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Fat storage: Ancient but effective
20 DECEMBER 2007

can of round yeast cell, green around edge, orange and red in the middle, white droplets concentrated in center Beyond the fact that we humans love a good sourdough, and baker's yeast helps raise that loaf, what else do we have in common with these lowly fungi? Globs of fat stored inside our cells, that's what.

No, we're not talking butter. We're talking triglyceride -- a concentrated form of energy that's tucked away inside the cells of every single organism with a nucleus, pretty much everything above bacteria on the evolutionary scale.

In this x-ray image of a yeast cell, red shows the nucleus (the smaller sphere) and large vacuole. Lipid droplets are white, and cytoplasmic structures are orange or green. Photo: Berkeley Labs

The nucleus appears in baker's yeast, which separated from our lineage 2.6 billion years ago. After so much evolutionary divergence, we look kinda different from baker's yeast, but we share this essential trait: globs of stored fat inside our cells.

Fat storage is "a very crucial pathway for survival," says David Silver, an assistant professor of biochemistry at the Albert Einstein College of Medicine in New York.  Ghostly group of white, sphere-shapes emerge from black background"When yeast are starved they begin to store fat, but when given some food, they put their stored fat to use so they can divide."

Stored fat is also found in human beings, and the mosquitoes that are, at any given moment, drinking human blood. Even the malaria parasite inside those mosquitoes has those fat-bearing globules inside its single cell.

A mouse fat cell (an adipocyte) contains many lipid droplets -- globs of fat. A comparable energy-storage system appears in all organisms with a cell nucleus -- everything above the bacteria, that is. Photo courtesy David Silver, Albert Einstein College of Medicine.

The production of triglyceride in cells has been understood for decades, but only now do we finally get details on the formation of fat globs, er, "lipid droplets." "We were interested in identifying the proteins that are involved in the process of taking the triglyceride and packaging it into the lipid droplets in the cell," Silver says.

Packing away the pounds
In a new study, Silver and colleagues report that the process relies on two "fat-inducing transcript" proteins, called FIT1 and FIT2, made by genes of the same name.

In studies of cells and whole animals, the researchers found several links between the FIT proteins and lipid droplets:

The proteins appear only in the place where triglyceride is synthesized;

Cells in culture that make more FIT proteins also make more lipid droplets;

When the proteins are blocked in fish embryos, dramatically fewer lipid droplets appear.

Any time you unravel a basic process used by a huge division of life (in this case, all "eukaryotes" -- all species that contain a cell nucleus), you have done something commendable. "The discovery we made is very fundamental," says Silver. "We have now identified a protein that allows all eukaryotic cells to store fat. Now we can see if it can be used as a drug target, to reduce body weight and treat obesity."

A particular concern is type 2 diabetes, in which insulin fails to transport enough sugar from the blood into the cells. Like its genetic relative, type 1 diabetes, high blood sugar in type 2 causes system-wide damage to small blood vessels, especially in the eye and kidney.

Graphic of a cell sliced through the center, reveals organelles shaped like spheres, kidney beans and labyrinth mazes
The smooth endoplasmic reticulum is where triglycerides are made. The proteins FIT1 and FIT2, which package fat into lipid droplets, are also found here. Graphic: NIH

Is less fat healthy or not?
Understanding the fat-storage mechanism could lead to drugs that block it, and because type 2 diabetes is tightly linked to obesity, you might think that such a drug would lead the body to burn the unstored fat, and thus treat type 2.

But Silver thinks the unstored fat is actually more likely to cause health problems -- even diabetes. After all, excess fatty acid in the blood (which can be released from breakdown of triglycerides in fat tissue) is one sign of diabetes (people with lipodystrophies, who lack fat cells due to a rare mutation, also have some of the metabolic problems of type 2 diabetes).

Evidence that it might be healthier to make more FIT2 protein, rather than block it, comes from the thiazolidinedione (TZD) drugs, which are already used to restore insulin sensitivity in diabetics, and which, Silver found, make FIT more active.

Curiously, the TZD drugs also cause weight gain, and given that type 2 diabetes occurs chiefly in obese people, Silver admits the results may seem "paradoxical. People taking TZD drugs become more insulin-sensitive, but gain weight. However, TZD drugs appear to enhance the ability of fat tissue to safely store fat (in part by increasing FIT levels), preventing the fat from being deposited in muscle or liver. So this function might explain part of the insulin-sensitizing effect of these drugs."

Overflowing basket of scrumptious looking yeast breads

Is fat the new thin?
Studies to further explore the relationship among FIT proteins, insulin sensitivity and weight gain have begun, using mice that either lack FIT genes, or carry extra copies. "Using these models, we can answer these questions about the physiological role of these proteins," says Silver.

One hopeful sign: Because the thiazolidinedione drugs are already on the market, any human experiments will be a lot easier to perform.

Diabetes is only one side of the larger obesity problem, and the new insight into fat storage could have broad application far beyond one disease. "We know we have uncovered a process that is evolutionarily conserved, and is involved in the pathway of storing fat," says Silver. "No other protein has been identified with this action, and we have seen it the same in yeast, fish and mouse."

- David Tenenbaum

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• Evolutionarily Conserved Gene Family Important for Fat Storage, Bert Kadereit et al, PNAS Online Early Edition, December 17-21 , 2007.

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