'Fatostatin' turns off fat cell genes
By Ruth SoRelle, M.P.H.
Dr. Salih Wakil, chair emeritus and distinguished service professor of biochemistry and molecular biology at Baylor College of Medicine, has spent decades studying fatty acids, obesity and insulin resistance.
Now, a small molecule he and and his collaborators have dubbed "fatostatin" appears to have answered some of his questions. Fatostatin turns off genes responsible for making fat cells.
Blocks transcription factors
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 Wakil. A report on the research appeared in a recent issue of the journal Chemistry and Biology.
"That is the exciting thing," said Wakil. "This goes to the most basic level of the expression of genes that cause fat."
When mice with a predisposition to be obese received fatostatin, they lost weight and their cholesterol and fatty acid synthesis decreased. They had less resistance to insulin (a factor in diabetes), and their livers, which were pale because of fat buildup, returned to a normal ruddy tone.
Less fat means more sensitive to insulin
"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.
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.
Compound derivatives
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.
Wakil is the Lodwick T. Bolin Professor of Biochemistry and Molecular Biology.
