Obesity gene mutation identified in mice

By Dr. Ananya Mandal, MDMar 20 2012

A new study has found why a mutation in a particular gene can lead to obesity. Mouse experiments suggested the body's message to “stop eating” was blocked if the animals had the mutation. The study, published in Nature Medicine, said the brain's response to appetite hormones was being disrupted.

The Georgetown University Medical Center researchers hope their findings could lead to new ways to control weight. Many genes have been linked to obesity, one of them - brain-derived neurotrophic factor gene - has been shown to play a role in putting on weight in animal and some human studies. However, scientists at the Georgetown University Medical Center said the explanation for this link was unknown.

In studies on mice which had been genetically modified to have the mutation, the mice consumed up to 80% more food than normal. After a meal, hormones such as insulin and leptin should tell the brain that the body is full and should stop eating explained the researchers. The researchers showed that in the mutated mice the message was not being passed on from the hormones in the blood to the correct part of the brain.

One of the researchers Prof Baoji Xu said, “If there is a problem with the BDNF gene, neurons can't talk to each other, and the leptin and insulin signals are ineffective, and appetite is not modified.” His team found the BDNF gene has ‘short’ and ‘long’ versions which form at an early stage in the womb. Those with the ‘long’ form successfully sent the chemical signals to say ‘I’m full’ through a ‘superhighway’ of neurons in the brain to the hypothalamus. However in those with the short form, the signals reached some brain cells but could not be picked up by the dendrites – the branch-like ‘fingers’ coming out of the cells which pass messages on to the right place.

Dr Xu said, “If there is a problem with the BDNF gene, neurons can’t talk to each other, and the leptin and insulin signals are ineffective and the appetite is not modified.” The hypothalamus is involved in learning and memory. Previous work has shown mice without the ‘long’ version of this gene also had memory problems. He said the discovery “may open up novel strategies to help the brain control body weight” such as finding a “drug that can stimulate BDNF expression”.

Prof Sadaf Farooqi, who studies the relationship between genes and obesity at the University of Cambridge, told the BBC, “Genes have a surprisingly large role, it's often underestimated. Between 40 and 70% of the difference in weight between two individuals is due to genetics.” She said completely disrupting the brain-derived neurotrophic factor gene had been shown to lead to severe obesity. However, she cautioned that the study was “entirely in mice” and the mutation was “very rare” in people.

Scientists will now be looking at whether the faulty transmission line can be modified, to help prevent and treat obesity. Dr Xu said, “We have opened the door to both new avenues in basic research and clinical therapies, which is very exciting.”

Tam Fry, spokesman for the National Obesity Forum said yesterday that the researcher were “on the right track” in believing that getting leptin messages to the brain could be the key to suppressing appetite. But Fry said, “Many others on the same track hoping to find the magic treatment to prevent or cure obesity. Understandably Xu is excited having got as far as he has but fixing the mutation may not be plain sailing. Even when its fixed in mice it will be years before his solution can he be used in humans.”