Switching Fat Cells from Energy Storage to Calorie Burning

A team of researchers at the Massachusetts Institute of Technology (MIT) and Harvard Medical School have identified the gene responsible for influencing fat cells to burn or store energy. This potential gene therapy for obesity was successful at helping mice control their weight.

“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 research. Earlier research has shown it’s possible to stimulate fat cells to burn energy, but it requires unpleasant activities such as doing vigorous exercise or experiencing cold temperatures.

There are several different types of fat present in the human body. White fat generally accumulates around the body’s midsection, acting as an insulator and an energy store. Brown fat is present in a much lower amount compared to white fat, but it’s able to expend energy without any effort input, to generate heat and keep our necks and spinal cords warm. Beige fat is a hybrid of white and brown fat; it’s able to burn calories just like the brown fat, but it’s found distributed within patches of white fat.

The gene responsible for telling the fat cells whether to save or spend energy is named FTO. This “genetic switch” was identified in 2007 and is among a handful of genes to be indisputably linked to obesity. A variant of FTO that raises a person’s risk of obesity by 30 percent, has been identified in 44 percent of Europeans. On average, the individuals carrying the variant have an increased body weight of approximately 3 kg.

While previous work suggests FTO may play a role in appetite and hunger in the brain, the current research out of MIT and Harvard implicate a role for the gene in the fat cells themselves. The researchers analyzed the genetic profile of fat cells collected from 100 people, 52 of whom carry the FTO risk-raising variant.

The variant form of FTO was found to turn-on two other genes – IRX3 and IRX5 – which induce the cells to store energy. In individuals who possess the “normal” version of the FTO gene, IRX3 and IRX5 were unexpressed which caused the fat cells to burn energy.

Kellis and his colleagues used genetic engineering to influence the FTO gene in fat cells to turn white fat into a calorie-burner, and beige fat into an energy store. Further, in people carrying the FTO gene variant, the IRX genes were two fold more active in white fat compared to people lacking the variant.

In opposition to the previous study showing FTO’s influence on brain cells, the researchers found only a 1% difference in FTO gene activity in the brain cells of the two groups, suggesting that FTO has a greater impact on the function of fat cells compared to cells in the brain. This research indicates that fat cell activity may be more important in maintaining weight compared to diet and exercise.

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

To test what would happen if the IRX genes were nonfunctional, the researchers fed IRX3 knockout mice a high-fat diet. These mice didn’t gain weight, while wild-type mice fed the same diet gained 15 percent of their body weight. Kellis and his team are now planning to manipulate both IRX genes to see if their absence can cause obese mice to lose weight.

“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.”

“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.”

Despite Merkestein’s skepticism, Kellis is hopeful that now that these mechanisms have been elucidated, the findings may lead to the development of drugs capable of treating obesity. He says, “We can intervene using this circuitry whether or not you have the genetic risk variant.”

Sources:

• Genetic switch makes fat cells burn energy rather than store it – https://www.newscientist.com/article/dn28076-genetic-switch-makes-fat-cells-burn-energy-rather-than-store-it/