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Stanford Report, January 26, 2000

Manipulating fat metabolism causes sterility in male mice

BY MITCH LESLIE

Genetically engineered mice that didn't get fat when expected to have provided researchers with new insights into fat metabolism and sperm production.

Because the mice lacked an enzyme crucial for breaking down stored fat, researchers expected them to grow chubby. Instead, the rodents stayed slim; but the males were sterile, producing virtually no sperm. Besides revealing a previously unknown metabolic pathway, the findings suggest that manipulating levels of the enzyme to treat diabetes or obesity -- a strategy several drug companies are pursuing -- might bring some unwelcome side effects.

Frederic Kraemer, MD, associate professor of medicine at Stanford and chief of endocrinology at the Veterans Affairs Palo Alto Health Care System, and 10 colleagues from Tokyo University reported results of their study in the Jan. 18 issue of the Proceedings of the National Academy of Sciences. The researchers used standard gene manipulation techniques to produce knockout mice that could not make the enzyme hormone-sensitive lipase (HSL). Inside the body's fat-storing cells, or adipocytes, this enzyme slices apart sequestered fat molecules to produce fatty acids, which escape into the bloodstream and are absorbed by body cells as a source of energy.

HSL performs other functions as well. In the adrenal glands, testes, ovaries and muscles, HSL is involved in cholesterol metabolism, helping break down the storage form of cholesterol. Through a role in the scavenger cells called macrophages, HSL may also contribute to cardiovascular disease. Macrophages in which HSL activity is low may accumulate cholesterol; and macrophages that are laden with cholesterol often lodge on the interior walls of arteries, creating fatty deposits of plaque that can lead to heart attacks or strokes.

The researchers expected that the HSL-deficient mice would become tubby because they were unable to break down fat they had already stored. But that's not what happened. Although the mice did have lower levels of fats in their blood and extra large fat cells, they kept their figures, weighing no more than normal mice.

For nearly 40 years, HSL has been considered the rate-limiting enzyme in fat breakdown, an idea that scientists may now have to discard. "HSL is important, but there seems to be another enzyme that is capable of carrying out that task," Kraemer said. "But it's not clear what that enzyme is," he added.

What surprised the researchers was that the male mice, while mating normally, sired no offspring. Their sterility, it turns out, was due to an extremely low sperm count. Inside the epididymis, a sperm staging area on the surface of the testes, the average knockout mouse had only 90 sperm, compared with 8 million to 9 million for a normal male.

Low sperm counts did not result from hormonal disruption -- the mice had normal levels of testosterone and other key hormones -- but probably from defective fat metabolism within the testes, which may starve developing sperm of the cholesterol or fats they need to grow.

Attracted by HSL's many talents, drug industry scientists are exploring the enzyme's potential as a treatment for diabetes and obesity. They have theorized that boosting HSL activity might help the obese shed excess body fat, and suppressing HSL activity might help diabetics reign in the high concentration of fatty acids in their blood.

By revealing added complexity in fat metabolism, the work of Kraemer and his colleagues raises doubts about the potential of these approaches. "It just points out that there are many other steps and systems in place that are regulating obesity," Kraemer said.

The results could also explain why no human diseases involving defects in the HSL gene have been discovered. Because a defective gene would cause sterility, it would be quickly eliminated by natural selection.

Kraemer's research was funded by the National Institutes of Health and the Department of Veterans Affairs. SR