An impressive large-scale genetic study, led by scientists at the University of Cambridge, has homed in on a number of specific variants in a single gene that can help people either lose or gain weight. The research revealed that some naturally-occurring variants in the MC4R gene can offer protection against obesity, and the hope is that this discovery will lead to new weight-loss drugs that mimic this genetic variation.

For several decades scientists have known the MC4R gene plays a major role in regulating appetite and metabolism. Variations that either disable or lower activity in the gene have been frequently identified in people suffering from morbid obesity. Animal studies mimicking those genetic mutations have resulted in demonstrations of unregulated appetite and overeating.

In order to help better inform future drug research targeting this specific gene, scientists examined data from around half a million UK subjects with different MC4R mutations. The study revealed 61 different MC4R gene variants, nine of which were associated with increased genetic activity. About six percent of the subjects studied were found to have one of the nine genetic variations, and those subjects displayed lower odds of obesity, diabetes and coronary artery disease.

"This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity," explains Sadaf Farooqi, one of the Cambridge researchers working on the project. "It doesn't mean that we can't influence our weight by watching what we eat, but it does mean the odds are stacked against some people and in favor of others."

Prior studies into drugs that stimulate MC4R activity have produced mixed results. Human trials into MC4R agonists around a decade ago were halted after significant side effects were seen. While weight loss was certainly instigated by those first generation of MC4R agonists, major blood pressure increases were also identified. More recent research into newer MC4R agonists have been proving more promising, however, and better understanding how naturally-occurring MC4R variants reduce obesity will help further develop safer drugs.

Through animal experiments, the new research revealed these nine beneficial MC4R variants seemed to preferentially send signals via a protein pathway known as beta-arrestin. The study hypothesizes that this 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.

"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," says joint lead author on the new study, Luca Lotta. "Our findings may pave the way for a new generation of weight loss therapies that activate MC4R preferentially via the beta-arrestin pathway."

This new research highlights the importance of closely studying the effects of naturally occurring genetic variants in large general population cohorts. We may have known for some time that the MC4R gene could be key to designing effective weight-loss treatments, but until now, uncovering the safest way to modulate that genetic pathway has been relatively unclear.

The new study was published in the journal Cell.