Lose Genes, Gain Weight

Obesity is a disease of excess, but a new study suggests that a few obese patients are actually lacking something--a piece of one of their chromosomes. The loss might remove a gene that helps the body manage blood sugar and appetite.

Obesity runs in families, and researchers have identified several genetic variants that seem to boost the odds of becoming obese. However, these variants only explain a minority of cases. In the last decade, researchers have discovered that genetic differences among people can stem from lost or duplicated sections of chromosomes, called copy number variants (CNVs). Because of CNVs, for example, you and your neighbor might carry different numbers of copies of particular genes. Previous studies have implicated CNVs in disorders such as autism that slow mental development or cause learning disabilities. Autistic patients sometimes have an extra segment on chromosome 15 or are missing a section of chromosome 16. Such patients are often heavy as well, suggesting a connection between CNVs and weight.

To search for that link, endocrinologist Sadaf Farooqi of the University of Cambridge in the U.K. and colleagues analyzed the genomes of 300 extremely obese children for missing or duplicated chromosome segments. As the team reports online this week in Nature, a number of CNVs were more common in the children than in a group of normal-weight people. The most prevalent of these was a deletion from chromosome 16, which occurred in 1.7% of the obese children but only 0.027% of controls. The same deletion also turned up in a separate group of more than 1000 heavyset children. Three subjects with this CNV inherited it from parents who were also obese, the researchers found. "This study shows for the first time that CNVs can cause a metabolic disease like obesity," says Farooqi.

The work also provides a clue about how. The missing segment of chromosome 16 holds nine genes, including one, known as SH2B1, that scientists had already fingered as a possible culprit in obesity. Mice lacking the gene become extremely fat and develop insulin resistance, a feature of obesity and diabetes in which cells become less responsive to insulin. SH2B1 is a key intermediary that enables insulin and leptin, a hormone that helps set appetite, to transmit their messages to cells.

"Given the biological plausibility, it seems to be an exciting finding," says geneticist Alan Herbert of Boston University School of Medicine. However, he cautions, it's too early to rule out the other eight genes on the deleted segment. The CNV on chromosome 16 is rare, and the search is on for other variants that contribute to obesity. "What it tells us," says Farooqi, "is that there is a lot more genetic variation to find."

Posted in Biology