Genetics: Mutation associated with childhood obesity uncovered

A new genetic mechanism associated with severe childhood obesity is reported in a study published this week in Nature Metabolism. The genetic rearrangement results in abnormal expression of a gene associated with hunger control and is not detected by most routine genetic tests for obesity.

Activation of the melanocortin 4 receptor (MC4R) gene in a brain region called the hypothalamus triggers the sensation of satiety, or not feeling hungry. Mutations that interfere with MC4R activation or function have been linked to persistent hunger and to childhood obesity.

Studying tissue samples from a teenage girl with severe obesity, Antje Körner and colleagues found that a particular gene, the agouti-signaling protein (ASIP) gene, was expressed at high levels in cells where it is not normally present—such as in fat cells, white blood cells and hypothalamic-like neurons—generated by reprogramming cells from the individual. A genetic analysis revealed a rearrangement that placed a copy of the ASIP gene next to an active promoter, a region of DNA that drives gene expression, thereby explaining why the gene was constantly expressed in high levels in every tissue. The nature of the identified chromosomal rearrangement also meant that most routine tests for genetic forms of obesity would not detect it. ASIP inhibits MC4R activation, and the abnormal ASIP expression in hypothalamic cells thus provides a potential explanation for the observed obesity.

The team then searched specifically for this rearrangement in a cohort of over 1,700 children with obesity and identified 4 additional carriers (3 girls, 1 boy), and confirmed ASIP overexpression in 3 of these. This observation is in line with a genetic mouse model of obesity, the agouti mouse, in which obesity is due to abnormal expression of the mouse version of ASIP; however, no similar mutations involving ASIP associated with obesity had been found in humans until now.

The authors argue that the comparatively high frequency of the genetic rearrangement in the tested cohort calls for additional targeted screenings in other patient cohorts. Although the experiments in isolated cells support their model, the authors note that they have not confirmed ASIP expression and MC4R inhibition in the patients’ brains. Definitively linking the genetic rearrangement with obesity in humans would require further studies in human and animal models.