Genetic mutation causes obesity

Researchers from the University of Cambridge and Boston Children’s Hospital have discovered a genetic cause of severe obesity which, although rare, raises new questions about weight gain and energy use.

In order to explore the role of the signaling protein Mrap2, Dr Joseph Majzoub, Chief of Endocrinology at Boston Children’s Hospital and lead investigator on the study, developed a mouse model in which the Mrap2 gene was missing. The research found that the mice lacking this protein gained a significant amount of weight even when they didn’t eat more food, suggesting that the affected gene appears to be involved in regulating metabolism. The research is published in the 19 July 2013 edition of the journal Science.

“Mice with the mutation gain more weight and are somehow more efficient with the food they eat,” says Majzoub. “They’re not burning it; they’re somehow holding on to it.”

To investigate the gene in humans, Majzoub collaborated with Professor Sadaf Farooqi from the University of Cambridge to examine groups of severely obese patients from around the world. The team found four rare mutations in the MRAP2 gene among the 500 people they screened; each of the four affected patients had only one copy of the mutation. While the finding suggests that these MRAP2 mutations may contribute to obesity in less than 1 percent of the obese population, the finding of a new gene could provide clues into the brain pathways that regulate weight, which could ultimately be useful for developing new treatments.

Professor Farooqi said: “The discovery that the disruption of MRAP2 causes obesity adds to a growing body of work that illustrates how certain genes work in the brain to regulate weight. Our aim is to find the genetic determinants of body weight and by doing so, to find better ways to prevent and treat obesity and associated health problems such as diabetes.”

The Mrap2 gene appears to work by fine-tuning signals through a receptor in the brain called the Melanocortin 4 receptor (Mc4r). MC4R is one of the critical control points in the brain for the regulation of appetite and energy expenditure (how we burn calories). Prof Farooqi and colleagues in Cambridge have previously shown that genetic changes that disrupt the MC4R gene can cause obesity in people, which often begins in childhood. This new discovery adds a further piece to the puzzle, by suggesting that defects in a different gene can indirectly impact on MC4R and thus contribute to obesity.

While changes in diet and levels of physical activity underlie the recent increase in obesity in the UK and worldwide, there is a lot of variation in how much weight people gain. This variation between people is largely influenced by genetic factors. The discovery of a new obesity gene, MRAP2, shows that the body’s mechanisms for regulating weight are likely to be complex. The Cambridge team is continuing to work to find other new genes for obesity, findings which they hope to translate into beneficial therapies in the future.

Professor Farooqi’s research was funded by the Wellcome Trust.