Can Geneticists Cure Obesity?

Jan. 11, 2006 — -- What makes us fat? A generation ago, the answer was simple -- eating more than we needed to.

That may still be true, but researchers investigating the genetics behind appetite, metabolism and weight gain have learned that putting on pounds is much more complicated than a simple equation of calories. They're finding certain genes allow some people to pig out and not gain weight, while others put on pounds after a slight overindulgence. Other research has shed light on genes that may play a role in how much we crave food.

But can these findings lead to surefire treatments to tackle this country's growing weight problem? A consensus among scientists is surprisingly optimistic.

"I truly believe that the discovery of obesity susceptibility genes will identify new molecules and pathways that will lead to effective new medications and other interventions," said Dr. Alan Shuldiner, head of endocrinology, diabetes and nutrition research at the University of Maryland's School of Medicine. Shuldiner adds, however, "I do not think this will occur in the near future."

Still, Andrew Greenberg, director of obesity and metabolism studies at Tufts University, pointed out that obesity research has accelerated in recent years, and that's bound to help scientists find cures sooner.

"The Internet has changed science," he said. "It has changed the pace at which we learn about each other's research and then build on it. Advances are happening faster than ever before."

In fact, the introduction of new treatments has already begun. In the coming year, the French pharmaceutical giant Sanofi-Aventis plans to release what many believe could be one of the first truly effective anti-obesity drugs. Preliminary data from large trials have suggested that weight loss is much greater than with any current drugs on the market.

The drug, rimonabant, targets receptors of cannabinoid 1, which stimulates appetite and other cravings (including nicotine) in the brain. By blocking cannabinoid 1's receptors, rimonabant helps people beat their cravings and lose weight.

Shuldiner said so far the trials for rimonabant have been "very impressive. "I believe it will be a very useful agent for weight loss. But not the end-all."

While a drug like rimonabant is designed to help any person beat cravings and lose weight, part of finding "end-all" treatments may lie in figuring out how people's genetics vary and tailoring drugs to match.

A recent study in Spain has offered insight into one such variation. The research, published in the Journal of Clinical Endocrinology & Metabolism, examined the role of a gene that may lie behind a phenomenon that so many find frustrating -- you cut back calories but still don't lose weight at the same pace as your thinner friends. Jose Ordovas, director of nutrition and genomics research at Tufts University, said those frustrated dieters may share a variation in a gene called perilipin.

Perilipin, he explained, creates a protein that settles around fat droplets and protects the fat from being destroyed.

"That may sound funny these days," Ordovas said. "But in old times, fat was difficult to hold on to, so this protein protected it."

Some versions of the perilipin gene (originally identified by Greenberg and colleagues) make this fat bodyguard stronger, while other mutations make it weaker.

"This means we have identified one of probably many genetic variations that help us distinguish between those who will and won't respond to diet," said Ordovas. "Some people think that patients don't lose weight because they don't follow the recommendations. But in some cases, their bodies may just be more thrifty with the fat."

Figuring out how people's genes react differently when it comes to weight loss might also help prevent dangerous side effects to obesity-fighting drugs as they emerge on the market.

Many may remember the controversy over phen-fen, a once popular obesity-fighting combination of drugs that was recalled in 1997 after some studies and reports showed it caused heart problems in some patients. By tailoring drugs to people with specific genomes, drug manufacturers may be able to avoid such fallouts in the future.

"Sometimes side effects only affect a minority of people," said Ordovas. "In the future, we can identify drugs and supplements and target them to people with specific genetic profiles."

The pace at which scientists identify new obesity-related genes has stepped up in the past few years as genetic research gains momentum. But Greenberg cautions that not every new discovery means new cures are on the way.

"We've come a long way in understanding obesity," he said. "But every study has to be carefully replicated. And exercise and diet will always form the cornerstone of any obesity treatment."