FORTY years ago, the advent of the Pill freed lovers from the fear of unwanted pregnancy. So why not a pill that would free foodies from the fear of getting fat? You can buy diet pills today, of course, but they work by suppressing appetite, and that’s a lot less fun than simply sidestepping the consequences of gluttony. After all, sitting down to a banquet when all you can stomach is a boiled egg is like going to bed with Brad (or Jennifer) when your only desire is to sleep.
Surely there must be a way to let you enjoy your food without piling on the weight. Whoever develops a pill to do that will earn billions. According to a report last year by the National Audit Office, nearly two-thirds of men and more than half of women in England are either overweight or obese. The annual cost is horrifying: 30,000 premature deaths, at least half a billion pounds for treatment, and possibly a further £2 billion of indirect losses to the economy. Not surprisingly, a market like that has got several drugs companies sniffing around with great interest, though none has a drug ready for commercial distribution yet.
Of course, there’s already a way to eat more without gaining weight: exercise. Even a brisk walk can boost the body’s resting energy consumption fivefold—and if you work out regularly you’ll build muscle, which burns calories even at rest. But exercise is hard work, so the drugs companies are after that beguiling substitute: a way to burn more energy without resorting to physical activity. Their attention is focusing on a process that biochemists call “uncoupling”.
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Ordinarily, the body captures the chemical energy in food by coupling the breakdown of sugar, fat and protein molecules to the production of ATP, the universal fuel for processes within the cell. ATP then powers the chemical reactions needed to move, think and do everything else in life. Any leftover ATP is used to produce fat, which is stored in fat cells throughout the body. Uncoupling allows the body’s cells to break down food without creating ATP, effectively flaring off the excess food energy as heat.
The notion of burning your way out of obesity—thermogenesis—is not new. Decades ago the hormone thyroxine looked like just the ticket for forcing up your metabolic rate. But enthusiasm waned when it turned out that thyroxine caused severe jitters, and much of the weight people lost came from lean tissue, not fat.
Attention later turned to a subset of the beta receptors, the molecular switches through which the body detects and responds to the “fight or flight” hormone adrenaline. The type known as beta-3 is found on fat cells, and activating these receptors boosts thermogenesis. The problem has been finding a drug that can stimulate only these, leaving the other beta receptors unruffled. A few molecules have been developed, but they still tend to lower blood pressure, produce tremors, and overstimulate the heart.
“It’s very tantalising,” says John Arch, a pharmacologist who spent many years in the drugs industry before joining Buckingham University’s Clore Laboratory. “The beta-3 drugs are the great hope that’s never been fulfilled.” Yet it’s not clear whether this is because we have failed to develop the right molecule, or because this approach is fundamentally flawed.
Recently, attention has shifted to another target—a family of molecules called “uncoupling proteins”, which interfere with the process that generates ATP and simply liberate food energy as heat instead. The hunt is now on for drugs that will either persuade the body to make more of these proteins, or else make the existing proteins work harder.
The best known of the uncoupling proteins, UCP1, occurs almost exclusively in a specialised tissue known as brown fat. At first glance, brown fat looks like the perfect target for a weight-loss pill, as its main job is to create heat by burning off energy through uncoupling. Find a drug that makes cells produce more UCP1, and you could lie back and glow while the fat just melts away. It’s a slimmer’s dream, but unfortunately adult humans have very little brown fat, and hence very little UCP1. Still, some recent research hints at the tempting possibility that we might increase the amount of brown fat we carry (see “The fat that slims”).
That’s a long way in the future, if it ever happens. In the shorter term two other uncoupling proteins, UCP2 and UCP3, offer more promising targets. People naturally have plenty of these molecules—UCP3 in muscle, and UCP2 in several tissues throughout the body. What’s more, it looks like they already play a significant role in our metabolism. By some estimates, uncoupling gobbles 20 to 30 per cent of a person’s energy intake, even without any artificial boost. Natural variation in UCP activity may help explain why some people stay effortlessly slender while others plump up on even a spartan diet. Last year, for example, researchers in Austria reported that people with a more active variant of the UCP2 gene were significantly less likely to be obese than those with a relatively sluggish variant.
Clues of this sort have been enough to tempt several drugs companies into hunting for ways to boost UCPs. Some serious problems remain, however—not least that no one knows what role UCP2 or UCP3 normally play in the body or what other processes might be upset by boosting their production. “UCP2 is expressed in the brain, and we don’t know what it does,” says Daniel Ricquier, a biochemist at CNRS, the French national research agency near Paris, who discovered UCP2 in 1997. “If you upregulate UCP2, what will be the consequences? I don’t know. It may be a disaster.” UCP2 is also involved in regulating insulin secretion, and both it and UCP3 may help the body cope with dangerous free radicals.
There’s a practical hurdle, too. UCPs aren’t “druggable”—that is, they don’t belong to one of the relatively few classes of proteins that pharmaceuticals scientists already know how to influence. That forces researchers to start from scratch, screening potential drugs more or less at random in the hope of finding one that boosts either UCP levels or their activity. A second approach is to search for genes or proteins that interact with UCPs in the hope of finding other, more druggable targets elsewhere in the genetic or biochemical pathways that influence UCPs. Using this approach, the American biotech companies Tularik and Millennium Pharmaceuticals have developed several possible drugs, though only one has yet begun tests in people.
