The genetic variant in the MC4R gene against obesity could pave way for development of weight-loss drugs, according to the report published on April 23, 2019.
The scientists at the University of Cambridge was conducting a large-scale genetic study on a number of specific variants in a single gene that can help people either lose or gain weight. Data from around half a million U.K. subjects with different MC4R mutations were examined by the scientists. They found 61 different MC4R gene variants and among these, nine subjects were associated with increased genetic activity. Around six percent of the subjects studied were found to have one of the nine genetic variations and they displayed lower odds of obesity, diabetes, and coronary artery disease.
Mixed results were obtained in the studies conducted on drugs that stimulate MC4R activity. Moreover, due to side effects, human trials into MC4R agonists around a decade ago were halted. The first generation of MC4R agonists instigated weight loss, however, it also showed high increase in blood pressure. Experiments were conducted on animals, which revealed that these nine beneficial MC4R variants seemed to preferentially send signals via a protein pathway known as beta-arrestin. According to the study, the highly specific activity could be driving both lower obesity and providing protection against the unwanted blood pressure side effects seen in more general MC4R stimulation.
Luca Lotta, joint lead author of the study said, “A powerful emerging concept is that genetic variants that protect against disease can be used as models for the development of medicines that are more effective and safer. Our findings may pave the way for a new generation of weight loss therapies that activate MC4R preferentially via the beta-arrestin pathway.” The importance of closely studying the effects of naturally occurring genetic variants in large general population cohorts is being highlighted in this research.