Rare Gene Mutations Suggest One More Path to Obesity

By Rebecca Voelker on July 18, 2013

Mutations in the Mrap2 gene cause mice to become obese (left). A similar effect is seen in humans. (Image: Boston Children’s Hospital)

New research suggests that people with rare mutations of a gene linked with regulating metabolism may be highly susceptible to becoming obese.
The gene involved is known as Mrap2 in mice and as MRAP2 in humans. It’s expressed predominantly in the brain, in some of the regions that regulate energy balance. The gene encodes a protein that apparently is linked with increasing metabolism and decreasing appetite.
To examine the gene’s effect on weight gain, researchers at Boston Children’s Hospital first inactivated Mrap2 in mice. The mice appeared normal until they were about a month old. Then they started to gain more weight, became excessively hungry, and ate more than their siblings with Mrap2 intact.
Even when their food was restricted to the same amount as their normal siblings, mice with the inactivated gene still gained more weight. They didn’t gain weight at the same rate as their siblings until they ate 10% to 15% less food. Mice with both copies of Mrap2 inactivated gained the most weight, but even mice with 1 working copy of the gene gained more weight and had bigger appetites than the normal mice.
When allowed to eat freely, mice with the inactivated gene ate almost twice as much as their siblings. They had more visceral fat, which surrounds organs deep in the abdomen and is linked with cardiovascular disease, diabetes, and colorectal cancer. They also had more fat in their liver, according to the results published online today in the journal Science
“These mice aren’t burning the fat; they’re somehow holding on to it,” the study’s lead investigator, Joseph Majzoub, MD, said in a statement.
Majzoub, chief of endocrinology at Boston Children’s, noted that he and his collaborators found similar mutations in obese participants in the Genetics of Obesity Study, an international effort to determine why some people become severely obese at a young age. They found 4 rare MRAP2 mutations in 500 obese study participants, all who had 1 working copy of the gene.
Rare MRAP2 mutations lead to obesity in fewer than 1% of people with such severe weight problems, the researchers said. But they suspect that other, more common mutations occur in the gene and may interact with various genetic and environmental factors to cause more widespread forms of obesity. They plan to expand the scope of their research to examine that possibility.