Many questions remain on 'obesity gene'

On Call

October 24, 1995|By Dr. Simeon Margolis | Dr. Simeon Margolis,SPECIAL TO THE SUN

I have heard that a gene for obesity has been identified. Does this mean that an effective treatment may soon be available for people like me who are unable to lose weight?

The discovery of a gene for obesity is an exciting advance, but it is not clear how soon, if ever, these new findings will lead to improved measures for weight loss.

In December 1994, a doctor at the Rockefeller University reported that a gene mutation was responsible for the obesity in a strain of mice called ob/ob. One out of four of these ob/ob mice inherits two abnormal genes, which lead to such extreme obesity that 80 percent of their body weight is fat.

The affected mice have voracious appetites and their physical activity is relatively low. The mutation interferes with the production of a protein, named leptin, that is normally made in the fat cells of these mice and secreted into the bloodstream.

When normal leptin was injected into these mice, they stopped overeating, became more physically active, and lost huge amounts of weight. Smaller amounts of weight loss were observed oven when leptin was injected into some normal weight mice, but not when injected into another strain (db/db) of genetically obese mice. These findings indicate that leptin acts as a specific hormone, just like the insulin secreted from the pancreas of the thyroid hormone produced by the thyroid gland.

Subsequent research has shown that a similar leptin protein is made and secreted into the blood by human fat cells. To date, however, no mutations have been found in the leptin gene in the more than 200 obese people who have been studied.

In addition, the levels of leptin in the blood and fat tissue is elevated in obese humans. When obese individuals lose weight over a period of 8 to 12 weeks, blood levels of leptin decline.

The findings of high blood levels of leptin in obese humans, and the failure of leptin injections to cause weight loss in the db/db mice, suggest that leptin may work by an interaction with a receptor protein on the surface of cells, most likely in the brain, that reduces appetite and simulates physical activity.

The abnormality in the db/db mice and in obese humans might then be due to a defect in the cell receptor for leptin. Such a defect would explain why leptin does not work in db/db mice and why blood leptin levels are elevated in obese humans.

Although this is a theoretical explanation, a number of rare endocrine abnormalities are known to result from a person's "insensitivity" to some hormones, a phenomenon known as hormone resistance. For example, people resistant to the action of thyroid hormone have elevated levels of the hormone in their blood, and yet exhibit the same symptoms as patients whose thyroid gland is not working.

In the light of the above findings, the administration of leptin is not likely to provide the hoped-for cure for obesity. But the discovery of this protein (hormone) has stimulated a tremendous amount of research that is likely to lead to a valuable new understanding of obesity.

Dr. Margolis is professor of medicine and biological chemistry at the Johns Hopkins School of Medicine.

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