Geneticists believe they have pinpointed the most important obesity gene yet, throwing up a possible target for drugs 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 say.
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 said.
Instead of affecting the FTO gene itself, the mutations triggers a reaction in a distant gene, IRX3, the new research say.
This causes an overproduction 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 zebra fish embryos, adult mouse brains and human cells, including brain cells, to show the interaction between IRX3 and FTO in the lab.
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", Nobrega said.
They weighed about 30 per cent 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 could 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 inheritance 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, obesity nearly doubled worldwide from 1980 to 2008. At least 2.8 million adults die each year as a result of being overweight or obese.
'Love hormone' oxytocin the latest potential weapon in anorexia battle
Oxytocin, a brain chemical known as the "love hormone", is showing promise as a potential treatment for people with the eating disorder anorexia nervosa, according to research by British and Korean scientists.
In studies of anorexic patients, researchers found oxytocin altered their tendencies to become fixated on images of fattening foods and large body shapes.
"Patients with anorexia have a range of social difficulties which often start in their early teenage years, before the onset of the illness," said Janet Treasure, of King's College London's Institute of Psychiatry. "By using oxytocin as a potential treatment for anorexia, we are focusing on some of these underlying problems."
In the first of two studies, Treasure's team analysed 31 patients with anorexia and 33 healthy controls who were given either oxytocin or a placebo. Participants were asked before and after taking the drug or placebo to look at images relating to weight, high and low calorie foods, and fat and thin body shapes.
The results showed that after taking oxytocin, anorexic patients reduced their focus on images of food and fat bodies.
In a second study, the researchers used the same participants, the same drug and placebo, but tested reactions to facial expressions. After taking a dose of oxytocin, patients with anorexia were less likely to focus on the "disgust" faces.
"Our research shows that oxytocin reduces patients' tendencies to focus on food, body shape, and negative emotions," said Kim Youl-ri, of Inje University in Seoul.