THE SKINNY ON A FAT GENE

    What's the difference between a fat mouse and a skinny mouse?

    Not a lot when they're unwelcome visitors in your house. But to two researchers at UMDNJ's Robert Wood Johnson Medical School (RWJMS), that difference led to the discovery of a gene that might help unsuccessful dieters and eventually may even eliminate obesity.

    According to Kiran Chada, PhD, a biochemist and director of the Genomics Center at RWJMS, if a gene called HMGI-C is missing or only partially expressed in mice, the animals do not gain weight even when fed a diet high in fat. Chada and Ashim Anand, PhD, a postdoctoral research fellow in biochemistry, made the discovery while studying a family of proteins-HMGI-C, HMGI and HMGI (Y)- to understand the chemical signals that control the growth of a developing mouse embryo.

    "These results are significant because obesity is the second leading cause of preventable death in the United States, but the development of safe and effective drugs to fight it has so far proven elusive," said Chada. "And anyone who has tried to lose weight by dieting knows permanent changes in behavior can be difficult." The study was published in the March, 2000 issue of Nature Genetics.

    The HMGI-C genes in mice and humans are 98 percent identical. Based on their research, the team realized all three genes, but specifically HMGI-C, are essential to cell growth and differentiation during embryo development. They designed a study to determine if HMGI-C in mice might have any effect on fat accumulation. The researchers discovered that the obese mice had HMGI-C in their fat tissues and the lean mice did not. To prove that the HMGI-C gene was the controlling factor in fat accumulation, they produced mice that lacked either one or both copies of the gene.

    The study found that mice lacking the gene completely, or mice that had only one copy, had an 87 percent decrease in the amount of fat tissue as compared to normal mice fed a diet equal in fat content to a high-fat American diet. The research revealed that mice lacking the HMGI-C gene did not gain any weight, and that mice with one copy of the gene also did not gain weight.

    "One of the most exciting results of our study is that if expression of the gene is inhibited by only 50 percent, weight gain does not occur. This has important implications for drug development because we have shown that the drug does not have to totally inhibit HMGI-C to have a significant effect," Chada added.

    Three New Jersey pharmaceutical companies have expressed interest in developing a drug based on this research. A drug might be available in five to 10 years following development and clinical trials, Chada said.

    The study was funded by the National Institutes of Health and the New Jersey Commission on Science and Technology, which presented the first $1 million research award to the Genomics Center.