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Gene Makes Muscles in the Obese Store More Fat

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Duke Health News 919-660-1306

DURHAM, N.C. – The gene encoding an enzyme that hinders
muscle from burning fat manufactures three times more enzyme in
the muscle of obese people than lean people, researchers from
Duke University Medical Center and Louisiana State University
have found. This causes the obese muscle tissue to both store
more fat and burn less fat, the researchers said.

"Obesity is a very complex disease, and this metabolic
pathway does not fully explain obesity, but it is a likely
contributor," said Deborah Muoio, Ph.D., senior study author
and assistant professor of medicine at Duke's Sarah W. Stedman Nutrition and
Metabolism Center
.

Excess fat storage in muscle tissue is a hallmark of
obesity, and may contribute to problems such as diabetes and
cardiovascular disease. The researchers discovered that
skeletal muscle tissue and cells from obese people were
programmed to store fat even when removed from the body and
forced to grow in the laboratory. This finding suggests the
gene is more active in obese people not only because of excess
calorie intake, but also as a result of heritable changes in
its regulation, Muoio said.

"The cells of obese people remembered their metabolic
program, which could help explain, in part, why losing weight
and maintaining weight loss is so difficult," Muoio said. "The
good news is it's possible to change your energy balance
through exercise. Exercise can enhance muscle's ability to burn
fat," Muoio said. "This discovery also provides a potential
drug target."

The results appear in the Oct. 12, 2005 issue of Cell Metabolism. The work
was supported by National Institute of Diabetes & Digestive
& Kidney Diseases, of the National Institutes of Health,
the Pennington Biomedical Research Foundation and the American
Diabetes Association.

Muoio suspects that the gene's behavior is altered in obese
people because of epigenetic control – alteration of gene
activity states without variations in the DNA code. These
changes can be triggered by environmental factors, such as
nutrition or chemical exposure, and carried forward even after
the stimulus is removed. The gene investigated in the study is
present in obese and lean people, but was overexpressed, or
more active, in obese muscle tissue and cells, which means the
obese tissue produced larger quantities of enzyme.

In their study, the researchers analyzed stomach muscle
tissue donated by non-diabetic obese and lean people who were
having surgery. They examined muscle tissue and muscle
satellite cells, which have the potential to develop into
muscle. Both the tissue and cells from obese people were
programmed to store excess fat in the form of fat droplets. The
cells and tissue also burned less fat because they produced
more of an enzyme that opposes fat oxidation. This excess fat
storage may be linked to type 2 diabetes because skeletal
muscle – muscle attached to bone – helps regulate sugar
metabolism.

When the muscle satellite cells were encouraged to develop
into mature muscle cells, they showed the same fat storage
programming as muscle tissue. "This is a very important clue,
because it indicates this program of fat storage is perpetuated
as these cells divide. It's not driven strictly by
over-nutrition," Muoio said.

To identify the gene controlling this fat storage pathway,
the research team relied on DNA microarrays, or "gene chips,"
to test the activity of thousands of genes at once. They also
selected a few candidate genes (they chose culprits based on
earlier research) to examine by a different method. In both
cases, they arrived at the same gene, called steroyl-CoA
desaturase 1 (SCD1), which was known to slow down fat burning
and promotes fat storage.

"We found that obesity was associated with a threefold
increase in SCD1 expression in obese muscle, as well as a
threefold higher level of SCD1 enzyme, compared to lean
muscle," Muoio said. The activity of other genes linked to fat
metabolism and obesity were comparable between the two
groups.

The researchers also investigated how muscle cells from lean
individuals behaved when forced to overproduce the SCD1 enzyme.
Using genetic engineering techniques, the team showed that
cells from lean people mimicked the metabolism of obese cells,
storing more fat droplets and burning less fat, when the amount
of SCD1 was increased.

Contributors include Matthew Hulver and Michael Carper,
Pennington Biomedical Research Center, Louisiana State
University; Jason Berggren, John Thyfault, G. Lynis Dohm and
Joseph Houmard, East Carolina University; Makoto Miyazaki and
James Ntambi, University of Wisconsin, Madison; and Eric
Hoffman, Children's National Medical Center.

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