City of Hope scientists have created a mutant mouse that can apparently eat all it wants without becoming overweight.
Shiuan Chen, Ph.D., professor and director of the Department of Surgical Research, and colleagues recently reported in the Journal of Biological Chemistry that mice lacking a gene encoding a protein called PNRC2 remain thin compared to regular mice — even when they eat food with “supersized” fat content.
“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 the enzyme aromatase, which helps the body make estrogen. Blocking aromatase activity is an effective therapy for estrogen-dependent breast cancer in postmenopausal women. The discovery of the lean mouse was a direct offshoot of these studies.
“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 are not skinny simply because they do not 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 do not gain weight.
Tests showed that the mice consume more oxygen and generate more heat than normal mice. Both can indicate a revved-up metabolism, which means that the mutant mice expend a lot more energy than their normal, chunkier cousins. They burn off more calories from food.
The PNRC2 protein, identified four years ago by Zhou, is a co-factor for proteins known as nuclear receptors, a large family that includes receptors responsive to sex hormones. That means these nuclear receptors need PNRC2 to help do their work.
Zhou believes that PNRC2 may be especially critical for nuclear receptors involved in metabolizing fats and using energy — but sex hormones might play an unknown role in the mice’s leanness, since the effect is stronger in males. The lab is currently investigating that connection. 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 are 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 are not — will live. The laboratory mouse lives about two years.
Contributors to the work include Ruoqing Shen, Jing Jing Ye, and Yuping Li, Ph.D., of Chen’s lab, Walter Tsark, Ph.D, co-director of the transgenic/knockout mouse facility, Donna Isbell of the Animal Resources Center and Patrick Tso, Ph.D., of the University of Cincinnati.
The National Institutes of Health funded the research.
