The sequences of our genes can carry small variations; sometimes they only involve a single base. These variations can have a wide range of impacts on our biology, and together they make us unique. Some gene variants can have beneficial effects. New research has identified a genetic variant that could help carriers resist obesity by promoting more efficient metabolism. The findings have been reported in Molecular Metabolism.
In this study, the investigators engineered a mouse model that carried the gene variant, which is found in the gene that encodes for the glucose-dependent insulinotropic polypeptide (GIP) receptor or GIP-R. This variant is associated with lower measurements of body mass index (BMI). The mouse model was found to be more efficient at breaking down sugar, and was able to maintain a lower body weight compared to mice that carried the more common version of the GIP gene.
The GIP receptor is triggered by the GIP hormone, which is released after a meal in response to rising levels of glucose.
Genetic studies have found that around 20 percent of people of European descent carry one copy of the efficient variant, Q354, while roughly 5 percent of people carry two copies of this variant. People with at least one copy of the variant are through to have a lower risk of obesity because of changes in their metabolism, noted lead study author, Dr. Lucie Yammine, a post-doctoral associate at Weill Cornell Medicine.
By changing only one amino acid in the mouse model, the entire body weight of the animals changed, and carriers became more sensitive to the GIP hormone.
Mouse pancreatic cells were also engineered to carry the variant and were exposed to glucose or the GIP hormone along with mouse pancreatic cells that carried the regular version of the gene. Cells that were altered with the variant generated more insulin when stimulated by glucose or the GIP hormone. This could explain why they are more efficient at processing glucose.
"What's interesting about these receptors is their location in the cell has a big impact on how they signal and their activity," noted senior study author Dr. Timothy McGraw, a professor at Weill Cornell Medicine. When GIP attaches to its receptor, the receptor goes into the cell from the surface. When the GIP hormone falls off, the receptor goes back to the cell surface. But the receptor variant stays inside of the cell for far longer, which could be improving metabolic efficiency.
"Our work suggests that the movement of the receptor from the cell surface to the interior is an important factor in controlling metabolism. Therefore, drugs regulating the GIP receptor behavior and location could provide an important new avenue to combat obesity," said Yammine.
Sources: Weill Cornell Medicine, Molecular Metabolism