Obesity Drugs

Drug Researchers Target Fat 'Thermostat'

Margie Wylie

Newhouse News Service c.2004

If you've read the recent reports that obesity-causing eating habits may be wired into the brain, put down that doughnut and listen up. There is hope.

The same research that led scientists to believe biology may have a stronger hand than willpower in obesity is spurring development of diet drugs that may actually work.

This new class of compounds, the first of which is expected in the next two years, may be able to rebalance faulty "fatstats," the fat thermostats in our heads.

Scientists think the body labors to keep fat stores at a certain level, or set point. When dieters shed pounds, the system notches up hunger and slows metabolism to try to regain the weight, said Jeffrey Friedman, medical investigator at Rockefeller University's Howard Hughes Medical Institute in New York. As a result, obese people who lose weight almost invariably gain it back.

"There is a very basic drive to eat that, in many people, is not so easily modified over the long term by voluntary factors like the conscious desire to eat less and lose weight," said Friedman, an author of the study that found fat hormones can actually rewire the brain.

In 1994, a team led by Friedman discovered the hormone leptin caused drastic weight loss in mice born without the ability to create leptin themselves. Injected into the obese mice, leptin melted off fat, leaving lean tissue untouched.

But the results were disappointing in obese humans, most of whom turned out to be leptin-resistant. Even if the obese could "just say no" to food, their bodies tend to fight them by storing more energy and burning less fat.

Leptin was shelved as an obesity treatment. But in the intervening decade, scientists have uncovered natural compounds in the body that work either upstream or downstream from leptin to suppress appetite and promote burning energy or, conversely, to promote hunger and fat storage.

It's this complex push-and-pull that keeps most of us within tolerable weight limits, said Tamas Horvath, a researcher at Yale University Medical School and lead author of the brain study with Friedman.

In obese people, Friedman said, the system has gone wrong. He is trying to figure out exactly how their brain wiring differs.

Meanwhile, drug researchers are looking for ways to nudge the eating and fat-burning cycles into more acceptable patterns by blocking or promoting the different signals.

Rimonabant, a candidate from the French pharmaceutical company Sanofi-Synthelabo, works by blocking endocannabinoids, marijuana- like substances in the body that play a part in stimulating normal appetite.

Last month, the company announced that its first human test subjects, all significantly overweight or obese, had lost an average of 20 pounds each after one year taking the pill and modestly cutting their daily food. The drug also increased subjects' "good" cholesterol by 23 percent, whittled down waists by 3.4 inches and, in a separate study, doubled the chances of quitting smoking while keeping the weight off those who quit and continued to take the drug, said Michael Pfeifer, senior medical director for Rimonabant in Sanofi-Synthelabo's New York offices.

Provided the remaining trials go well, Pfeifer expects Rimonabant to hit the market in the next two years.

Axokine, a drug developed by Regeneron Pharmaceuticals of Tarrytown, N.Y., to treat amyotrophic lateral sclerosis, or Lou Gehrig's disease, was found last year to induce mild weight loss in overweight and obese test subjects on a diet (about 6.2 pounds on average compared with 2.6 pounds for people on a placebo). Some 11.3 percent of drug testers lost more than 10 percent of their body weight, more than 30 pounds on average, according to the company.

Axokine acts on leptin-like pathways, but through a modified form of ciliary neurotrophic factor, another substance that occurs naturally in the body.

And Nastech Pharmaceutical Company of Bothell, Wash., is in early testing of its Nasal Peptide YY3-36, a nose spray that mimics a satiety factor released by the gut when it's full.

Although the weight losses attributed to these drugs may seem small, obesity experts regard them as significant given that the main concern in obesity is not cosmetic appearance, but the health risks: Type II diabetes, high blood pressure and coronary artery disease, among others.

Other possible drug targets include ghrelin, a hunger-inducing hormone produced by the stomach; cholecystokinin, an appetite suppressant produced in the gut; oleylethanolamide, a naturally occurring satiety factor; and, researchers reported in a mouse study last month, adenosine monophosphate-activated protein kinase, a hunger-suppressing factor that also appears to ramp up metabolism.

But it's nearly impossible to create diet drugs that don't have other effects, Horvath said. For example, researchers have linked endocannabinoids to addictive behaviors, memory and immune function. Tinker with these or other aspects of body chemistry and you may get consequences on systems besides appetite.

Horvath also warns that all of the studies, including his own, have focused on a primitive, more easily mapped portion of the brain, the hypothalamus. This means researchers don't understand what part higher brain functions, such as reasoning, play in feeding behavior.

There also is the chance if one hunger pathway is blocked, another may compensate by pumping up its signals, said Jean-Pierre Despres, lead investigator for Rimonabant's weight-loss study and a professor at Laval University in Quebec. Despres said he had seen nothing of that sort with the drug so far.

Post-script: Rimonabant was released in 2006, but withdrawn in 2009 due to psychiatric side-effects.