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Master gene found that orders fat cells to burn energy rather than store it 

DAILY NEWS 20 August 2015

Genetic switch makes fat cells burn energy rather than store it

Genetic switch makes fat cells burn energy rather than store it

There’s the potential for gene therapy to combat obesity (Image: Zhang tao/Imaginechina/Corbis)

A master gene that orders fat cells to burn energy rather than store it has been found. Tinkering with it made mice lose weight as their fat-storing cells were converted into fat-burning cells, raising the prospect of a gene therapy to treat obesity.

“You could say we’ve found fat cells’ radiator, and how to turn it up or down,” says Manolis Kellis, who co-led the team that carried out the work at the Massachusetts Institute of Technology and at nearby Harvard Medical School.

Not all fat is created equal. Humans carry several different types. White fat is the insulating stuff that builds up around our middles, storing energy rather than burning it. Brown fat, which is found in small pockets around our neck and spinal cord, does the opposite – burning calories to produce heat. Beige fat is somewhere in between. It has a different origin to classical brown fat and is dispersed within white fat cells – but it also burns calories without us expending any effort.

In the past few years, we’ve realised that it may be possible to turn people’s white fat cells into beige fat. But it’s not easy and involves doing things like exposing yourself to cold temperatures or doing strenuous exercise. Kelis’s team’s work suggests that there might be an easier way – just flip a genetic switch.

Storer or burner?

The genetic switch is called FTO. Discovered in 2007, it is one of the only genes to be definitively linked to obesity. Some 44 per cent of Europeans carry a variant that raises their risk of obesity by around 30 per cent, increasing body weight by about 3 kilograms.

Previous studies have shown that FTO works in the brain and so may influence appetite and hunger, but the latest work suggests it exerts a more potent effect in fat cells themselves.

To dig deeper into how FTO works, a team led by Kellis and Melina Claussnitzer of Harvard Medical School looked at the genetic profiles of fat cells from 100 people, 52 of whom had the risk-raising gene variant.

In cells taken from people with the risk variant, the team found that FTO activates two other genes – called IRX3 and IRX5 – which direct the cell to store energy. In cells from people with the normal variant, the same two genes are switched off and this causes the cells to burn energy.

Powerful cells

Kellis’s team was able to use gene editing techniques to adjust the functioning of the FTO gene in fat cells, converting fat-storing cells into fat-burning cells – effectively turning white fat beige – and vice versa.

The IRX genes were twice as active in white fat cells from people that carry the risk variant as they were in cells from people without the variant, meaning that these cells were super-storers of energy.

There was practically no difference – just 1 per cent – between brain cells in the different groups, suggesting that the impact of FTO on fat cells far outweighs that in the brain. This suggests that, for some people, the activity of their fat cells might play a greater role in dictating weight than exercise or diet.

“There’s a dogma that it all depends on appetite and exercise. That it’s your choice, and everything is decided by your brain,” says Kellis. “We’re showing that your fat cells have a very strong role in all this, independent of the brain.”

Gene therapy for obesity?

What’s more, when Kellis and his colleagues deactivated the IRX3 gene in mice fed a high-fat diet, the animals resisted piling on the pounds – mice with the IRX3 gene active gained an extra 15 per cent of their body weight. Kelis thinks that once the IRX3 and IRX5 genes are inactivated, the fat cells are able to burn energy all the time, irrespective of how much the mice eat and exercise while awake.

Kellis’s team now plans to see whether tinkering with the IRX genes can make obese mice lose weight. He says they are also exploring avenues for possible treatments, including gene therapies that alter fat cells so that they burn instead of store energy. Alternatively, it may be possible to develop a pill that switches off or turns down the activity of IRX genes.

“What this work shows very elegantly is that a key risk-FTO variant acts by limiting the development of beige fat cells,” says Myrte Merkestein of the University of Oxford. “As these burn energy rather than storing it as white fat cells do, a reduction in beige fat cells is predicted to reduce energy expenditure and predispose to obesity,” she says.

“Whether these findings will lead to new therapies for obesity is less certain,” Merkestein says, “because it’s likely the switch between beige and white fat cells is set during development of the embryo, and therefore it may already be too late to intervene in adulthood.”

Kellis, however, thinks that now the genetic circuitry for FTO and the IRX genes is established, drugs or treatments can be devised that interfere with it to combat obesity. “We can intervene using this circuitry whether or not you have the genetic risk variant,” he says.

https://www.newscientist.com/article/dn28076-genetic-switch-makes-fat-cells-burn-energy-rather-than-store-it/?utm_source=NSNS&utm_medium=SOC&utm_campaign=twitter&cmpid=SOC%7CNSNS%7C2014-GLOBAL-twitter