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News from the LDI
 
15/03/2012
Lady Davis researcher succeeds in generating a genetically skinny mouse
By eliminating a particular protein known as Sam68, scientists at the Lady Davis Institute of the Jewish General Hospital have succeeded in producing a mouse that is genetically lean, has increased energy, greater tolerance for a high fat diet, and long-term protection against the onset of obesity. The findings are reported in the March issue of the prestigious journal Molecular Cell.

“It was very striking to observe how the mouse model from which we had eliminated the Sam68 protein were visibly leaner and produced less fatty tissue than other mice,” said Dr. Stéphane Richard, James McGill Professor of Medicine and Oncology at McGill University, whose lab made the discovery. “One of the exciting rewards of basic research is these unexpected discoveries, which can lead us in directions we wouldn’t have otherwise thought to pursue.”

It was one of those serendipitous findings that sometime occur in the lab when scientists are looking for one thing and discover another. Dr. Richard began knocking out mice without Sam68 in 1998. He became interested in this particular protein because it is found in every cell, but its functions were unknown. He was actually trying to determine whether he could affect the animal’s susceptibility to cancer and has, in fact, determined that they are protected against certain forms of breast cancer. In 2005, he published the finding that these mice were also protected against age-onset osteoporosis.

The predisposition of the mice to be leaner was first noticed in 2004. But it took all the ensuing time to identify the molecular cause. Researchers had to perform sophisticated microarrays of the mouse’s genome in order to identify the enzyme mTOR as the critical pathway, out of a possibility of 700,000 specks on slides.

Dr. Richard has determined that Sam68 serves to regulate the production of mTOR, which is essential to how the body processes nutrients and the production of adipose tissue, or fat. It determines whether the body stores nutrients, which affects how one gains weight. Without Sam68, significantly less mTor is produced, resulting in less fat being created and stored. Nonetheless, the mice without Sam68 still have enough fat necessary to support a healthy metabolism. These mice also sustain a normal lifespan. Thus far, the only detrimental side effects are infertility in males and reduced fertility in females, as well as very slight ataxia, or unsteadiness in their gait.

“mTOR has long been a targeted pathway for cancer therapies,” Dr. Richard points out, “and Sam68 could now emerge as a new avenue to this pathway. Our research has highlighted a new link to mTOR, which could be exploited by subsequent research. Curing mice of obesity is a long way from curing humans, but it does illuminate interesting possibilities for us to continue to explore. At this point, almost nothing is known about this particular area of adipogenesis, so we think we have opened up a very interesting line of inquiry with respect to obesity and links to diabetes.”

The article, “The Sam68 STAR RNA-binding protein regulates mTOR alternative slicing during adipogenesis,” was co-authored by Dr. Richard and Marc-Etienne Huot, Gillian Vogel, Amber Zabarauskas, and Chau Tuan-Anh Ngo, all from the Terry Fox Molecular Oncology Group and Bloomfield Centre for Research on Ageing at the Lady Davis Institute, and Jacek Majewski and Jasmin Coulombe-Huntington of the Department of Human Genetics at McGill and the Genome Quebec Innovation Centre. Dr. Huot is currently an Assistant Professor at the Laval University Cancer Research Centre at the Hôpital Hôtel-Dieu de Québec.


For further information, and to arrange interviews, contact:

Tod Hoffman
Research Communications Officer
Lady Davis Institute
Tel.: 514-340-8222 x 8661
Email: thoffman@jgh.mcgill.ca


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