Being Overweight May Be More in the Genes Than Previously Thought, Researchers Find

BOSTON — October, 1998 — Scientists at Joslin Diabetes Center in Boston have found one more clue that obesity may be a genetically-determined disorder. Their study, published in a recent issue of the New England Journal of Medicine, has identified a new human gene mutation associated with obesity. Previously, researchers have reported on only one other human biochemical pathway linked to obesity and this was present in one family.

In their article, a research team headed by Joslin Diabetes Center Director C. Ronald Kahn, M.D., and his colleague Michael Ristow, M.D., describe one of the first human obesity syndromes that can be attributed to a specific genetic mutation. Researchers at the University of Cologne and Ruhr-Universitat Bochum in Germany also collaborated on the study, and provided the patient population which was studied.

There is increasing evidence that genetic factors lead to obesity, but the exact genes involved have not been defined. The researchers explored whether mutations in the gene peroxisome-proliferator activated receptor gamma 2 (PPARę2), which is involved in making fat cells and in energy storage, might predispose people to becoming obese.

Previously, researchers had pinpointed a mutation in the coding sequence of the leptin gene and the leptin-receptor gene as being linked to obesity, but screening of thousands of obese subjects have identified this defect in only a very few obese individuals. In this study, the researchers investigated 358 unrelated German people, including 121 whom were deemed obese, with a body-mass index greater than 29. (For someone 5'10" tall, this would correspond to a body weight of 200 pounds.) They examined the 358 individuals for genetic mutations in the gene for PPARę2.

"We found four of the 121 obese subjects had a mutation in the gene for PPARę2, compared with none of 237 normal weight subjects," said Dr. Kahn, Director of Research at Joslin and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. "All of the subjects with the mutant gene were markedly obese, with body mass indexes ranging from 37.9 to 47.3, compared with an average of 33.6 in the other obese subjects. We concluded that a mutation in PPARę2 increases growth in fat cells and may cause obesity in humans," Dr. Kahn said.

Obesity is the most common health problem in developed countries. It is the second most common cause of preventable death in the United States. Obesity in humans is believed to result from a combination of environmental influences and genetic factors that affect energy storage and caloric intake. More simply put, it results from an imbalance between chronic energy intake and energy expenditure. Previous studies in twins suggestion that up to 80 percent of obesity is attributable to genetic factors.

People who are obese are at a markedly increased risk of developing type 2 diabetes, which affects an estimated 16 million Americans and is a leading cause of heart disease, strokes, kidney disease and premature death.

The PPARę2 mutation was found in approximately 3 percent of obese subjects in a German population, or about 1 percent of all subjects screened, the researchers reported. The researchers do not know how common the mutation may be in the United States. The findings did not appear to be related to whether or not the people had type 2 (adult onset) diabetes. Further studies will be needed to determine the prevalence of this mutation in other populations and in families with obesity, the researchers concluded.