Eat all you want without becoming overweight? It sounds too good to be true, but it’s reality for certain special mice in the lab of Shiuan Chen, Ph.D.
Chen, director and professor in City of Hope’s Department of Surgical Research, and colleagues recently reported in the Journal of Biological Chemistry that mice engineered to lack a specific gene remain thin compared to regular mice, even when fed a super-sized menu.
“This effect is much more obvious when mice are fed a high-fat diet,” said Chen. “Regular mice tend to get chubby on this diet, but the mutants stay skinny.”
The findings impact research on obesity, which is linked to heart disease, stroke, diabetes and cancer. United States Surgeon General Richard Carmona calls obesity the greatest threat to public health today.
Chen’s group is best known for identifying compounds that inhibit a natural substance called aromatase, which helps the body make estrogen. Blocking aromatase activity is an effective way to fight estrogen-dependent breast cancer. The discovery of the lean mouse was a direct offshoot of these studies.
The researchers are studying a gene that encodes a protein called PNRC2.
“This project started because we were interested in whether PNRC2 regulated aromatase in breast cancer,” said Chen. Instead, the researchers found mice without the gene had fewer fat cells. That effect was most pronounced in male mice.
And the mice aren’t skinny simply because they don’t eat. Associate research scientist Dujin Zhou, M.D., Ph.D., lead author of the study, actually thinks they may eat a little more than normal mice. They just don’t gain weight.
Tests showed that the special mice consume more oxygen and generate more heat than normal mice. Both can indicate a revved-up metabolism, which means that the mice expend a lot more energy than their normal, chunkier cousins. They burn off more calories from food.
Certain key proteins in the body need PNRC2 to help do their work. Zhou believes that PNRC2 may be especially critical for proteins that are key to metabolizing fats and using energy.
Metabolic disease is a new direction for Chen’s lab. “We now need to understand why these mice are thin at the molecular level,” said Chen, noting that they’re looking for drugs that block PNRC2 activity. “We are interested in whether we can manipulate PNRC2 activity and apply it to obesity in humans.”
The lean mice are about a year and a half old and still healthy, Zhou said. Research has linked calorie restriction to longer life spans in organisms from worms to mice, so the investigators will watch how long these mice — who appear calorie-restricted even though they’re not — will live. Lab mice typically live for about two years.
