Obesity and diseases associated with obesity are among the leading causes of death worldwide, but its causes are not yet fully understood. However, it is known that several factors are responsible for the development and progression of the disease and that genetic factors also play a role. In most of the individuals affected, the combination of an unhealthy lifestyle and a genetic predisposition called a polygenic disorder leads to severe obesity. A polygenic disorder is one in which several genes are affected.

Researchers also want to identify the rare cases of monogenic obesity. In these patients, defects in a single gene are the cause of the disease. Those affected often show a decreased sensation of satiety in early childhood and suffer from a constant feeling of hunger.

While studying tissue samples from a girl with severe obesity, the researchers found that a specific gene, the agouti-signalling protein (ASIP) gene, was produced at high levels in cells where it is not normally present (e.g. in fat cells, white blood cells and neuronal cells).

The mutation places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase promoter, driving the generation of ASIP in patient-derived native and induced pluripotent stem cells for all germ layers and hypothalamic-like neurons.

The patient’s phenotype of early-onset obesity, overgrowth, red hair and hyperinsulinemia is concordant with that of mutant mice ubiquitously expressing the homolog nonagouti. ASIP represses melanocyte-stimulating hormone-mediated activation as a melanocortin receptor antagonist, which might affect eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the index patient.

Project head said, “This discovery is a kind of missing piece of the puzzle in research on monogenic human obesity. It is also evidence for the importance of key molecular regulatory mechanisms of energy balance and body weight via melanocortin 4 receptor neurons in humans and provides us with a unique opportunity to study these mechanisms.”

The type of mutation found in the current study escapes standard genetic screening algorithms, which means that it remains undetected in many affected patients. Thanks to targeted screening, the team has identified four additional patients with the same mutation.

“Given this discovery, I believe we need to rethink the strategies we use to identify patients with monogenic obesity. The ultimate goal of our research is to transfer the findings from genetic studies to future personalised treatment options for obesity,” said the author.

https://www.nature.com/articles/s42255-022-00703-9

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