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Researchers at Weill Cornell Medicine have uncovered a human genetic variant associated with heightened resistance to obesity. This variant, found in a receptor responsible for increasing insulin release, operates differently within cells, potentially leading to more efficient metabolism. The study, published online in Molecular Metabolism on Nov. 2, provides valuable insights into how specific genetic variations influence an individual’s susceptibility to weight gain.
The team developed mice carrying a human genetic variant in the glucose-dependent insulinotropic polypeptide (GIP) receptor, associated with a lower body mass index (BMI). These mice displayed enhanced sugar processing abilities and maintained a leaner physique compared to mice with a more common variant of the receptor.
The findings hold promise for potential strategies in combating obesity, a condition affecting over 100 million adults in the United States, as per the Centers for Disease Control and Prevention. Dr. Timothy McGraw, the senior author of the study and a professor at Weill Cornell Medicine, highlighted the significant impact of these GIP receptors on metabolism and weight regulation at a cellular level.
Genetic variants, differences in DNA sequences among individuals, particularly in the GIP receptor, were identified through genome-wide association studies. Roughly 20 percent of people of European descent possess one copy of the GIP receptor with the Q354 gene variant, while approximately 5 percent have two copies. Studies suggest that individuals with at least one copy of this variant exhibit altered metabolism, reducing their susceptibility to obesity.
Using advanced CRISPR-Cas9 technology, the team engineered mice to harbor this gene variant, mirroring the human version. The results showcased that female mice with the variant stayed leaner on a standard diet compared to their counterparts without it. Meanwhile, male mice with the gene variant exhibited similar weights on a regular diet but were protected from weight gain when exposed to a high-fat diet.
Dr. Lucie Yammine, the lead author of the study, emphasized that even a single amino acid change in the GIP receptor gene significantly impacted body weight. Mice with the variant exhibited heightened sensitivity to the GIP hormone, leading to increased insulin production, which aids in glucose metabolism and energy conversion.
Further investigation revealed that the location of these receptors within the cell plays a crucial role in their signaling and activity. The variant receptor remained inside the cell four times longer than the typical receptor, potentially enabling more efficient sugar processing.
The team’s findings open avenues for potential treatments targeting the GIP receptor to address obesity. Dr. Yammine expressed optimism about using drugs that regulate the receptor’s behavior and location as a potential strategy against obesity.
However, more research is warranted to confirm the effects of this variant on receptor behavior in different cell types, especially brain cells, which regulate hunger. Understanding how individuals with different genetic variants respond to existing weight loss medications could pave the way for precision medicine approaches in combating obesity, as suggested by Dr. McGraw.
