Experts Say Gene Linked to Weight Gain Found

Researchers at UC Davis say they have discovered a gene that explains why some people can eat whatever they want and stay slim while others consume exactly the same food and get fat--a finding that could have a major impact on the continuing battle against expanding waistlines.

The gene is the blueprint for a protein that determines whether the body converts all those excess calories in marbled roast beef and cherry Danishes into harmless surplus body heat or stores it as fat like a squirrel preparing for winter, the team reports today in the journal Nature Genetics.

“This is a gene that determines whether a high-fat diet makes you fat or not,” said Dr. Richard S. Surwit of Duke University Medical Center, a co-author. “We believe that it is at the heart of what happens in people who get fat.”

In the study they found that animals with high levels of the protein, called UCP2, in their tissues are resistant to gaining weight, while those with lower levels gain weight easily.

The team has identified existing drugs that can increase levels of UCP2 in the body, and they expect to work with pharmaceutical companies to develop new ones that will be targeted more directly at the UCP2 gene.

The discovery is “a major breakthrough . . . that is likely to have important implications for the treatment of human obesity,” according to an editorial in the Nature Genetics.

“It opens up a whole new way of looking at things,” added biochemist Jean Himms-Hagen of the University of Ottawa. “It could be more important than leptin,” the protein discovered two years ago that plays a role in regulating appetite.

Drugs targeted against it could have other applications as well, said Dr. Elliot Danforth Jr. of the University of Vermont. Compounds that block the activity of UCP2 might prevent wasting in patients with cancer or AIDS and might lower fevers in patients with bacterial or viral infections. “It’s very exciting,” he said.

Most previous discoveries in obesity research, such as leptin, have dealt with controlling appetite and, thereby, the amount we eat, said physiologist Eric Ravussin of the National Institutes of Health’s Phoenix Indian Medical Center in Arizona. “This is the first discovery that looks at the other side of the equation, energy expenditure.”

Researchers had previously discovered a related protein called UCP1 that performs a similar function, but UCP1 is present only in so-called brown adipose tissue or brown fat. Animals have a lot of brown fat, and drugs that stimulate the production of UCP1 in animals cause them to lose weight without reducing food intake.

Researchers have been looking for drugs that stimulate UCP1 in humans. Unfortunately, humans have very little brown fat--almost microscopic amounts. Even if researchers could find a drug to stimulate UCP1, it is not clear that there is enough brown fat for such drugs to be useful.

UCP2, however, has been found in the normal white fat that is the bane of humans, as well as in a broad variety of other tissues, such as muscle and bone marrow. Even a small increase in its production could have a major impact on weight loss.

Through a complicated series of reactions, the body burns proteins, fat and sugars, with the energy released during the burning stored in a compound called ATP, which is crucial to the building of fat.

ATP is “the body’s currency,” Danforth said. It is used to drive all the chemical reactions carried out within the cell. To build a protein or fat, the cell must “spend” some ATP to get the energy for the synthesis. About 70% of the energy normally present in food is converted into ATP, with the rest released as waste heat--which is why our bodies normally remain at about 98.6 degrees.

In brown fat, however, the synthesis of ATP can be “uncoupled” from the burning of fats and proteins by UCP1--which stands for uncoupling protein 1. In effect, it reduces the efficiency of ATP synthesis from the normal 70%, dropping it down as low as 10% to 20%. More heat is produced and, ultimately, less fat is formed.

It is heat produced in this fashion that helps hibernating animals survive and a sudden release of heat in the spring that brings them out of hibernation.

The team thought a similar process might be at work in white fat, but that it was based on a different protein. Working independently at first, but together later, the team at UC Davis, Duke and the French Centre National de la Recherche identified and cloned the gene for uncoupling protein 2.

They found that levels of UCP2 can be manipulated by varying the calorie content of the diet, but the response was more pronounced in animals that didn’t gain weight. A high-fat diet caused a larger increase in UCP2 levels and body temperature in animals that are resistant to weight gain than in those that gain weight easily. The team hopes that increasing UCP2 levels artificially with drugs might make the weight-gainers more resistant as well.

Subsequent studies have shown that the same protein is also present in human tissues. The researchers have not yet shown, however, that its concentration is lower in obese humans, but they are confident that this is what they will find when they look. Surwit noted that increasing body temperature by one degree would be equivalent to burning off an extra 10 pounds a year.

Both Surwit and Warden cautioned that they have a lot of work left to do before UCP2 levels could be manipulated clinically, but they have high hopes. “This is not a gene that is missing, which is good news,” Surwit said. “The gene is already present in everyone. We just need to tweak it a bit with a drug.”