Do YOU have the 'fat gene'? Discovery of protein that controls metabolism could lead to anti-obesity drug

• A protein called IRX3 regulates metabolism and energy expenditure
• Mice deficient in it are 30% slimmer than those who have the protein
• They also do not gain weight when fed a high-fat diet
• They are better able to process glucose and are protected from diabetes

By EMMA INNES

A 'fat gene’ has been identified, bringing the possibility of an anti-obesity drug a step closer, scientists have revealed.

The protein, called IRX3, regulates metabolism and energy expenditure - and researchers found mice deficient in it are 30 per cent slimmer on average.

The study found the ‘slim mice’ weighed less despite eating the same amount and doing as much physical activity as their counterparts.

When fed a high-fat diet, mice without IRX3 retained the same weight and fat levels as on normal diets, whereas others given the same food gained almost twice as much weight.

Fat cells in IRX3-deficient mice were smaller and increased levels of brown fat - which burns up unhealthy white fat - were observed. 

In addition, these mice were better able to process glucose.

Professor Chin-Chung Hui, of the University of Toronto, said: ‘These mice are thin. They lose weight primarily through the loss of fat. But they are not runts.

‘They are also completely resistant to high-fat diet induced obesity. They have much better ability to handle glucose - and seem protected against diabetes.’

The researchers said IRX3 interacts with another gene known as FTO which for some time has been known to be the most strongly related to being overweight.

Scientists say people carrying variants of this gene produce more of IRX3 - revealing a possible cause of obesity.

Professor Marcelo Nobrega, of Chicago University, said: ‘IRX3 is probably a master regulator of genetic programmes in the cells where it is expressed.

‘We're interested in what its targets are and what they alter. The goal is to identify downstream targets of IRX3 that become models for drug targeting.’

Researchers showed the connection between IRX3 and FTO occurs in humans, mice and zebrafish - suggesting an evolutionary link across different species going back thousands of years.

The study, published online in Nature, implies variants in FTO regulate obesity-related traits through links with IRX3 - identifying it as the likely ‘fat gene’.

Professor Nobrega said: ‘Our data strongly suggest IRX3 controls body mass and regulates body composition. Any association between FTO and obesity appears due to the influence of IRX3.’

Tests on mice showed IRX3 interacts with FTO even though its locality on the genome is a long way away. 

An analysis of a human genetic database then found the same thing happens in people which was confirmed in experiments on human cells in the lab.

Using data from 153 brain samples of Europeans the researchers then discovered the mutations to FTO affecting body weight are associated with IRX3 expression.

Obesity-related FTO variants enhanced the expression of IRX3 but did not seem to play a direct role in this interaction themselves.

The researchers also discovered mice with altered IRX3 function in the hypothalamus - the portion of the brain known to regulate feeding behaviour and energy expenditure - showed an identical pattern of leanness as those which completely lacked the gene.

So hypothalamic function of IRX3 seems to control body mass and composition in these animals - indicating the genetic predisposition to obesity is wired in the brain.

IRX3 codes for a protein that regulates other genes and is present both in and outside the brain, in organs and cells such as fat cells.

Professor Nobrega and colleagues are currently investigating how IRX3 interacts with genes and molecules it regulates and hope to identify targets for the development of drugs against obesity and diabetes.