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
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