Scientists have identified the most important obesity gene, paving way for possible drug targets to tackle a dangerous and growing epidemic.
Mice bred to lack a gene dubbed IRX3 were almost a third lighter than rodents with the gene, they said.
The equivalent gene exists in humans, and its functioning may explain why some people are more prone to obesity than others.
"Our data strongly suggests that IRX3 controls body mass and regulates body composition," said Marcelo Nobrega of the University of Chicago, who headed the investigation published in the journal Nature.
It likely does so by regulating metabolism.
The discovery may help solve a riddle that has confounded researchers delving into the genetics of girth.
Previous research had identified a gene called FTO as the main genetic culprit in obesity after observing an apparent link between variants within the gene and surplus body fat.
But no-one has been able to show that these mutations actually change the functioning of the FTO gene in any way.
"Now, we offer an explanation for that. They were looking at the wrong gene," Nobrega told AFP.
Instead of affecting the FTO gene itself, the mutations triggered a reaction in a distant gene, IRX3, the new research said.
This causes an over-production of IRX3 protein in the brain, possibly affecting the hypothalamus, where metabolism and appetite are regulated.
"The mutations that are predisposing to obesity occur inside the FTO gene, hence the wide belief that they were connected to the function of FTO," Nobrega said.
"Even though the mutations are inside FTO, they are actually impacting the function of the IRX3 gene, not FTO."
The scientists used mouse and zebrafish embryos, adult mouse brains and human cells, including brain cells, to show the interaction between IRX3 and FTO in the lab.
- More energy burnt -
They then engineered mice without the IRX3 gene, resulting in animals "that are thin, resistant to obesity and diabetes, and that burn energy more efficiently," said Nobrega.
They weighed about 30 percent less despite eating and exercising the same amount as mice with the gene.
Nobrega said the ultimate goal was to identify which cell functions were being altered by IRX3, and how, so that drugs can be developed to block the obesity-causing effects.
The study "clearly demonstrates a previously unappreciated role for IRX3 in controlling body weight," David Gorkin and Bing Ren of the Ludwig Institute for Cancer Research in California wrote in a comment also carried by Nature.
Obesity and related diseases like diabetes have gained epidemic proportions in many developed countries.
The causes are complex: a lack of exercise, high-fat and high-sugar diets, and genetic heritance are all believed to contribute. Numerous other genes have been fingered in obesity before, and experts have cautioned against placing too much hope on a swift and simple pharmaceutical solution.
According to the World Health Organisation (WHO), obesity nearly doubled worldwide from 1980 to 2008.
More than a third of adults, some 1.4 billion, were overweight in 2008, and more than one in ten, about half-a-billion people, were obese.
At least 2.8 million adults die each year as a result of being overweight or obese, says the UN's health organ.