Fundamental Discovery By Einstein Researchers Reveals How Fat Is Stored In Cells

In discovering the genes responsible for storing fat in cells, scientists at the Albert
Einstein College of Medicine of Yeshiva University have answered one of biology's most fundamental
questions. Their findings, which appear in the December 17 to 21 "Early Edition" online issue of the
Proceedings of the National Academy of Sciences, could lead to new strategies for treating obesity and
the diseases associated with it.


Scientists had previously identified the genes responsible for synthesizing fat within cells. But
the genes governing the next step--packaging the fat inside a layer of phospholipids and proteins to form
lipid droplets-have long been sought, and for good reason.


"Storing fat in lipid droplets appears crucially important for enabling cells to use fat as an energy
source," says Dr. David Silver, assistant professor of biochemistry at Einstein and senior author of the
article. "From yeast to humans, partitioning fat into droplets is a universal feature among animals. And
in humans, of course, acquiring excessive amounts of these fat droplets in our fat tissue leads to
obesity." [See photomicrograph of lipid droplets in fat cells at end of press release].


Dr. Silver and his colleagues identified two genes that are crucial for packaging fat into lipid
droplets. They called the genes FIT1 and FIT2 (for Fat-Inducing Transcripts 1 and 2). Both genes
code for proteins that are more than 200 amino acids in length, and the two genes are 50
percent similar to each other. The amino acid sequences of the FIT proteins do not
resemble any other known proteins found in any species, indicating that the FIT genes
comprise a novel gene family.


The researchers conducted several different experiments to confirm the roles of
FIT1 and FIT2 in fat storage. In one experiment, they overexpressed both FIT1 and FIT2
genes (i.e., inserted extra copies of them) in human cells. While the rate of fat synthesis
stayed the same in both "overexpressed" and control cells, the number of lipid droplets in
the "overexpressed" cells increased dramatically, between four- and six-fold.


Using a different tactic to evaluate FIT function, the researchers next "knocked
down" FIT2 in mouse fat cells (FIT1 is not expressed in these cells). Their reasoning: If
FIT2 is indeed essential for lipid droplet formation, then suppressing FIT2 expression
should abolish lipid-droplet accumulation. Examination of these fat cells for lipid
droplets revealed that cells with suppressed FIT2 expression had a drastic reduction in
lipid droplets.


Finally, the researchers carried out a similar FIT2 "knock down" experiment in a
whole animal-the zebrafish. Zebrafish eggs were injected with a segment of DNA
designed to interfere with FIT2 expression. Then, to induce lipid droplet formation in
zebrafish larvae (where it is localized mainly in the liver and intestine), free-swimming
six-day-old larvae were fed a high-fat diet for six hours. Although the larvae had
exhibited normal feeding behavior, examination of their livers and intestines revealed a
near-absence of lipid droplets.


"These lines of evidence supported our conclusion that FIT genes are necessary
for the accumulation of lipid droplets in cells," says Dr. Silver. "Now that we've
identified the genes and the proteins they code for, it should be possible to develop drugs
that can regulate their expression or activity. Such drugs could prove extremely valuable,
not only for treating the main result of excess lipid droplet accumulation-obesity-but
for alleviating the serious disorders that arise from obesity including type 2 diabetes and
heart disease."


Other Einstein scientists involved in the research were lead author Bert Kadereit,
Pradeep Kumar, Wen-Jun Wang, Diego Miranda, Erik L. Snapp, Nadia Severina, Ingrid
Torregroza and Todd Evans.

Albert Einstein College of Medicine