Scientists who analyzed the cell-level circuits surrounding the activity of the FTO gene - the one most strongly associated with obesity - have discovered a metabolic pathway that appears to exert overall control over whether our fat cells store or burn calories.

 

Researchers have discovered a cell circuit that controls whether fat cells burn or store fat is regulated by a master gene that differs among individuals.

The discovery - published in The New England Journal of Medicine - may lead to new approaches to prevent and even cure obesity, says the team, from Massachusetts Institute of Technology (MIT) in Cambridge, and Harvard Medical School in Boston, MA.

 

Obesity is one of today's biggest challenges to global health. It affects over 500 million people worldwide and contributes to type 2 diabetes, cancer, and cardiovascular disorders - all diseases that can lead to early death.

 

In the US, where more than one third (78.6 million) of adults are obese, the burden on the economy is estimated to be at least $200 billion a year.

 

Senior author Manolis Kellis, professor of computer science at MIT, says:

 

"Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual's metabolism."

 

Since its discovery in 2007, scientists have been trying to find out about the cell-level mechanisms that link the FTO gene and its surrounding region to obesity.

 

While a number of discoveries have been made - for example, some studies have suggested the FTO region is linked to brain circuits that control appetite or urge to exercise - none have yet explained how genetic differences in the region lead to obesity.

 

Obesity gene acts on fat cells without involving the brain

First author Melina Claussnitzer, an instructor in medicine at Harvard Medical School and a visiting professor at MIT, says their findings reveal that the FTO region acts on immature fat cells without involving the brain.

 

For their study, the team examined known gene control circuits from over 100 tissues and cell types. They discovered evidence of a major gene control switchboard in human adipocyte progenitor cells - immature cells that become fat cells.

 

The researchers say this evidence supports the idea that genetic differences among individuals control how their bodies store and burn fat.

 

To explore this idea further, the researchers studied genetic differences in adipocytes, or fat cells, from healthy Europeans carrying either the high-risk version of FTO or the non-risk version.

 

They found that the high-risk version of FTO activates a major gene control switch that, in turn, switches on two genes in another part of the genome: IRX3 and IRX5.

 

In further experiments, they established that IRX3 and IRX5 control thermogenesis - a cell process for using energy stores to generate heat - in fat cells. They, therefore, established a link from FTO to the control of whether fat cells burn or store fat, without going via the brain.

 

Pathway controls fat-burning in white fat

Considering why the pathway has not been discovered earlier, Prof. Claussnitzer suggests:

 

 

"Early studies of thermogenesis focused primarily on brown fat, which plays a major role in mice, but is virtually nonexistent in human adults. This new pathway controls thermogenesis in the more abundant white fat stores instead, and its genetic association with obesity indicates it affects global energy balance in humans."

 

Using human fat cells, the researchers found they could manipulate FTO in cells from individuals with the obesity-prone version to switch off IRX3 and IRX5, restore thermogenesis to non-risk levels and switch off genes that promote fat storage.

 

The researchers also showed they could manipulate the pathway to reverse the pro- and anti-obesity genetic makeup of both human cells and in mice. Prof. Kellis concludes:

 

"By manipulating this new pathway, we could switch between energy storage and energy dissipation programs at both the cellular and the organismal level, providing new hope for a cure against obesity."

The team is now linking up with research centers and industry partners to move their findings from the lab to the clinic. They also plan to use the techniques they developed in the study to understand the circuits that underlie other disease-associated regions of the genome.

 

Meanwhile, Medical News Today recently reported on a small study published in Cell Metabolism that showed how a low-fat diet is more effective than a low-carb diet for losing body fat. The findings suggest that over time, our bodies reduce fat differences between diets that contain equal amounts of calories, regardless of their carbohydrate-to-fat ratios.

 

By Catharine Paddock PhD

Medical News Today