Sometimes obesity “seems” like it should be so easy: if someone is obese, they obviously eat a lot more food than someone who is normal weight. However, when you look at years of extensive data and studies, you find that the causes of obesity are incredibly complex. One piece of the puzzle is genetics, and new research has linked a gene mutation with obesity. Though rare, the mutation causes severe obesity, and has lead researchers to further examine weight gain and energy use in the general obese population. The study from Boston Children’s Hospital found that mice with mutation of the Mrap2 gene gained weight; but what’s especially interesting is that they gained weight even while eating the same amount of food as other mice in the experiment. The gene is likely involved with regulating metabolism and food consumption.

There are so many pieces to understand when researchers look at activities that may affect obesity. In this case, the important components are a gene, the protein it creates, hormones, and a receptor in the brain. There’s a protein created by the Mrap2 gene, which seems to be involved in signaling to a receptor in the brain called Mc4r. This receptor is known to be part of a larger signaling chain involved in energy regulation. The hormone leptin is produced by fat cells, prompting receptors in the brain to initiate production of another hormone, called αMSH. The Mc4r receptor detects this hormone with the help of Mrap2, which leads to a decrease in appetite and weight. The likelihood of obesity is known to increase when there are mutations in this signaling chain, including in Mc4r.

For the study, the researchers looked at mice with the Mrap2 gene knocked out both overall and just in the brain. In both experiments, the mice roughly doubled in size without the normally-functioning Mrap2 gene. When both copies of Mrap2 were knocked out, weight gain was greatest; however the mice still gained weight with one working copy of the gene. In addition, when mice without Mrap2 were given a high-fat diet, their weight gain was even more pronounced than when normal-weight mice were given a high-fat diet.

The researchers then decided to look for mutations of the equivalent gene in humans (MRAP2). In a group of 500 severely obese people, four people had only one copy of the mutation, suggesting that the mutations directly cause obesity in less than 1% of the obese population. However, researchers think that different mutations in the gene might happen more frequently and may interact with other mutations, as well as environmental factors, to cause more common forms of obesity.

Dr. David Voellinger, expert bariatric surgeon in North Carolina, commented on the study. He said, “As bariatric surgeons, we see and understand the complexity of morbid obesity every day. We have known for years that obesity is not simply overeating, but it is a chronic, multi-factorial disease of metabolism, consumption and energy balance. This article helps shed some light on the potential role of genetics as one of the major contributing factors to this disease. In the years to come, genetic analysis and even gene therapy may become tools to help treat the disease of obesity.”
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