A new genetic mechanism associated with severe childhood obesity is detailed in a study published in “Nature Metabolism”.
It is, specifically, that a mutation in the melanocortin 4 receptor (MC4R) gene in a region of the brain called the hypothalamus triggers the feeling full, or not feeling hungry. Mutations that interfere with MC4R activation or function have been linked to persistent hunger and childhood obesity.
Childhood obesity is a serious health condition that affects children and adolescents. It is particularly problematic because being overweight often leads to health problems in children that were previously considered adult problems, such as diabetes, high blood pressure and cholesterol alto.
Studying tissue samples from a severely obese adolescent girl, Antje Körner and colleagues at the University of Leipzig, Germany, discovered that a particular gene, agouti signaling protein (ASIP), was expressed at high levels in cells in those not normally present – such as fat cells, white blood cells and hypothalamic-type neurons – generated by reprogramming the person’s cells.
A genetic analysis revealed a rearrangement that placed one copy of the ASIP gene next to an active promoter, a region of DNA that drives gene expression, thus explaining why the gene was consistently expressed at high levels in all tissues.
The nature of the identified chromosome rearrangement also meant that most routine tests for genetic forms of obesity would miss it. ASIP inhibits MC4R activation, so abnormal ASIP expression in hypothalamic cells could explain the observed obesity.
Obesity in agouti mice is due to abnormal expression of the mouse version of ASIP
The team then specifically looked for this rearrangement in a cohort of more than 1,700 children with obesity and identified 4 additional carriers (3 girls and 1 boy), and confirmed ASIP overexpression in 3 of them.
This observation is consistent with a genetic mouse model of obesity, the agouti mouse, wherein obesity is due to abnormal expression of the mouse version of ASIP; however, no similar ASIP mutations have been found to be associated with obesity in humans until now.