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Fatostatin blocks fat at most basic level

HOUSTON -- (September 3, 2009) -- A small molecule, dubbed "fatostatin" by its Baylor College of Medicine and Japanese discoverers, turns off genes responsible for making fat cells, according to a report in the journal Chemistry and Biology.

Fatostatin blocks a transcription factor in the cell (SREBP or sterol regulatory element binding protein) that starts the cascade of events that turns on the 63 genes in the nucleus responsible for the generation of fat cells, said Dr. Salih Wakil, chair emeritus and distinguished service professor of biochemistry and molecular biology at BCM.

"That is the exciting thing," said Wakil. "This goes to the most basic level of the expression of genes that cause fat."

Fatostatin also benefits muscles, liver

When mice with a predisposition to be obese received fatostatin, they lost weight, their cholesterol and fatty acid synthesis decreased. They had less resistance of insulin (a factor in diabetes), and their livers, which were pale because of fat buildup, returned to a normal ruddy tone.

"When there is less fat in the muscles and cell membranes, the muscles and liver become sensitive to insulin. They drag glucose into the cells so they can use it for energy," said Wakil. Lowering the glucose level corrects type 2 diabetes (also known as adult-onset diabetes).

Drugs that lower cholesterol already exist, but they block only a single enzyme in the fat-generating pathway. Fatostatin stops the process at the beginning, said Wakil.

Next steps

Wakil said one of his colleagues, Dr. Motonari Uesugi, now of Kyoto University in Japan, discovered the compound by screening a library of an estimated 10,000 compounds. Dr. Lutfi Abu-Elheiga, associate professor of biochemistry and molecular biology at BCM and long-time collaborator, was also a major contributor to the work.

In the future, Wakil said, he hopes they may look at derivatives of this compound in an attempt to find some that work better. He expects the effort to move into other animals and eventually humans.

Others who took part in the research include Qian Mao, Ziwei Gu, Youngjoo Kwon, Shin-ichi Sato and Koko Asakura, all of Baylor College of Medicine; Shinji Kamisuki; Akira Kugimiya, Tokuyuki Shinohara, Yoshinori Kawazoe and Hea-Young Park Choo, all of Kyoto University in Japan and Juro Sakai of the University of Tokyo in Japan.

Funding for this work came from the U.S. Department of Defense Prostate Cancer Research Program, the Suzuken Memorial Foundation, Kato Memorial Bioscience Foundation, MEXT (Japan Ministry of Education, Culture, Sports, Science and Technology), the National Institutes of Health and Hefni Technical Training Foundation.

For more information on basic science research at Baylor College of Medicine, please go to www.bcm.edu/fromthelab or www.bcm.edu/news.