Scientists Build Perfect Metabolism Gene Mutations On Mice May Help Drug Development

University of Washington scientists have created in mice an ability that is sheer fantasy to millions of humans: a way to eat high-fat food and stay skinny.

The experiments involve creating genetic mutations in stem cells, which produce all other cells in the body. So the mouse method is not something researchers want to try with humans. But they hope the understanding they’ve gained may someday lead to a drug that would help control obesity.

“I think there’s enough of a chance (for drug development) that pharmaceutical companies will certainly want to investigate it,” says Dr. Stanley McKnight, a University of Washington professor of pharmacology and director of the study reported in today’s edition of the journal Nature.

The experiments by McKnight and his colleagues involved disabling a gene that produces an enzyme important in fat-cell metabolism in most animals, including humans. When the mutation was engineered, the mice remained thin, even when on a diet that derived 50 percent of its calories from fat.

Scientists altered the gene in mouse embryo cells in their earliest stage of development. Then the cells were returned to the female mouse for normal development in the uterus.

The enzyme, called RII, helps regulate how much fat is stored and how much is used for energy. Removing RII through the mutation, the researchers found, increased the mice’s fat metabolism, causing the animal to use more food and fat stores for energy in the form of heat.

“It’s like we reset the metabolic thermostat in mice,” says McKnight. The animals with the mutation also did not have some of the adverse effects of a chronic high-fat diet: Insulin, used to metabolize sugar, was not made ineffective (a precursor of diabetes), fat did not accumulate in organs like the liver, and the animals did not become hyperactive.

McKnight said the research mainly has helped scientists better understand how the body balances storage and use of fat. It has shown how important the enzyme is in fat cells.

The question is whether a drug could be developed to inhibit the enzyme within the cell - or accomplish the same thing the genetic mutation does. Because the enzyme also is found in the brain, the drug would need a mechanism to protect those cells.