Children’s Hospital of Philadelphia (CHOP) researchers have discovered a causative genetic variation that is highly linked to juvenile obesity. The work offers fresh perspective on the significance of the brain’s hypothalamus and its connection to prevalent pediatric obesity. Additionally, the target gene could be used as a pharmacological target for upcoming therapeutic approaches. The journal Cell Genomics publishes the findings.
There’s no doubt that genetic and environmental variables contribute significantly to the rising prevalence of childhood obesity. Although the precise contribution of genetics to childhood obesity remains unclear, previous research indicates that the hypothalamus’s neural connections regulate food intake and play a major part in the condition.
Previous global genome-wide association studies (GWAS) conducted by CHOP researchers discovered particular loci, or genetic markers, connected to obesity. The majority of these research identified genes that are equally linked to obesity in children and adults. These genes are mostly found in non-coding sections of the genome, which means they do not code for particular proteins, making it considerably more difficult to understand how they work.
The locus chr12q13, which is home to the neighboring gene FAIM2, was the subject of this most recent study. It was found that childhood obesity produced a significantly stronger signal than adult obesity.
Sheridan H. Littleton, Ph.D., a postdoctoral research associate who worked as a member of the Center for Spatial and Functional Genomics team at CHOP, authored the first study. “By focusing specifically on this locus, we were able to pinpoint a causal variant associated with one of the strongest genetic signals we have implicated in childhood obesity,” noted Littleton.
“With more research, there’s potential to learn how the target of this variant’s action may be a target for new therapies specifically designed to treat childhood obesity.”
Apart from its association with childhood obesity, this locus has also been linked to several other related health problems, including as an increased risk of type 2 diabetes, a higher proportion of body fat in both adults and children, and an earlier onset of menstruation. The researchers focused on rs7132908, a single nucleotide polymorphism (SNP), or variant, at the locus, using a number of methods.
The hypothalamus is involved in appetite, a characteristic that may be connected to pediatric obesity, according to earlier relevant CHOP study. The hypothalamus is particularly difficult to investigate since it is located deep within the brain.
The researchers employed stem cells that develop into hypothalamic neurons, a crucial cell type linked to eating behavior, to examine the variant’s alleles in order to better understand the implications of the rs7132908 variant. The obesity-related mutation affected the expression of the FAIM2 gene and reduced the amount of neurons generated during stem cell differentiation, indicating that the variant is also linked to neurodevelopment.
Struan F.A. Grant, Ph.D., Director of the Center for Spatial and Functional Genomics and the Daniel B. Burke Endowed Chair for Diabetes Research at CHOP, said, “A study like this demonstrates how extra effort can reveal important information about hitherto uncharacterized genetic variants and the role they play in a variety of childhood and adult illnesses, in spite of a series of challenges.”
“This work further underscores how the brain is central to the genetics of obesity and provides us with a strategy for further study.”