Fat? Thin? Molecular switch may turn obesity on or off
Identical twins may be alike in everything from their eye color to their favorite foods, but they can diverge in one important characteristic: their weight. A new study uncovers a molecular mechanism for obesity that might explain why one twin can be extremely overweight even while the other is thin.
Heredity influences whether we become obese, but the genes researchers have linked to the condition don’t explain many of the differences in weight among people. Identical twins with nonidentical weights are a prime example. So what accounts for the variation? Changes in the intestinal microbiome—the collection of bacteria living in the gut—are one possibility. Another is epigenetic changes, or alterations in gene activity. These changes occur when molecules latch on to DNA or the proteins it wraps around, turning sets of genes “on” or “off.”
Triggered by factors in the environment, epigenetic modifications can be passed down from one generation to the next. This type of transmission happened during the Hunger Winter, a famine that occurred when the Germans cut off food supplies to parts of the Netherlands in the final months of World War II. Mothers who were pregnant during the famine gave birth to children who were prone to obesity decades later, suggesting that the mothers’ diets had a lasting impact on their kids’ metabolism. However, which epigenetic changes in people promote obesity remains unclear.
So when—many decades later—physiologist J. Andrew Pospisilik of the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany, and colleagues noticed an odd pattern of weight gain in some mutant mice, they were intrigued. The mice had only one copy of a gene called Trim28, and the researchers found that most them were either obese or lean, with few animals in between.
To discover why, the scientists measured gene activity in the animals. Trim28 controls the activity of several other genes, making it an epigenetic modifier. In the obese mice, the activity of an interacting set of genes was turned down. Previous studies have implicated these genes in body weight management, and some are activated in fat cells and the hypothalamus, the brain area that triggers hunger. The functions of the genes remain unclear, but Pospisilik and colleagues hypothesize that Trim28 helps form an epigenetic switch that can flip on obesity by suppressing these genes.
But could the same mechanism foster obesity in humans? After all, the mice have only one copy of the Trim28 gene, whereas people have two copies. To find out, the team took fat samples from children who were in the hospital for surgery. TRIM28 activity was abnormally low in fat from kids who were obese. “There’s a subset of children who look very much like the obese mice” in their TRIM28 measurements, Pospisilik says. The researchers also analyzed data on 13 pairs of identical twins in which one twin was obese. TRIM28 activity was diminished in fat from the obese twins, the scientists report online today in Cell.
“We show that you can have a strong phenotype [obesity] with absolutely no genetic underpinnings,” Pospisilik says. He notes that researchers used to think that epigenetic effects might tweak our weight by only a few kilograms. But if people gained an amount of weight equivalent to what the mice gained, he says, it would mean the difference between being “on the rugby team instead of the badminton team.”
“The study gives us a new potential mechanism of obesity,” says genetic epidemiologist Jeanne McCaffery of Brown University who wasn’t connected to the research. And that could be good news for researchers who are looking for ways to prevent or reverse the condition, she says. “There may be multiple subtypes of obesity that may be amenable to different treatments.”
Pospisilik suggests several risk factors for obesity in children, such as their mothers’ smoking and eating habits during pregnancy. But “the big question now is what is the trigger” that flips the obesity switch, says genetic epidemiologist Paul Franks of the Lund University Diabetes Center in Malmö, Sweden. “If you could determine what that was, you’d have the basis for intervention.”