Genes help determine weight gain—and loss.

Genes help determine weight gain—and loss.

Celso Pupo

Identifying the gene switch that turns fat cells bad

Researchers may have finally explained how an obesity-promoting gene variant induces some people to put on the pounds. Using state-of-the-art DNA editing tools, they have identified a genetic switch that helps govern the body’s metabolism. The switch controls whether common fat cells burn energy rather than store it as fat. The finding suggests the tantalizing prospect that doctors might someday offer a gene therapy to melt extra fat away.

Along with calories and exercise, genes influence a person’s tendency to gain—and keep—extra pounds. One of the genes with the strongest link to obesity is called FTO. People with certain versions of the gene are several kilos heavier on average and significantly more likely to be obese. Despite years of study, no one had been able to figure out what the gene does in cells or how it influences weight. There was some evidence FTO helped control other genes, but it was unclear which ones. Some researchers had looked for activity of FTO in various tissues, without finding any clear signals.

Melina Claussnitzer, Manolis Kellis, and their colleagues at Harvard University, Massachusetts Institute of Technology, and the Broad Institute in Cambridge, turned to data from the Roadmap Epigenomics Project, an 8-year effort that identified the chemical tags on DNA that influence the function of genes. The researchers used those epigenetic tags to look at whether FTO was turned on or off in 127 cell types. The gene seemed to be active in developing fat cells called adipocyte progenitor cells.

Following this clue, the researchers checked the activity of eight genes suspected of interacting with FTO in adipocyte progenitor cells from healthy European subjects. About half of the people carried the version of FTO associated with obesity risk and two genes, called IRX3 and IRX5, were more active in their cells than in those of people without the gene variant. That gene pair, in turn, seem to determine what kind of fat cells the progenitors form, the researchers report today in The New England Journal of Medicine.

Increased activity of IRX3 and IRX5 prompt the developing cell to become a white adipocyte, which stores energy as fat. Lower levels lead to a beige adipocyte, which uses energy to produce heat. (Beige fat is best known for keeping animals warm in cold environments.) The version of FTO that can prompt weight gain apparently is unable to turn off IRX3 and IRX5, leaving the progenitor cells more likely to form white fat instead of beige fat.

The researchers strengthened their case by using the increasingly popular gene-editing method called CRISPR-Cas9 to convert the obesity-promoting FTO variant to the more common version in adipocyte precursor cells, which had been collected from donors. The treated cells had lowered levels of IRX3 and IRX5, took on characteristics of beige adipocytes, and dramatically spun up their energy-burning machinery.

Understanding how FTO works in fat cells “is of huge clinical relevance,” and the work is convincing, says Shingo Kajimura of the University of California, San Francisco, who studies the cell biology of obesity.

Kellis predicts that doctors in the future will be able to flip the FTO switch to help obese people melt away extra pounds. “We now have the circuits, and can turn the knob to energy storage or energy dissipation,” he says.

That might be possible someday, Kajimura agrees. But although the new work “suggests that beige fat is playing an important role in human obesity,” he cautions that it is not yet clear that increasing beige fat can induce weight loss, whether in experimental animals or humans.