The hormone leptin may also make a good model for an uncoupling drug. Initially thought to be merely an appetite suppressant, leptin is now known to trigger the burning of surplus fat and sugar throughout the body as well. David Carling of the Medical Research Council’s Clinical Sciences Centre in London, together with colleagues at Harvard Medical School, have shown that it does this by stimulating the production of something called AMP-activated protein kinase. AMPK is an enzyme that is also stimulated by exercise. A drug that boosts this enzyme could bypass both exercise and leptin and deliver the uncoupling effect directly.
Researchers already know of drugs that activate AMPK. But the enzyme plays a critical role in maintaining the energy balance in all cells, and the known drugs are too indiscriminate to make good weight-loss treatments. “If we were to activate AMPK in every cell type, some of its effects would be deleterious, if not fatal,” says Carling. But there may be a way round this. Different tissues have subtly different forms of the enzyme—some 12 variants in all—so chemists ought to be able to develop drugs that target each one separately.
What might such a selective drug be capable of? Some of the medical complications of obesity, such as Type 2 diabetes and heart disease, are caused by the build-up of fat molecules in muscle, liver and other cells. Burning off this fat might overcome these complications. But what of the main fat stores: the fat cells in the thick, white fatty tissue making up most of obese people’s bulk? It’s hard to make these cells burn more fat directly, but Carling thinks they could still be targeted indirectly. This is because tissues that do respond replenish the fat they burn off by taking it from the fat cells, which would then shrink.
Clearly, drugs companies are betting that one of these strategies will pay off soon. But there are still two obvious hurdles to clear. The first is ethical: in a world where hundreds of millions of people are starving, is it moral to make a pill that allows the wealthy to overeat? Janet Radcliffe-Richards, a bioethicist at University College London, says such worries are misplaced. Such a drug would only be morally repugnant, she says, if one person’s hunger was the direct result of another’s overeating. That isn’t the case. “I don’t see why eating is intrinsically morally worse than any other kind of thing you spend your money on,” she adds.
The second concern is a practical one: a fat pill that boosts your energy expenditure might also make you eat more, offsetting any benefit. Oddly, there isn’t much data on this from animals, and even less from humans. But studies on exercise and metabolism suggest there’s little to worry about. John Blundell of the University of Leeds and a colleague, James Stubbs of Aberdeen’s Rowett Research Institute, put small groups of normal-weight men and women on a regime of hard exercise: three daily 40-minute sessions on a stationary bicycle. Then they watched to see how the workouts affected what the volunteers ate.
“We were surprised to find that quite large doses of daily exercise did not immediately drive up food consumption, contrary to what everybody believed,” says Blundell. Some of the people did eat a little more, but not enough to make up the difference in energy expenditure. “There’s a possibility that people would compensate in the longer term,” says Stubbs. “But that’s the same for exercise and diet, or anything else.” And clearly, the findings do contradict the notion of an instant hike in eating, and so offer some grounds for optimism.
There is, however, an even more fundamental worry. Like the Pill, these fat-control pills would be taken over the very long term. That requires the drugs to prove their safety record beyond any doubt. “This really matters, because an obese girl aged 13 is going to finish taking her course of tablets when she’s 85,” says Bloom.
For similar safety reasons, any pill would probably win approval only to help severely obese people lose weight—not to give slim foodies carte blanche to gorge. “When they’re going to allow any drug to be used long-term for people who are not having health problems is an open question,” says Allan Haberman, a biotech consultant with the Biopharmaceutical Consortium in Wayland, Massachusetts. “We just don’t know what the side-effect profile is going to be in the long term.”
Even merely raising the metabolic rate brings risks, since obese people typically are short of breath anyway. “If you gave someone a drug that kept their metabolic rate well above normal, day and night, you’d have to be jolly careful not to drive them into heart failure,” says John Garrow of the University of London. Still, even a modest increase—10 per cent or so—would help keep the flab off.
The arrival of the contraceptive Pill helped trigger big changes in sexual behaviour. Would an anti-obesity pill do something similar for eating? With our spiralling food consumption, ever-widening range of tastes, and our gradual move away from set meals towards continuous and varied grazing, we are already well down the road towards gastronomic promiscuity. So an anti-obesity pill might only fuel the shift rather than trigger any dramatic change.
But don’t forget: the influence of the Pill altered attitudes to more than just sex. Could the fat pill likewise seed revolutions that we can’t yet imagine?
The fat that slims
Brown fat, with its rich supply of the uncoupling proteins that burn off excess food energy, would make a perfect weight-loss organ. There’s only one problem—people don’t have much of it. Infants, whose small size necessitates special ways of generating heat, have a little. But as the child grows, this tissue dwindles and vanishes.
That’s needn’t be the end of it, however. Even though we lack the cells naturally geared up to perform thermogenesis, we may be able to persuade others to join in. Last year, for example, Nahum Sonenberg and Kyoko Tsukiyama-Kohara of McGill University in Montreal and their colleagues in Canada, the US and Japan found that knocking out a particular gene in mice converted ordinary white fat into brown fat, increasing heat production (Nature Medicine, vol 7, p 1138). Would a similar deletion in humans—or a drug which mimicked it—make our tissues do the same? Yes, reckons Bob Farese of the University of California at San Francisco. “I think it’s conceivable, in theory anyway, that one could flip the switch. This could boost thermogenesis.”
Hubert Chen, one of Farese’s colleagues at UCSF, agrees, adding that UCP1 is already expressed to a limited degree in the white fat of adults. Like Farese, he is cautiously optimistic that turning white fat into brown may help combat obesity. “But that’s a long way from saying it’s probable,” he warns. “Lots of experiments in animal models, not to mention human trials, will need to be performed before any real conclusions can be reached.”