A large population study found that some people carry genetic variants of the MC4R gene that seem to protect them from obesity, pointing out a signaling pathway possible to harness for creating new weight loss therapies.
The findings appear in the report, “Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity,” published in the journal Cell.
MCR4 mutations represent the most common cause of genetic obesity due to a single gene, with studies in the U.K. reporting they account for 5% to 6% of severely obese people.
The gene gives instructions for production of the MCR4 protein, a brain-specific receptor with a key role in controlling appetite and regulating weight. After a meal, this receptor acts like a switch in the brain to suppress appetite.
Among other problems, people with MCR4 deficiency have an increased drive to eat and have a feeling of insatiety (less fullness after a meal).
A team at the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge was interested in looking at the small natural variations of MC4R naturally occurring in the population, as this may inform the design of drugs to treat obesity and its complications.
First, they examined genetic MC4R variants among nearly half a million people who are participants in the UK Biobank, finding 61 distinct gene variants occurring in the general population.
Then, researchers examined the relationships between those variants and people’s weight, as judged by their body mass index (BMI), obesity, and related cardiometabolic diseases, including type 2 diabetes and coronary heart disease.
While some variants seemed to predispose people to obesity, others were associated with lower BMI and lower odds of becoming obese or having diabetes or heart 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,” Sadaf Farooqi, MD, PhD, a principal investigator at the Institute of Metabolic Science in Cambridge and senior author of the study, said in a press release.
“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,” he said.
To understand what distinguished variants linked to a higher risk from those protective against obesity, the team investigated their consequences at the molecular level in a couple of laboratory assays.
They found that gene variants associated with higher obesity risk stopped the MC4R receptor from working, causing a loss of function, whereas variants that reduced that risk kept the receptor more active, or turned “on,” leading to a gain of function.
A more detailed analysis revealed that 88% of the change in the association of MC4R variants and people’s body mass index was explained by their effect on a specific signaling route of MC4R known as the beta-arrestin pathway.
Beta-arrestin is one of the pathways through which MC4R can send signals to cells in the brain, but has not previously been linked to weight regulation.
However, scientists discovered that genetic variants with a bias to signaling through this pathway were the ones driving association with lower risk of obesity and related conditions.
Around 6% of study participants were carriers of one or two copies of gain-of-function variations favoring MC4R signaling through beta-arrestin.
Those people weighed less, and had a lower risk for obesity, with a stronger effect on carriers of two copies of those variants — on average they weighed 2.5 kg less than people without such variants, and were about 50 percent less likely to have obesity, type 2 diabetes, or coronary artery disease.
These findings lay the ground for designing drugs that mimic MC4R protective variants and work as activators, or agonists, of the beta-arrestin pathway, to provide new therapies for weight loss and obesity-associated metabolic diseases.
One important observation was that variants tied to lower obesity risk were not associated with increased blood pressure or heart rate, which means they may be used to develop safer drugs.
“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,” said Luca Lotta, MD, PhD, a researcher at the MRC Epidemiology Unit and one of the study’s lead authors. “Our findings may pave the way for a new generation of weight loss therapies that activate MC4R preferentially via the beta-arrestin pathway.”
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