The mice were eating their usual chow and exercising normally, but they were getting fat anyway.
The reason: Researchers had deleted a gene that acts in the brain and controls how quickly calories are burned. Even though they were consuming exactly the same number of calories as lean mice, the mice were gaining weight.
So far, only one person a severely obese child has been found to have a mutation in the same gene that completely disables it. But the discovery of the same effect in mice and in the child a finding published Wednesday in Science may help explain why some people put on weight easily while others eat all they want and seem never to gain an ounce. It may also offer clues to a puzzle in the field of obesity: Why do studies find that people gain different amounts of weight while overeating by the same amount? Scientists have long thought that 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 that adoptees tended to have weights like their biological parents, not the ones who reared them. As researchers developed tools to look for the genes, they found evidence that many maybe even hundreds of genes may be involved, stoking appetites, making people voraciously hungry.
This rare gene-disabling mutation, though, is intriguing because it seems to explain something different, a propensity to pile on pounds even while eating what should be a normal amount of food.
Investigators are now searching for other mutations of the same gene in overweight people that may have a similar but less extreme effect. The hope is that, in the long term, understanding how this gene affects weight gain might lead to treatments for obesity that alter the rate at which calories are burned.
"The history of obesity for many, many years has been one of blaming people for lack of self-control," said Dr. Joseph Majzoub, chief of endocrinology at Boston Children's Hospital and lead author of the new paper. "If some of it is due to a slow metabolism, that would completely change the perspectives of parents and patients. It really would change the way we think of the disease." In their paper, 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," 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 that 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.
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 whether 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 scientists 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, Birmingham, who was not involved in the study.
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," Majzoub said.