A paper published this week in Nature Metabolism reports a novel genetic mechanism associated with severe childhood obesity.
It is a gene rearrangement resulting from abnormal expression of a gene associated with hunger control that is undetectable by most conventional genetic tests for obesity.
The melanocortin receptor 4 (MC4R) activation gene is located in a brain region called the hypothalamus and stimulates feelings of satiety or lack of hunger.
Variants that interfere with MC4R activation or exert function have been linked to persistent hunger and obesity in childhood.
By studying tissue samples from an adolescent girl with severe obesity, the researchers found that the spiny mouse signaling protein (ASIP) gene, which is expressed at high levels in cells that normally would not express the gene, was found in cells that normally do not express the gene.
These cells included adipocytes, leukocytes and hypothalamic-like neurons generated by individual cell reprogramming.
Genetic analysis showed that the rearrangement placed a copy of the ASIP gene next to a promoter, thus explaining why the gene is consistently expressed at high levels in every tissue and is not found in most conventional tests for genetic forms of obesity.
ASIP inhibits MC4R activation, so the abnormal ASIP expression in hypothalamic cells provides a possible explanation for obesity.
The team then specifically searched for this rearrangement in a cohort of over 1,700 obese children, identified four carriers (three girls, one boy), and confirmed ASIP overexpression in three of them.
This observation is consistent with the obesity genetic mouse (agouti mouse) model, a model in which obesity is caused by a mouse version of abnormal ASIP expression.
However, similar mutations involving ASIP associated with obesity in humans have not been identified until now.
