Researchers have found a genetic mutation that may help explain why some people can eat the same amount as others but gain more weight.
Scientists have long thought explanations for why some people get fat might lie in their genes. They knew body weight was strongly inherited. Years ago, for example, they found that twins reared apart tended to have similar weights and adoptees tended to have weights like their biological parents, not the ones who reared them. As researchers developed tools to look for the actual genes, they found evidence that many — maybe even hundreds — of genes may be involved, stoking appetites, making people voraciously hungry.
In a recent study, Dr. Majzoub and his colleagues describe figuring out how the gene they deleted, known as MRAP2, acts in the brain to control weight. They discovered that it is a helper gene. It normally acts in the brain to signal another gene already known to be involved in controlling appetite. So they developed a hypothesis. If the helper gene was deleted, the brakes should come off the gene that controls appetite. Animals should eat voraciously.
The first thing they noticed was that the mice got fat, ending up weighing twice as much as their normal siblings, with most of that extra weight due to fat accumulation.
“During the mouse equivalent of childhood and adolescence they were becoming rapidly obese,” Dr. Majzoub said.
The surprise came when the researchers figured out why. When the mice were young, they had normal appetites. The researchers measured what they and their normal siblings ate and determined they were eating the same amount of food. Yet the mice with the deleted gene still gained weight. The only way the obesity-prone mice could be kept slim was to be fed 10 to 15 percent less than their siblings.
But as adults, the mice with the missing gene developed monstrous appetites. Given a chance, they ate much more than their siblings, exacerbating the effects of their tendency to turn food into fat.
That led the researchers to ask if the same genetic phenomenon could be making people obese. They contacted Dr. Sadaf Farooqui of the University of Cambridge, whose group has been mapping the genes of massively obese children, and studied the data on 500 of the children, searching for mutations that disabled the same gene they had deleted in mice.
One child clearly had a gene-disabling mutation and three others had mutations that the investigators suspect might render the gene nonfunctional. None of the normal-weight children who served as controls had a mutation in the helper gene.
“From a basic science point of view, this is really interesting and exciting,” said David Allison, an obesity researcher at the University of Alabama in Birmingham who was not involved in the study. Any discovery that helps fill in the details of how the brain controls eating and weight gain is important, he added.
Jeffrey Friedman, an obesity researcher at Rockefeller University, who also was not involved in the study, said, “It is another piece in a very important puzzle.”
Dr. Majzoub and his colleagues are now trying to determine whether additional mutations in the gene they discovered — ones that hinder its function but do not completely disable it — might explain why some people gain weight.
“All we can do is hope,” Dr. Majzoub said.