Study Identifies A New "Fat Gene"

City of Hope
Monday, 29 December 2003

In some of the latest obesity research, scientists report that a gene needed for youthful growth in laboratory mice can also make them thin when it is absent in adulthood, according to a study published by City of Hope researchers in the current issue of the journal Biochemical and Biophysical Research Communications.

"While the chief causes for obesity are eating more and exercising less, there is ample evidence that genetic variations play a significant role in determining a person's susceptibility to obesity," said the study's lead author, Robert Whitson, PhD, City of Hope research scientist.

He said the latest "fat gene," Mrf-2, is one of about half a dozen genes whose absence leads to extreme leanness in mice, while a much larger number of genes lead to extreme obesity when they are absent.

Dr. Whitson said some of these genes work primarily in the brain, where they regulate the intake of food energy by controlling appetite; others work primarily in tissues, such as liver, fat or muscle, where they regulate the storage and expenditure of energy. Removal of these genes disrupts the balance between energy input and energy expenditure. The Mrf-2 works primarily in fat.

Scientists hope that understanding the processes that maintain this balance will lead to improved treatments for obesity and the diseases that are strongly correlated with it, such as heart disease and cancer.

Dr. Whitson's previous studies showed that the Mrf-2 protein has a unique structure that binds to specific DNA sequences. Proteins with this ability almost always control the expression of other genes, but the genetic targets for Mrf-2 were not known.

To identify them, Whitson's research team studied mice in which both copies of the Mrf-2 gene were inactivated.

He said these "knockout mice" grew normally as embryos, but were much smaller than their normal brothers and sisters by the time they were five days old. "Mrf-2 knockouts did gain weight as they matured into adults, but never weighed as much as normal mice of the same age and sex," Dr. Whitson said.

Careful examinations of the adult Mrf-2 knockouts revealed that, although they had a normal distribution of fat tissue, the amount of fat they stored was drastically reduced.

Dr. Whitson said that, in fact, their overall percentage of body fat was about one-third to one-half that of the normal mice. He said it is not yet completely clear why the Mrf-2 knockouts were so lean. Compared to their body weight, they ate as much as normal mice, and even when they were fed a high-fat diet they didn't gain weight or accumulate more fat.

His further studies suggested that Mrf-2 is essential for the final stages of fat cell differentiation and may activate the expression of enzymes that are needed to synthesize and store fat. "This makes the loss of Mrf-2 expression deleterious in very young mice, since they must accumulate fat very rapidly after birth in order to maintain their body temperatures," he said.

The City of Hope research team included Keiichi Itakura, PhD, Professor of Molecular Biology, and Ting Huang, PhD, support scientist.

For more information, or to contact City of Hope, see their website at: www.cityofhope.org