HEALTH SENSE
Still no quick fix for obesity
By Judy Foreman, Globe Correspondent, 10/22/2001

Leptin and Diet Drugs

Three obese Turkish cousins got very lucky this year. They spent a few months in Los Angeles getting injections of leptin, the ''satiety'' hormone discovered in 1994 that was hailed as a magic bullet to cure obesity. The cousins had been born with defective genes for leptin and could not control their weight.

The three, a 27-year-old man who weighed 312 pounds, a 35-year-old woman who weighed 253 pounds, and a 40-year-old woman who weighed 194 pounds, were miserable, they said through an interpreter.

The man was so fat that he couldn't get a job, or a girlfriend. One woman worked at home as a seamstress because people made fun of her if she went outside. The other had given up her dreams of marriage, devoting herself to taking care of her parents.

By the time they headed back to Turkey after their treatments, they had each lost roughly half his or her body weight, said the researcher who treated them, Dr. Julio Licinio, professor of psychiatry and medicine at the David Gergen School of Medicine at UCLA.

So, that's the good news: There is a handful of obese people who can be helped with leptin, and - let's be generous here - perhaps several thousands more who can be helped modestly and temporarily by other drugs. And that's pretty much it, folks.

After all the hoopla, all the hype, all the hope, and all the research, anti-obesity drugs, at least so far, have largely been a bust. And barring some secret miracle concoction now in development, there will simply not be a pharmaceutical fix for fatness in the near future.

Two-thirds of Americans are now overweight, the latest government figures show, and one in every three is obese. Obesity is defined as having a body mass index, or BMI, by having a BMI of 25 to 30. (To calculate your BMI, multiply your weight in pounds by 703; then divide that number by your height in inches squared.)

Yet, aside from repeating the old mantra of diet and exercise, and maybe a mention of gastric-bypass surgery, there's still very little that doctors have to offer the millions of Americans stuck in weight-loss hell.

''There is certainly nothing on the horizon in terms of a drug that will solve obesity,'' said Dr. Eric Colman, medical team leader for the metabolic and endocrine division at the US Food and Drug Administration.

The more researchers try to find a magic bullet for weight loss, the more they are discovering that the biochemical pathways in the brain that control appetite and weight maintenance are devilishly complicated.

At the moment, for instance, there are only two prescription weight-loss drugs on the market - Meridia and Xenical - that are approved for long-term use. Meridia promotes a feeling of satiety by increasing levels of serotonin, norepinephrine and dopamine, chemical messengers in the brain. But, as the Harvard Heart Letter of March 2002 noted, the drug only works as long as you take it, and even then, only modestly, resulting in a 5 to 10 percent weight loss. This amount of weight loss can help lower blood pressure and cholesterol, but may not make a huge dent in what you see in the mirror.

Nor is Xenical a magic answer. It acts in the digestive tract to stop absorption of fat from foods by blocking enzymes called lipases. Like Meridia, it can result in a 5 to 10 percent weight loss, but all that unabsorbed fat can cause uncontrollable bowel movements.

There still are a few other weight-loss drugs on the market, including those containing phentermine (the ''phen'' of the old fen-phen combo). But these aren't approved for long-term use.

So, where does this leave the millions of Americans who are either overweight or obese? Still fat and still desperate.

Some people resort to gastric-bypass operations - surgery to reduce the size of the stomach, which limits the amount of food a person can take in. About 40,000 Americans underwent this procedure in 2000, almost double the number performed five years earlier, Ellen Ruppel Shell, codirector of the Knight Center for Science Journalism at Boston University, reports in her new book, ''The Hungry Gene.''

But the costs are high. ''Gastric-bypass surgery kills one out of every 100 patients on the operating table, and not everyone recovers from the complications,'' Shell said.

On the other hand, gastric surgery may work not just by limiting stomach volume, but biochemically as well, according to a recent paper in the New England Journal of Medicine.

Cells in the stomach produce a chemical called ghrelin that has been shown to stimulate feeding and obesity in animals. Unlike the weight loss induced by dieting, weight loss induced by gastric bypass may lead to longer-term maintenance of weight loss because of reduced ghrelin levels, according to Drs. Jeffrey Flier, an endocrinologist and chief academic officer at Beth Israel Deaconess Medical Center, and Eleftheria Maratos-Flier, director of the obesity section at the Joslin Diabetes Center in Boston in an editorial accompanying the research. This suggests that a grehlin-blocking drug might work where others have failed.

And someday, there may be other pharmaceutical options.

Millenium Pharmaceuticals in Cambridge, has been looking at a compound called MLN 4760, which is now in early human safety trials, according to Lou Tartaglia, a company vice president.

Tartaglia said he believes that the reason that the drugs marketed so far have failed is because they are crude and essentially act ''by hitting the brain with a hammer.'' New drugs could work better because they are targeted to more specific molecules in the brain.

But even then, there are no guarantees. Take leptin, for example, a highly specific drug.

Amgen, a company based in Thousand Oaks, Calif., has been trying for years to develop a leptin-based drug, with no success.

Why? For one thing, obese people often turn out to have perfectly normal or even higher than normal levels of leptin, which is made in fat cells and travels to the brain to deliver ''satiety'' or ''I'm full, stop eating'' signals.

The Turkish cousins were genetically leptin-deficient, so giving leptin to them worked. But most obese people are not leptin-deficient, perhaps in part due to the sheer number of their fat cells. These fat cells, which never go away, even when a person loses weight, keep cranking out leptin. But obese people, one current theory goes, may become resistant to their own leptin, much as people susceptible to diabetes can become insensitive to their own insulin.

In the meantime, it's same old, same old: Diet and exercise. Turn off the TV and take a walk instead. Eat more vegetables veggies and less processed junk. At the very least, if you are already overweight, don't give up and let the problem get even worse.

Judy Foreman is a freelance columnist who can be contacted at foreman@globe.com.

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