Why Skinny Moms Sometimes Produce Fat Children

Obesity is on the rise in nations across the globe, and more than diet and genetics may be to blame. A new study suggests a third factor is at work: DNA-binding molecules that can be passed down from mother to child in the womb. The finding could explain why what a woman eats while pregnant can sometimes influence the weight of her child—even into adulthood.

Scientists first began to suspect that a mother’s diet could affect the weight of her offspring in 1976. Studying the Dutch famine of 1945, when the German army cut off food supplies to western Holland, researchers found that people born to mothers who were pregnant during the famine were more likely to be obese as adults. Rat studies at the University of Auckland in New Zealand bolstered the findings: mothers who were undernourished during pregnancy gave rise to obese adults. One possible explanation is that the moms are somehow programming their children to live in a food-scarce world by increasing their appetites and ability to store fat—and if the children grow up with plenty to eat, they become overweight.

In the past few years, researchers have begun to suspect that so-called epigenetic modifications are behind this programming. Often these are chemical tags called methyl groups that can bind to DNA, where they act a bit like a volume knob, turning up or down the activity of certain genes. In a 2005 study at the University of Auckland, for example, researchers found that they could prevent obesity in rats born to starved mothers by removing methyl tags from their DNA. A recent survey of methyl groups on the DNA of adult people has also suggested that these tags are linked to obesity. But in that study, the authors could not determine whether the epigenetic changes were a consequence of being overweight or the cause of the obesity in the first place.

To determine if epigenetic changes can trigger obesity in humans, researchers at the University of Southampton in the United Kingdom and colleagues analyzed the diets of 78 pregnant British women using diet questionnaires that were crosschecked by blood tests that detect the residues of certain foods. When the babies were born, the researchers extracted DNA from their umbilical cords. Nine years later, they measured the body fat of the children using a low-dose x-ray scan. Infants with more methylation of a gene known as retinoid X receptor-α (RXRα), which codes for a protein involved in the development of fat cells and fat metabolism, were more likely to be obese at age 9.

The team repeated the study on another 239 pregnant women in the United Kingdom, this time measuring the body fat of the children at the age of 6, the earliest age at which they expected to see major differences in obesity. The relationship held: Of the 78 genes the researchers examined for epigenetic marks, only the methylation of the RXRα gene showed a strong relationship with obesity. As the percentage of the RXRα genes that were methylated went from 40% to 80%, the children’s percentage of body fat crept up from 17% to 21%, the team reports this month in Diabetes. The authors suspect that methylation inhibits the ability of the RXRα protein to play its normal role in the development and metabolism of fat cells, resulting in obesity.

Overall, a statistical analysis showed the methylation of the RXRα gene explained about a quarter of the differences in the children’s fat levels. The team could not find any DNA sequence changes in the RXRα gene or other genetic differences in the children that could explain the result. And when the researchers examined the mothers’ diets during pregnancy, they found a link between low carbohydrate intake early in pregnancy and methylation of the RXRα gene.

It’s not uncommon for pregnant mothers in the United States and the United Kingdom to follow a low carbohydrate, Atkins-style diet, says epidemiologist and lead author Keith Godfrey. That may send a starvation-like signal to their fetuses, which puts the children out of sync with the high-calorie world into which they are born. The findings, he says, could also help explain the obesity epidemic in countries like China, where the children of poorly nourished mothers are now obese, middle-aged adults.

Still, the researchers can’t be certain that the mother’s diet caused the epigenetic changes. But the strong correlation has experts excited. “It’s a pivotal finding,” says Jeffrey Craig, a geneticist at the Murdoch Childrens Research Institute in Melbourne, Australia. “This is the first time an epigenetic change detected at birth has been shown to predict a clinically important finding,” he says.

“This suggests that even in normal pregnancies, the fetal environment has major effects on subsequent development,” adds fetal physiologist and co-author Peter Gluckman of the University of Auckland. Mark Hanson, a cardiovascular physiologist at the University of Southampton and a co-author of the study says: “Five to 10 years ago, we thought obesity would be controlled by genes and there was nothing we could do. The fact that these changes are epigenetic means we can do something about it, possibly by targeting these children for interventions early in life.” One possible intervention, he says, is administering micronutrients like folic acid that can alter epigenetic tags.

Posted in Biology