A small molecule that was earlier believed to have anti-fat and anti-cancer abilities, has now also proved its potential in putting off fat-making genes, say researchers at Baylor College of Medicine.
Such action in mice genetically prone to obesity causes the animals to become leaner, they say.
AdvertisementThe researchers have also found the molecule to lowers the amount of fat in the mice's livers, along with their blood sugar and cholesterol levels.
"We are frankly very excited about it. It goes to the origin of [fat synthesis] - all the way back to gene expression," said Salih Wakil at Baylor.
Unlike cholesterol-lowering statins in use today, which block a single enzyme in the pathway, the chemical the researchers call fatostatin, "hits fat from the very beginning," said Motonari Uesugi.
As a result, fatostatin influences many of the genes involved in fat production and in various aspects of metabolic syndrome - a collection of risk factors including obesity, high cholesterol and insulin resistance - 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 these genes were known to be under the control of SREBP - a transcription factor which act as a well-known master controller of fat synthesis.
After more detailed analysis, the researchers found that the drug candidate blocked SREBP by preventing it from becoming active and entering the nucleus, where it would otherwise switch on the fat-making program.
According to them, it operates by binding another protein (called SCAP), which serves as SREBP's escort into the nucleus.
It was found that 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.
They explained that cells need fatty acids and cholesterol to build their cell membranes and continue growing.
Researchers 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. It could have a broad impact on the key diseases we all suffer from," said Wakil.
Uesugi said that fatostatin or its analogs may also serve a tool for gaining further insights into the regulation of SREBP and fat metabolism.
The study has been published in the journal Chemistry and Biology.
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