How Common Are Monogenic Forms of Obesity And What Can We Do About Them?

Most of obesity is clearly polygenic, meaning that many (perhaps hundreds) of gene variants may cumulatively or synergistically increase genetic predisposition in a given individual. In contrast, monogenic forms of obesity, where a single gene variant (e.g. loss-of-function leptin deficiency) may have a profound effect on body mass, are thought to be exceedingly rare. 

However, a recent paper by Kaitlin H Wade, published in Nature Medicine, suggests that some monogenic forms of obesity may be a lot more frequent than we think. 

In this study, the researchers examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children and found that heterozygous loss-of-function (LoF) mutations in MC4R affected around 1 in 337 (0.3%) individuals with profound effects on body weight. 

At age 18 years, carriers of LoF mutations were almost 18 kg heavier with a BMI almost 5 points higher than non-carriers. 

Extrapolating this to a country like Germany with almost 20 million people living with obesity, LoF mutations in the MC4R gene could be the key culprit in almost 6,000 individuals. Clearly, genetic screening for both children and adults who experience significant weight gain in early childhood appears prudent to identify such individuals.

For them, the good news is not only that they can stop blaming themselves for their excess weight, but also that there may be promising treatments on the horizon. 

Thus, the MC4R-agonist setmalonitide, recently approved by the FDA for treatment of derangements of the melanocortin pathway caused by pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor (LEPR) deficiency, may turn out to also be effective in people with MC4R mutations. 

This may be attributable to the fact that setmelanotide appears to be significantly more potent at the MC4R than the endogenous ligand alpha-melanocyte stimulating hormone (α-MSH) and (at least in vitro) can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. 

Specific clinical trials with setmelanotide in individuals with MC4R mutations are currently underway. 

DrSharma
Berlin, D