Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy

Mutations in the gene that encodes a protein called the melanocortin-4 receptor are the most common genetic cause of early onset obesity in children. These mutations occur in about 1 in 1,500 people. The melanocortin-4 receptor is mostly found in the brain where it helps to balance how much a person eats with how many calories they burn. A mutation in just one of the two copies of the gene a person gets from their parents is enough to cause severe obesity. Mice that have been genetically engineered to lack this gene develop all the same symptoms as humans with the mutation. These symptoms include early onset obesity, a slower than normal heart rate, and reduced activity in the nerves that communicate with many body tissues including the gut. Patients with this syndrome are less likely to develop obesity-linked high blood pressure, which could be considered protective from some of the ill effects of excess weight. As a result, studying the animal model of the syndrome may help scientists better understand why mutations in the gene for the melanocortin-4 receptor cause obesity and how to better care for people with these mutations. Now, Litt et al. show that, contrary to expectations, mice lacking the gene for the melanocortin-4 receptor have a higher risk of heart failure than normal mice. An ultrasound scanner showed that the left side of the heart in the mice without the melanocortin-4 receptor becomes progressively larger and weaker. This reduces the heart’s ability to pump blood. Additionally, Litt et al. showed that the energy-producing structures within cells, called mitochondria, are defective in the heart cells of these mice. These defects cause the mitochondria to work harder and produce more harmful byproducts. The mitochondria in the animal’s muscles, however, appear normal. Further experiments showed that the genes active in the hearts of the mice lacking melanocortin-4 receptors are similar to genes active in heart cells treated with doxorubicin, a cancer drug that is toxic to the heart. This drug is known to cause heart failure in some people. The experiments suggest that physicians should watch for signs of heart failure in people who have mutations that affect their melanocortin-4 receptors. Mice with one good copy of the gene did not have signs of heart failure, but they appeared more sensitive to the toxic affects of doxorubicin. These findings suggest that clinical studies are needed to determine if there are potential heart problems or drug sensitivities in patients with mutations that affect the melanocortin-4 receptors.