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Doctors used to joke that the best way to combat obesity was to build up your biceps ... in order to push yourself away from the table. Then came the discovery in 1995 of genes that regulate leptin, the hormone that controls how much fat your body stores. Since then, scientists have identified dozens of compounds related to weight, some released in the brain and others in the gut.
All of which has set off a pharmaceutical feeding frenzy, because every compound scientists can identify as weight related represents a potential target for drug development. And any drug that can safely prevent or reduce weight gain is not only a potential blockbuster but a lifesaver as well.
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Finding those drugs, however, won't be easy. Weight may be a single number, but it represents the sum of a bewildering network of overlapping metabolic pathways, all designed to protect the body from starvation by packing on as many pounds as possible. In addition, not everybody gains weight the same way, so a drug targeting one pathway will probably not work for all overweight people. "The whole feeding mechanism is a survival mechanism, and it is strongly defended for that purpose," explains Ken Batchelor of GlaxoSmithKline. "What we are attempting to do with pharmacology is to reverse that process."
Scientists are channeling their efforts toward two main targets: the feeding center in the brain, which is supposed to tell the body when to eat and how much, and the myriad signals that originate in the gut and then flow into the brain, triggered by the amount of food you eat. These messages order the body to burn calories right away or store them as fat for later use.
On the eating side, researchers at Glaxo are studying cholecystokinin, which is released by the intestines after a meal to signal the brain that the body has had enough. Giving obese patients a synthetic form of cholecystokinin before meals tricks the body into feeling full, so patients eat less. About 25% of the participants in an early trial lost almost 7 lbs. in the first eight weeks.
Scientists at Regeneron, based in New York, are tapping into the same feeding hub in the brain but through a different protein that is more closely related to leptin. Regeneron's agent, Axokine, fools the brain into thinking that the body's fat stores are well stocked, short-circuiting the need to eat. People who took Axokine and stayed on a low-calorie diet and exercise program lost twice as much weight as those who relied on diet and exercise alone.
At Pfizer, researchers have stumbled upon an agent that curbs the brain's attraction to fatty foods — but so far, only in mice. More studies will show if the same effect occurs in people.
On the other end of the spectrum are therapies that aim directly at fat tissue. Scientists at M.D. Anderson Cancer Center in Houston are trying to starve fat cells by attacking proteins embedded in the blood vessels that feed those cells. In experiments on obese mice, their excess fat melted away in a matter of weeks. Not only did this strategy eliminate fat tissue — the animals lost 30% of their body weight — but mice that were dangerously overweight quickly regained their health. In fact, early signs of diabetes reversed, fat no longer accumulated in the liver, and cholesterol and glucose levels dropped to normal. "We don't know if this will happen in people," warns Dr. Wadih Arap, a co-leader of the study. "But conceptually, it's possible."
Even more exciting is a compound that appears to attack obesity through both the brain and the gut. Called rimonabant, and developed by Paris-based Sanofi, it is entering the final stages of human testing. Like Axokine and leptin, rimonabant was designed to make the body feel full. But scientists were pleasantly surprised to find that it also lowered triglyceride levels 15% and raised good cholesterol 22%--far more than would have been expected from weight loss alone. There is also evidence that patients on rimonabant may become more sensitive to the action of insulin, which can halt the progression from prediabetes to diabetes. "In addition to reducing food intake, rimonabant may have an effect on fat cells themselves," says Dr. Jean-Pierre Despres of Laval University in Montreal, who is leading one of the drug's clinical trials. "That's clearly exciting."
Whatever form the new drugs for obesity may take, one thing is clear: the most effective treatments will probably involve a mix of agents chosen to match each patient's needs. "A few years ago, we were all looking for a single magical cure for all obesity," says Dr. George Yancopoulos, chief scientific officer of Regeneron. Now the answer seems more likely to come, as weight loss usually does, one hard-fought-for step at a time.
- Alice Park