German scientists said on Sunday they had shown how a gene long associated with obesity might make people fat, a finding that could lead to new drugs to help control weight.Mice without the FTO gene did not become obese and had less fat tissue overall because they burned off more calories even though they moved less and ate more, according to the study published in the journal Nature.

FTO has been long linked to obesity. Studies have shown people with two copies of the “obese” version of the gene on average weigh nearly 7 lbs (3 kg) more and are about 70 percent more likely to be obese than those with other versions.

People and mice are similar genetically.

“So, this work provides a crucial piece of evidence supporting the notion that the FTO gene itself is likely to be involved in the effects of common human genetic variants on body fat,” Stephen O’Rahilly of the University of Cambridge, who was not involved in the study, said in a statement.

“This finding will promote research into the development of drugs that modulate FTO activity.”

Obesity, which raises the risk of diseases such as type 2 diabetes and heart problems, has increasingly become a global problem with people exercising less and leading more sedentary lifestyles.

The World Health Organization classifies about 400 million people around the world as obese, and the numbers are increasing.

In their study, Ulrich Ruther and colleagues at the University of Dusseldorf in Germany took a group of mice and knocked out, or inactivated, the FTO gene to see if they could figure out why the gene might make animals, and people, fat.

Animals lacking the gene were thin because they spontaneously burned off many calories, suggesting FTO plays a direct role in controlling metabolism, they reported.

“The human FTO gene has previously been shown to be linked to human obesity, however, this research helps unlock the complex interplay between factors expressed in the brain that control both appetite and metabolism,” said David Cameron-Smith, an obesity expert at Deakin University in Australia.

“A cure, genetic or pharmaceutical, for human obesity is many years away, although any new knowledge on how the brain controls hunger and growth will help solve the complex disease.”

Scientists have found a role for the GABA neurotransmitter, one of the master communicators among neurons, in the much complicated weight-control puzzle.

Headed by scientists at Beth Israel Deaconess Medical Center (BIDMC), the study may help in forming a clearer picture of the numerous events that lead to weight gain and weight loss.

“Body weight maintenance is made up of three basic stages. In the first stage, the brain receives sensory input from the body [including information provided by circulating hormones such as leptin and ghrelin and from fuels such as glucose and fatty acids,” Nature magazine quoted the paper’s senior author, Dr. Bradford Lowell, a Professor of Medicine at Harvard Medical School, as saying.

He said that in the second stage, the brain combine this sensory information with environmental cues (such as aromas and other enticements), as well as information gathered from the organism’s emotional state.

Finally, in the last stage, the brain’s neurocircuitry plays a major role by enabling the brain to make appropriate alterations in food intake and energy expenditure in order to maintain energy balance, and in turn avert weight gain and obesity.

Earlier scientists focused on identifying the neuropeptides involved in this process, which often proves essential to maintaining energy balance - but not always.

“It is well known that AgRP [Agouti-related protein] neurons play a critical role in feeding and energy balance regulation. However, the deletion of AgRP and NPY [two neuropeptides released from the AgRP neurons] produces little metabolic effect,” explained Qingchun Tong, PhD, a postdoctoral fellow in the Lowell laboratory and the study’s first author.

In an alternate theory, the scientists suggested that release of the GABA neurotransmitter was mediating the function of AgRP neurons.

The researchers generated a group of mice with disrupted release of GABA specifically from the AgRP neurons, and it was confirmed that genetically altered mice exhibited profound metabolic changes.

“The mice with AgRP neuron-specific disruption of GABA release were lean, had higher energy expenditure and showed resistance to diet-induced obesity. We also found that these animals showed reduced food intake response to the hormone ghrelin. This suggests to us that the neurocircuit engaging GABA release from the AgRP neurons mediates at least part of ghrelin’s appetite-stimulating action,” said Tong.

He added: “As these new findings demonstrate, GABA release is an important component that mediates the function of AgRP neurons. Discoveries such as this will ultimately help us to design an efficient strategy to tackle the current epidemic of obesity and metabolic disease.”

The study is published in the latest on-line issue of Nature Neuroscience.