commercial value of an appetite-control pill.
The Eureka moment came in 1996. Glaxo鈥檚 Elizabeth Sugg and her colleagues found a synthetic CCK agonist that can be taken by mouth and cuts appetite in rats and primates. 鈥淚t鈥檚 exquisitely potent,鈥� she says. Depending on the dose, Sugg can cut the amount of food a rat or a primate eats, or eliminate feeding entirely. The drug has not yet been tried in humans (though clinical trials are planned) but she predicts that once the right dose is found it will be possible to cut the amount someone eats by between 10 and 20 per cent.
Sugg鈥檚 CCK agonist is seven years or more from the marketplace, but at least one other drug could be on the shelves in the US by the end of the year. Orlistat, a drug developed by Hoffmann-La Roche, is expected to win FDA approval this year. Usually, the stomach and intestines squeeze out every last bit of nutritional value from food-which is part of the problem for overweight people. A thousand years ago, when food was sometimes scarce, efficiency made sense. But in today鈥檚 affluent societies, people eat much more than they need, and many would be better off if their digestion weren鈥檛 so competent.
Orlistat helps achieve that goal by attaching itself to lipase enzymes in the stomach and intestines, and interfering with their cleaving of fat molecules, leaving much of the fat undigested. In clinical trials, orlistat cut fat absorption by up to 30 per cent, and over two years people on a moderate diet lost 65 per cent more weight than dieters given a placebo. The main side effects are a lowering of blood cholesterol-a potentially good thing -and mild bowel problems, such as loose stools, caused by the extra fat passing through the large intestine.
With or without lipase enzymes, our cheeseburger, having passed through the stomach and intestines, is now unrecognisable. The amino acids, sugars and fatty acids have crossed the gut wall into the portal vein that takes them to the liver. In the liver, much of the glucose is turned into glycogen and stored there, with some of the excess making its way to the fat cells. Some of the fatty acids go to make cholesterol and hormones, such as oestrogen. Many more-if our cheeseburger-muncher is already Rubensesque-are shipped to the fat cells and stored as triglycerides. Amino acids are used to build muscles, make hormones, or to produce more glucose. To be brutal, everything in that cheeseburger, be it fat, protein, or carbohydrates, can end up on the hips.
But the opportunities for weight control do not end with the end of the cheeseburger as we know it. Its distribution across the hips and thighs may take less than a day, but the body鈥檚 memory of that cheeseburger lasts far longer. The body has a remarkable ability to fine-tune its weight in the long term. Fat or thin (with the exception of the most avid dieters), adult weight remains constant with perhaps a gain of a kilo or so a decade.
Bathroom scales
Two and a half years ago, at the Rockefeller University, New York, Jeffrey Friedman and his colleagues made headlines when they got to the heart of those internal scales with their discovery of the ob-for 鈥渙bese鈥�-gene in mice, and its human equivalent Ob. Mice without a functioning ob gene balloon to twice their normal weight because their fat cells do not make a protein-named leptin after the Greek word for thin-that tells the brain how much fat is stored in the body. Leptin is the equivalent to the read-out on the bathroom scales. The more and bigger fat cells a mouse-or a person-has, the more leptin is produced. Too much leptin, and the hunger dial in the hypothalamus is turned down. Too little, and it is turned up.
The mutant mice that Friedman studied made no leptin at all, which meant that they behaved as if they were in a constant state of starvation, even when they became so fat they could hardly move. Now, a research team led by Stephen O鈥橰ahilly at the University of Cambridge has discovered that a lack of leptin does the same thing in humans (This Week, 28 June, p 7). Writing in Nature, O鈥橰ahilly and his colleagues described, two cousins whose mutant Ob genes do not produce functioning leptin. One, an eight-year-old girl, weighs 86 kilograms, while her two-year-old boy cousin weighs 29 kilograms. Both have been constantly hungry since early infancy.
Eight months after they discovered the ob gene, Friedman鈥檚 team and two others, one at Amgen and one at Hoffmann-La Roche, showed that giving leptin to mice with the defective ob gene brought their appetite and their weight back to normal. The three teams also showed that leptin causes weight loss in normal mice. The weight loss was modest, only about 10 per cent, but that finding helped to clinch one of the most lucrative deals ever for a piece of basic research. In May 1995, Amgen paid $20 million for exclusive rights to the Friedman patent.
Insensitive people
The researchers had originally hoped that human obesity might be a simple matter of having too little leptin. But in 1996, Jose Caro鈥檚 team at Thomas Jefferson University in Philadelphia showed that obese people actually have higher-than-normal levels of leptin; the two cousins are the only known exceptions. It seems that the heaviest among us are, for reasons still unknown, actually less sensitive to leptin. The hope now is that if you give obese people even more leptin it will help them lose weight.
And in June this year, Amgen announced to the media some mildly promising results. In the first phase of clinical trials, about 30 obese people injected with varying doses of leptin lost an average of between 2 and 4 kilograms over three months, compared with some 1.5 kilograms for people who got the placebo. Not exactly a miracle drug, but proof of the concept, at least. Now, Amgen researchers are trying to improve leptin鈥檚 effectiveness by modifying it so that it gets transported to the brain more efficiently.
