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Obesity researchers discover new gene mutation in children

Featured Publication, HI-MAG,

A research team from Helmholtz Munich and the Leipzig University’s Faculty of Medicine has discovered a new mechanism that is associated with severe obesity in children. This genetic rearrangement leads to an unusual expression of a gene that can affect hunger control and is not detected by most routine genetic tests for obesity. The findings were published in the journal Nature Metabolism.

Obesity and associated comorbidities 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 our obesogenic environment and a genetic predisposition leads to severe obesity. This genetic predisposition is based on variants in multiple genes, so called polygenic disorder.

Researchers from the Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) at Helmholtz Munich and the Leipzig University Hospital also aim to identify the rare cases of monogenic obesity. In these patients, defects in a single gene are the cause of the disease. These patients 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 neuron-like cells).

Antje Körner, professor of paediatric research and paediatrician said, “This discovery is a kind of missing piece of the puzzle in research on monogenic human obesity. It is also underlining the importance of key molecular regulatory mechanisms of energy balance and body weight via melanocortin 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. Only with targeted screening of the Leipzig Childhood Obesity cohort, Professors Körner’s team has identified four additional patients with the same mutation.

“Given this discovery, I believe we need to rethink our currently applied strategies 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 Professor Matthias Blüher, director of HI-MAG.


Original publication:

Kempf et al. (2022): Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity. Nature Metabolism. DOI: 10.1038/s42255-022-00703-9