A new genetic mechanism associated with severe childhood obesity

Beijing, Dec.
20 (Zhongxin.
com) -- In a new genetic paper published in Nature Metabolism, a professional academic journal owned by Springer Nature, researchers report a new genetic mechanism
associated with severe childhood obesity.
This is a genetic rearrangement caused by abnormal expression of genes related to hunger control, which is undetectable
by most obesity with routine genetic testing.

According to the paper, the melanin cortisol receptor 4 (MC4R) activation gene is located in a brain region called the hypothalamus and stimulates feelings
of fullness or not hunger.
Variants that interfere with MC4R activation or function are associated
with persistent hunger and childhood obesity.

Corresponding author Antje Körner of the University of Leipzig in Germany, and colleagues and other collaborators studied tissue samples from a severely obese adolescent girl and found that a specific gene, the Agouti Signaling Protein (ASIP) gene, is expressed at high levels in cells that normally do not express the gene, including fat cells, white blood cells, and hypothalamic-like neurons
produced by individual cell reprogramming 。 Genetic analysis showed that the rearrangement placed a copy of the ASIP gene next to a promoter—the region of DNA that drives gene expression, thus explaining why the gene is consistently expressed
at high levels in each tissue.
The confirmed nature of chromosomal rearrangements also means that most conventional tests for genetic forms of obesity do not detect it
.
ASIP inhibits MC4R activation, so abnormal ASIP expression in hypothalamic cells provides a possible explanation
for obesity.

The research team then specifically searched for this rearrangement in a cohort of more than 1,700 obese children, identified 4 carriers (3 girls, 1 boy), and confirmed ASIP overexpression
in 3 of them.
This observation is consistent with the Agouti mouse model, where obesity is caused
by abnormal expression of the mouse version of ASIP.
However, it is only now that similar mutations
involving ASIP associated with obesity in humans have been identified.

The authors believe that the frequency of gene rearrangements in the test cohort is higher and that additional targeted screening
is needed in other patient cohorts.
While these experiments in isolated cells support their model, the authors caution that they have not yet confirmed that ASIP expression in patients' brains is associated with MC4R inhibition, and that further studies
in human and animal models are needed to definitively link gene rearrangements to obesity in humans.
(End)