The fat researchers suspect that once leptin has made its way to the hypothalamus, it incites the ebb and flow of a variety of appetite-changing chemicals. For example, as an animal loses weight, its blood leptin falls, and the amount of neuropeptide Y in the hypothalamus increases. When neuropeptide Y is injected into a rat鈥檚 hypothalamus, it eats ravenously.
Conversely, when melanocortin-4, or MC-4, receptors in the hypothalamus are stimulated, the mouse eats less. And injecting drugs that mimic-or block-the action of other brain chemicals like galanin, glucagon-like peptide-1 and corticotropin-releasing hormone also changes an animal鈥檚 appetite. No one knows yet how all these chemical changes fit together, but, says Arthur Campfield of Hoffman-La Roche in Nutley, New Jersey, it seems likely that 鈥渓eptin is the conductor鈥�.
Indeed, he reckons that the best bet for weight-control drugs may be to bypass leptin (poor Amgen) and work on one of the pathways by which it turns the hunger dial up or down. Campfield and his colleagues are, for instance, trying to develop an MC-4 agonist to block appetite in humans. And over at Synaptic Pharmaceutical in Paramus, New Jersey, researchers are looking for ways to block the receptor that neuropeptide Y uses to stimulate feeding.
So, as our cheeseburger approaches its end, there is just one last chance to intervene. The leptin from fat-laden cells not only decreases appetite, but also signals the body to speed up its metabolism and burn off calories. If you had avoided the cheeseburger temptation and shrunk a few fat cells, your leptin levels would drop and your metabolism slow. In effect, the more you diet, the harder your body tries to hang on to its fat stores. Exercise can help, but only to a point.
This means that researchers must look for drugs that can boost the rate you burn your fat in a more direct way than sibutramine, whose noradrenaline-boosting action affects various targets of the sympathetic nervous system pretty indiscriminately.
Several drugs companies are experimenting with chemicals that trigger the beta-3 receptors, the molecular switches on the surface of fat cells that signal them to burn off triglycerides. This spring, Robert Dow from Pfizer Pharmaceuticals in Groton, Connecticut, reported at the American Chemical Society meeting in San Francisco that he had found a chemical that activates human beta-3 receptors while leaving alone the vital beta-1 and beta-2 receptors, that control muscle tissues in the heart and lungs. In mice and rats, beta-3 agonists are very good fat burners, but the effect is mainly limited to brown fat, which is plentiful in rodents, but sparse in humans. White fat, the main fat in humans, has few beta-3 receptors. But, says Dow, there鈥檚 some evidence that beta-3 agonists can trigger the production of brown fat cells, perhaps by signalling the progenitor cells that make both brown and white fat cells. 鈥淚t has a chance,鈥� Dow says.
Cocktail party
Nobody knows which of these quests to block the cheeseburger will pay off. The doctor of the future may even be able to customise weight-loss therapies by mixing and matching drugs that suppress appetite, block digestion, and speed up metabolism. 鈥淵ou will see combination therapies like you do with hypertension,鈥� says Pi-Sunyer. For the moment, the coming generation of weight-control drugs will be prescription-only and pitched at the truly obese. 鈥淭hese drugs are for people who are ill,鈥� says Sugg. Still, human nature being what it is, most researchers foresee the drugs eventually finding their way in to the hands of casual dieters who just want to fit into the clothes they wore at university. For those people, the health risks could outweigh the cosmetic benefits-witness the disease links with dexfen, fenfluramine and phentermine.
Then there鈥檚 another more frivolous risk associated with superdrugs. Without the guilty knowledge that the meat and cheese are headed straight for your hips, that cheeseburger just might not taste so good.
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Can you be too skinny?
ONCE, dieters had a consolation when faced with annoying people who downed dozens of fudge sundaes and gained not an ounce: research showed that the skinniest people, like the fattest, were more likely to die young. When mortality rate was plotted against the body mass index-the weight in kilograms divided by the square of height in metres-the graph was J-shaped: mortality was lowest at 鈥渘ormal weights鈥�, somewhat higher at the lowest weights, and with a sharp jump for the very fattest (see Graph).FIG-mg20964901.GIF
Now, it appears that at least part of the old saying is true: you can never be too rich or too thin. 鈥淎 substantial part of the J-shape is due to tobacco and illness,鈥� says Tim Byers, who studies public health and nutrition at the University of Colorado School of Medicine in Denver. Many thin people who die younger than expected are smokers, while others are underweight because of illness. If these two groups are removed from the calculations, thinness carries little or no health risk. There is still some debate about whether the superskinny-a long, tall model who weighs 8 stone, for instance-have a slightly higher mortality rate, but if the phenomenon exists, it is small.
For BMIs up to 27 or 28-say, a 5-foot-6 person who weighs 12 stone-weight is not closely related to mortality. 鈥淯p above 28 to 30, however, there is pretty good evidence that the weight itself becomes a factor,鈥� says Byers. At this point, extra fat increases blood pressure and cholesterol levels, makes a heart attack more likely and, by triggering diabetes, can lead to kidney failure.