MC4R variants found in obese people reveal new mechanisms for weight regulation

Mutations in Melanocortin 4 receptor (MC4R) are the most common genetic cause of obesity. Approximately 6% of patients participating in the Genetics of Obesity Study carry a genetic variant in MC4R and over 300 different mutations have been identified by teams all over the world (www.mc4r.org.uk). Most of these disrupt the function of MC4R in the brain centre responsible for controlling appetite by reducing or completely switching off the receptor which loses its ability to make a signal called cyclic AMP (cAMP).

Until recently, measuring cAMP levels in cells has been the main way scientists test if a genetic variant found in a patient is likely to cause their weight problem. Strikingly, for 1 in five people with obesity who have a variant in MC4R, the test is negative.

In this new study we focused on variants (gene changes) in MC4R which gave negative results in the cAMP test. Using new experimental tools, we identified a range of molecular mechanisms important for the full activity of MC4R in cells. Many of these mechanisms were disrupted by these genetic variants. This is important as it means that MC4R can stop working for many different reasons. These results will allow us to give a genetic diagnosis to many more people whose gene changes were previously thought to be “normal”.

We show that mutations in MC4R can disrupt endocytosis and homodimerization. This information means that developing new drugs that target the full range of mechanisms may be useful to achieve weight loss.

You can read the paper here.