Muscle gene influences fat storage in mice; may be target to prevent or treat obesity and diabetes

For mice genetically altered to get fat, knocking out a particular gene keeps them both leaner and healthier, Johns Hopkins School of Medicine scientists report in the March 1 issue of the Journal of Clinical Investigation.

That "lean" gene is the blueprint for myostatin, a protein known to limit muscle growth, they report. Previous Hopkins studies found that mice without myostatin are muscle-bound "mighty mice." Now the scientists show that mice without the protein, even mice that usually become obese, gain much less fat as they age.

"This tells me that myostatin might be a useful target for preventing or treating obesity and associated conditions, like diabetes," says Se Jin Lee, M.D., Ph.D., professor of molecular biology and genetics in the school's Institute for Basic Biomedical Sciences. "However, we've been studying genetic knock-outs; we don't know yet whether we can block myostatin in adult animals and see similar effects. In fact, myostatin-blocking agents still need to be developed."

In their experiments, Lee and postdoctoral fellow Alexandra McPherron crossed myostatin-free mice with each of two kinds of obese mice to get "doubly engineered" offspring. These second- generation mice lack myostatin and also have a genetic change that causes obesity. One line of fat mice, officially named "obese," eat excessively because they lack the hormone leptin. The other fat mice eat too much because their production of a protein called "agouti" is abnormal.

By examining amounts of fat and muscle in mice, the scientists discovered that regular and obese mice without myostatin gained less fat as they got older, even though they ate about the same amounts of food as other mice. In fact, "mighty mice" outweigh their counterparts when young, but by 10 months of age or so weighed the same or less than other mice, which had bulked up with fat.

"Some normal mice put on a lot of fat as they age and others not as much, but animal

Contact: Joanna Downer
Johns Hopkins Medical Institutions

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