'Fatostatin' is a turnoff for fat genes

Aug 27, 2009

A small molecule earlier found to have both anti-fat and anti-cancer abilities works as a literal turnoff for fat-making genes, according to a new report in the August 28th issue of the journal Chemistry and Biology, a Cell Press journal.

The chemical blocks a well known master controller of fat synthesis, a transcription factor known as SREBP. That action in mice that are genetically prone to obesity causes the animals to become leaner. It also lowers the amount of fat in their livers, along with their blood sugar and cholesterol levels.

"We are frankly very excited about it," said Salih Wakil of Baylor College of Medicine. "It goes to the origin of [fat synthesis] - all the way back to gene expression."

Unlike cholesterol-lowering statins in use today, which block a single enzyme in the pathway, the chemical, which the researchers call fatostatin, "hits fat from the very beginning," added Motonari Uesugi, who is now at Kyoto University.

In doing so, fatostatin influences many of the genes involved in fat production and in various aspects of - a collection of risk factors including obesity, high cholesterol and - in one go.

Studies in cell culture showed that fatostatin, previously known only as 125B11, significantly lowers the activity of 63 genes, including 34 directly associated with fatty acid or cholesterol synthesis. Many of those were known to be under the control of SREBP.

More detailed analysis reveals that the blocks SREBP by preventing it from becoming active and entering the nucleus, where it would otherwise switch on the fat-making program. It operates by binding another protein (called SCAP), which serves as SREBP's escort into the nucleus.

Obese mice injected with fatostatin show noticeable reductions in their weight despite little difference in their eating habits, the researchers report. After four weeks of treatment, the animals weighed 12 percent less and had 70 percent lower blood sugar levels. Their cholesterol levels (both LDL and HDL) were down too. The concentration of fatty acids in their blood was actually higher, a sign of their greater demand for fat to burn.

While the livers of the obese mice were heavy and pale with fat, treated animals' livers were more than 30 percent lighter and were a healthy-looking red.

Although less obvious, the SREBP-blocking ability might also explain the molecule's earlier reported effects against prostate cancer cells in culture as well. Cells need fatty acids and cholesterol to build their cell membranes and continue growing, they explain.

Fatostatin is not the first molecule to act on SREBP, according to the researchers, but it appears to do so in a somewhat different way than those described previously. Many steps remain, but they are optimistic that fatostatin could prove to be clinically useful in the context of obesity, and perhaps cardiovascular disease and diabetes as well.

"Hopefully down the road, fatostatin or a derivative of fatostatin may be helpful," said Wakil, who has been studying the enzymes involved in fat synthesis ever since he discovered them in the late 1950s. "It could have a broad impact on the key diseases we all suffer from."

Fatostatin or its analogs may also serve a tool for gaining further insights into the regulation of SREBP and fat metabolism, Uesugi said.

Source: Cell Press (news : web)

Explore further: Researchers create designer 'barrel' proteins

add to favorites email to friend print save as pdf

Related Stories

Missing link between fructose, insulin resistance found

Mar 03, 2009

A new study in mice sheds light on the insulin resistance that can come from diets loaded with high-fructose corn syrup, a sweetener found in most sodas and many other processed foods. The report in the March issue of Cell Me ...

Hormone discovery points to benefits of 'home grown' fat

Sep 18, 2008

A hormone found at higher levels when the body produces its own "home grown" fat comes with considerable metabolic benefits, according to a report in the September 19th issue of the journal Cell, a Cell Press publication. The ne ...

New culprit behind obesity's ill metabolic consequences

Jul 07, 2009

Obesity very often leads to insulin resistance, and now researchers reporting in the July 8 issue of Cell Metabolism, a Cell Press publication, have uncovered another factor behind that ill consequence. The newly discovered culpri ...

Secreted protein sends signal that fat is on the way

Dec 02, 2008

After you eat a burger and fries or other fat-filled meal, a protein produced by the liver may send a signal that fat is on the way, suggests a report in the December issue of the journal Cell Metabolism, a Cell Press public ...

Recommended for you

Amino acids key to new gold leaching process

Oct 24, 2014

Curtin University scientists have developed a gold and copper extraction process using an amino acid–hydrogen peroxide system, which could provide an environmentally friendly and cheaper alternative to ...

Researchers create designer 'barrel' proteins

Oct 23, 2014

Proteins are long linear molecules that fold up to form well-defined 3D shapes. These 3D molecular architectures are essential for biological functions such as the elasticity of skin, the digestion of food, ...

User comments : 2

Adjust slider to filter visible comments by rank

Display comments: newest first

Sean_W
not rated yet Aug 28, 2009
While I am sure people will gripe about weight lose being made too easy and how everyone wants a quick fix these days weight gain tends to make weight loss harder and giving people a tool to help provide observable success sooner will result in fewer people giving up. And helping them slim down will mean they are more productive, less prone to depression, have less abscenteeism and result in scores of other benefits to society. I am not saying that this is the discovery that does all that but the importance of such a discovery is not to be underestimated.
mjb_TO
not rated yet Aug 28, 2009
Be careful what you wish for. Without the feedback information of accumulating adipose deposit, who knows what other deleterious effects would compound from over-eating. Belly girth might be the proverbial canary in the mine--might not be wise to get rid of the canary.