Gene Defect Found to Cause Obesity

By William J. Cromie

Gazette Staff

A genetic mutation that allows cells to accumulate more and more fat has been found. Although it causes obesity in only a small percentage of people, its discovery may lead to new treatments for all obese people as well as for the most common form of diabetes.

Normally, a gene known as PPAR controls the amount of fat cells that are made and the size of those cells. "With this mutation, the gene gets stuck in the 'on' position causing more fat cells to form," says C. Ronald Kahn, Mary K. Iacocca Professor of Medicine at Harvard Medical School. "And these cells get fatter faster than normal fat cells."

This mutation was found among 121 obese Germans. A person is considered overweight if he or she has a body mass index (weight in kilograms divided by the square of height in meters) of 25 or more. For example, a 5-foot-8-inch person weighing more than 165 pounds would be classed as overweight.

People who top 29 on the index (190 pounds at 5 feet, 8 inches) are called obese. Germans of this height with the mutated gene weighed between 250 and 311 pounds.

"We found that only 3 percent of the people we checked had the mutation," notes Michael Ristow, a Harvard research fellow. "It is not known if the same proportion of people in the U.S., or anywhere else, have the mutation." If they did, more than 8 million people in this country would possess the altered gene.

To determine if this is the case, Kahn and other researchers at the Joslin Diabetes Center in Boston are analyzing genetic material from 220 obese people. Kahn is director of the Center. He is also collaborating with researchers at Columbia University in New York City to learn if the same mutation is more common in children who develop diabetes at a young age than in adult-onset diabetes.

Ristow, Kahn, and three scientists from Ruhr-Universität Bochum in Germany published a report of their work in today's New England Journal of Medicine.

Linking Genes and Food

The PPAR alteration is the second mutation of a human gene found to be involved in obesity. The other gene regulates production of a hormone called "leptin," which suppresses appetite when fat cells become too full. Like PPAR, mutation of this gene occurs in only a small number of people.

Some experts believe that as much as 80 percent of obesity is genetically linked. That doesn't mean the genes cause obesity directly; rather, individuals who carry these genes are more susceptible to becoming obese.

"You need both the gene and an environment where plenty of food exists," explains Kahn. "If these people lived in famine conditions, they probably couldn't get fat."

What's so interesting about the PPAR gene is that the protein it produces may also regulate insulin resistance in diabetics. People with the mutation seem to use insulin more effectively to control their blood sugar, although some of them do develp diabetes.

"Determining precisely how such insulin sensitivity occurs should provide us with clues for designing new drugs to help diabetics, whether they are obese or not," Kahn notes.

A drug now available, called troglitazone, increases insulin effectiveness by binding to the protein produced by PPAR genes. Harvard researchers announced last month that troglitazone can also force cancerous colon cells in mice to become non-cancerous growths. Thus, further study of the gene might result in better drugs for cancer.

Additionally, researchers in the future may find ways to tightly control the PPAR gene so it can't lead to obesity. "That kind of gene therapy might work for both mutated and normal PPAR," Kahn says. "Indeed, it might work for treating all people whose genes make them susceptible to obesity."