Nutritional genomics identifies a potential weight-loss resistance gene

Friedman School of Tufts: Nutrition notes

Two obese people follow the same low-calorie diet and do not exercise, but one loses much more weight than the other. Genetic factors may explain this phenomenon, according to José Ordovas, PhD, director of the Nutrition and Genomics Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University. In a study published in the Journal of Clinical Endocrinology & Metabolism, Ordovas and colleagues identified a variation in the perilipin gene that appears to render some people resistant to weight loss from calorie restriction. This research builds on their earlier work on perilipin and obesity.

“It is as if the connection between calorie intake and body weight is interrupted,” explains Ordovas, who is also a professor at the Friedman School of Nutrition Science and Policy at Tufts. “Carriers of this gene variant appear to have more stable mechanisms for controlling their body weight,” Ordovas says. “In people that have become obese, this leads to a blunting of the weight-loss effect we would expect to see with calorie restriction.”

Andrew Greenberg, MD, director of the Obesity and Metabolism Laboratory at the USDA Center at Tufts, one of the scientists who discovered perilipin, notes that in an earlier study this same gene variant was linked with a lower risk of obesity, but in this study, it was associated with weight loss resistance.

“It may make sense,” Greenberg says, “if we consider that this perilipin gene variant induces a sort of buffer against changes in how the body burns and stores food energy. It appears to protect against weight gain in lean women, while preventing weight loss in men and women who have become obese.”

The clinical study was led by Dolores Corella, PhD, of the Genetic and Molecular Epidemiology Unit, University of Valencia, in Spain, who is a visiting scientist at the HNRCA and a long-term collaborator with Ordovas. These investigators studied 48 severely obese men and women who were following a low-calorie diet for one year. Subjects, who did have the more common variants of the perilipin gene lost an average of approximately 20 pounds during the study period. In contrast, carriers of the variant gene did not experience significant weight changes.

The researchers determined that the difference in weight loss between the two groups could not be explained by the fact that the variant gene carriers weighed less at the start of the study. When asked why the subjects had not lost more weight, Ordovas noted, “These subjects were closely followed during the study period and the compliance was considered to be excellent regardless of the perilipin genotype. Given the difficulty of keeping weight off long-term, the loss of 20 pounds is a significant achievement.”

The perilipin gene controls the production of perilipin, a protein that regulates the release of fat from cells. The Tufts researchers’ earlier study linking two variations in the perilipin gene to a lower risk of obesity in women was described in a Friedman Nutrition Note released earlier this year, entitled, “Genetics Research Unlocks a Key Regulator of Weight in Women.”

Ordovas cautions, “First of all, it is very important to point out that both of these studies were conducted on the same general ethnic population in Spain. We do not know what we might find in other countries or ethnic groups. And secondly,” he adds, “nutritional genomics is not yet in a position to contribute significantly to treatment of obese patients. But we are finally beginning to piece together how genetics might be used in the future, perhaps to help predict who is likely to respond well to dietary weight-loss interventions.”