Gene ups obesity, accelerates diabetes.

The Pima Indians of Arizona suffer from some of the highest rates of obesity and diabetes in the world: Roughly half of all Pimas will develop diabetes by age 40. But the reason for their susceptibility remains a mystery.

Now, the discovery of a genetic defect in a cellular protein thought to help the body burn fat may offer the first clues to the Pimas' health problems.

Researchers from the Johns Hopkins University School of Medicine in Baltimore found that a mutated form of a protein that ordinarily converts fat into body heat appears to promote obesity and accelerate adult-onset diabetes.

"If we could identify people with this gene, we could intervene with diet and exercise," says study leader Alan R. Shuldiner. "And eventually we may be able to circumvent the [protein]."

The protein in question is the beta-3-adrenergic receptor. Rodent studies have shown that this receptor receives signals from the sympathetic nervous system that help to set the animals' metabolic rate. The signals encourage so-called brown fat to generate heat. Researchers believe the same process occurs in humans, but confirmation of this hypothesis remains difficult because people carry, in their trunks and abdomens, only small amounts of brown fat.

Because brown fat appears to play a role in metabolism, Shuldiner's group examined the Pimas for mutations in the DNA that encodes this protein. As the researchers report in the Aug. 10 New England Journal of Medicine, roughly half of all Pimas carried the mutated form of the receptor. "And these people suffered diabetes at a significantly earlier age," Shuldiner points out.

Pimas carrying this mutation developed diabetes 5 years earlier than their counterparts with normal receptors. The mutation also appeared to increase obesity, especially in the abdomen and chest. This "apple" pattern of fat deposition substantially increases the risk of diabetes and heart disease.

Among other groups in the United States, the researchers found that 25 percent of African Americans and Mexican Americans, as well as 12 percent of Caucasians, carry the mutation.

Collaborations with Finnish and French researchers published in the same issue of the journal support these findings. Finns with the mutation experienced apple-pattern obesity and earlier onset of diabetes, while morbidly obese French with the mutation gained weight faster and became heavier than similarly obese French without the mutation.

Susan Yanovski of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., finds the work "an interesting piece of the puzzle." But she notes that obesity and diabetes result from many genes and that the mutation's effects were modest.

Shuldiner agrees that the findings will not be a magic bullet and points out that diet and exercise remain important. He notes that Pima Indians in Mexico, who still eat a traditional diet, suffer no excess obesity or diabetes.