Genetic variants key in regulating appetite—for better or worse

Two studies published April 18 in the journal Cell have shined new light on the role genetics can play in developing obesity—or protecting against it.

The first used 2.1 million genetic variants to develop a risk score, and those in the top decile were found to be 25 times more susceptible to severe obesity, or a body mass index (BMI) of 40 or higher. In a longitudinal birth cohort, weight trajectories differentiated as soon as early childhood and reached a 12-kilogram difference—or 26.5 pounds—by age 18 at opposite ends of the polygenic risk spectrum.

The other study uncovered a genetic mutation that makes people feel constantly full, effectively muting their appetite. It was associated with lower odds of obesity, type 2 diabetes and coronary artery disease and was present in 6% of the study participants, who were of European ancestry.

Disruptions in the melanocortin 4 receptor (MC4R) have been linked to a greater risk of obesity. Previous research has demonstrated that several MC4R variants cause loss of function in the gene and prevent feelings of satiety. The appetite-regulating gene is essentially never flipped on to signal a feeling of fullness, causing carriers to remain hungry and making them susceptible to overeating.

But in the new study, Sadaf Farooqi, MBChB, PhD, and colleagues found for the first time that certain mutations are associated with a gain of function. In this case, the gene is always flipped on, meaning carriers constantly feel full and therefore have little appetite.

“This proves that MC4R is an important, if not the most important, controller of weight,” Farooqi, professor of metabolism and medicine at the University of Cambridge, told The New York Times.

Both studies used U.K. Biobank data, which includes DNA samples and medical records from approximately 500,000 adults aged 40 to 69. And both offer potential solutions to combat obesity, either by pharmacologically inhibiting appetite through targeting MC4R or by using the polygenic score to identify at-risk children earlier and offer targeted interventions.