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Research Reveals How Cells Store Fat

Researchers say they've spotted the genes that cells use to store fats, a discovery that might someday lead to new weight-loss therapies.

The genes produce proteins that are key to fat storage, the U.S. researchers report in this week's issue of the Proceedings of the National Academy of Sciences.

"We know from our studies that if you reduce the level of these proteins in cells, the cells lose the ability to store fat," said senior researcher David Silver, an assistant professor of biochemistry at Albert Einstein College of Medicine in New York City.

As Silver explained, the genes "store fat in the form of droplets as an energy reserve for later use. These make proteins involved in fundamental processes, and they are conserved throughout evolution."

Searching databases, Silver and his colleagues have established that the two genes they identified -- dubbed FIT1 and FIT2 -- are present in the most primitive members of the advanced cell type called eukaryotes, which make up the human body. "One ancient gene goes all the way back to yeast," Silver said.

Other scientists had already identified genes responsible for synthesizing fat within cells, he noted. The new discovery describes the genes that package that fat into liquid droplets within a layer of molecules called phospholipids and proteins.

Both genes produce proteins that consist of more than 200 subunits called amino acids, and the two genes are 50 percent similar to one another. The amino acid chains of the FIT genes do not resemble those of any other protein found in any species, the researchers said.

Meanwhile, several series of experiments have confirmed the role of the FIT genes in fat storage, Silver said.

In one experiment, extra copies of the genes were inserted in human cells. The rate of fat synthesis was unchanged in those cells, but the number of fat droplets produced in those cells increased four- to sixfold.

Another experiment reduced the expression of one FIT gene in mouse fat cells. A drastic reduction in fat droplet production was found in those cells.

Then, the researchers injected genetic material designed to block activity of the genes into an experimental animal, the zebrafish. The fish were fed a high-fat diet for six hours, but examination of their livers and intestines found almost no fat droplets.

Mouse models that lack the genes are being developed to see what happens to an animal that cannot package its fats, Silver said. The question is, "Where will it go if the body can't store it?" he said.

There are two possibilities -- One is that "the body responds in a positive way and burns it," Silver said. "The other outcome is some kind of toxicity, with the fat deposited elsewhere. At the moment, we don't know the answer to that question."

Now that the genes have been identified, it should be possible to develop drugs that modify their activity -- drugs that could be useful not only against obesity but also against conditions such as diabetes and heart disease.

"We could engineer the very fundamental process by which all life stores fat," Silver said. "That is a very basic discovery."

It is a "seminal discovery," said Dawn L. Brasaemle, an associate professor of nutritional sciences at Rutgers University, who has been working on lipid droplets since they were first described in the early 1990s. The field is so new that the first scientific meeting on them was just held this past summer, she said.

The first challenge facing Silver is to learn how these genes work with others involved in lipid packaging, Brasaemle said. "Then we have to know what is their importance for health," she added. "Is there a way to manipulate them with pharmaceutical agents? Are they likely to be targets for pharmaceutical intervention to determine fat storage? It is very early in the study of these two genes."

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