Obesity 'switch' offers new drug hope

A weight gain "switch" has been discovered in the brain that could open up new ways of tackling obesity.

Consuming too many calories sends out messages from the brain that upset the body's finely-tuned energy balance, research shows.

As a result, food intake goes up and more sugar is stored as fat.

The mechanism also has a direct link to obesity-linked disorders such as as type 2 diabetes and heart disease, scientists believe.

Suppressing the pathway - possibly by means of drugs - could provide a new strategy for restoring a healthy weight and metabolism, the study suggests.

Scientists working with mice made the discovery in the hypothalamus, a part of the brain that links the nervous system to the hormones affecting metabolic processes.

Among other things, the hypothalamus helps to regulate body temperature, hunger and thirst.

The cell-signalling switch, a protein complex called NF-kappaB, is primarily associated with the immune system. When activated by the enzyme IKKbeta, it triggers low-level inflammation in many parts of the body. But the new research showed that it also influences food intake and metabolism.

Normally the IKKbeta/NF-KappaB pathway is inactive. Scientists think that some time in the distant past it may have played an important role helping the body defend itself against infection.

Dr Dongsheng Cai, from the University of Wisconsin-Madison in the US, who led the research, said: "In today's society, this pathway is mobilised by a different environmental challenge - overnutrition."

One of its effects is to create resistance to insulin and the "feeling full" hormone leptin, which controls appetite.

This can lead to more food being eaten and the generation of extra fat.

Dr Cai's team found that a chronic high-fat diet doubled the activity of the IKKbeta/NF-KappaB pathway in the brains of mice. Its activity was also much higher in mice genetically predisposed to obesity, the scientists reported in the journal Cell.

When they "knocked out" the gene for IKKbeta, the signalling pathway was suppressed.

"The animals were significantly protected from energy over-consumption and obesity development," said Dr Cai.

The research suggested that inflammation and obesity were "quite intertwined", he added.

Inflammation affecting metabolic tissues such as the muscles and liver could produce some of the effects underlying type 2 diabetes, said the researchers.

They wrote: "Our work marks an initial attempt to study whether inhibiting an innate immune pathway in the hypothalamus could help to calibrate the set point of nutritional balance and therefore aid in counteracting energy imbalance and diseases induced by overnutrition.

"We recognise that the significance of this strategy has yet to be realised in clinical practice; currently, most anti-inflammatory therapies have limited direct effects on IKKB/NF-KappaB and limited capacity to be concentrated in the central nervous system. Nevertheless, our discoveries offer potential for treating these serious diseases."

The scientists pointed out that since the "switch" was inactive and functionless under normal circumstances, such an approach was likely to be safe.