A preclinical study shows that a specific human genetic variant of a receptor that stimulates insulin release may help individuals be more resistant to obesity.
The study provides new insight into how human genetic variations affect an individual’s susceptibility to weight gain. The researchers developed mice with a human genetic variant in the glucose-dependent insulinotropic polypeptide (GIP) receptor associated with leaner body mass index (BMI). They found that the mice were better at processing sugar and staying leaner than mice with a different, more common variant of the receptor.
Genetic variants are differences in DNA sequence that occur naturally between individuals in a given population. Genome-wide association studies, which use statistics to carefully link genetic variants to particular traits, show about 20 percent of people of European descent have one copy of the GIP receptor with the Q354 gene variant and about 5 percent have two copies of the variant. The GIP receptor interacts with a hormone released in response to glucose levels after a meal. “Studies suggest that people with at least one copy of this GIP receptor variant have altered metabolism that reduces their risk of developing obesity,” said the study’s lead author Dr. Lucie Yammine.
To understand how this gene variant may be decreasing the risk of obesity, the team used CRISPR-Cas9 technology to genetically engineer mice with the variant in the gene encoding the GIP receptor, similar to the human version. They found that female mice with the variant were leaner on a typical mouse diet than female littermates without it. Male mice with the gene variant were about the same weight as litter mates without it while consuming a regular diet, but the gene variant protected them from weight gain when fed a high-fat diet, which caused obesity in litter mates.
“We found that a change in one amino acid in the GIP receptor gene affected the whole body in terms of weight,” Dr. Yammine said. Mice with the variant were more sensitive to the GIP hormone that triggers the release of insulin which controls blood sugar levels and helps the body convert food into energy.
The researchers compared what happened to mouse cells with and without the variant when exposed to glucose or the GIP hormone. Pancreatic cells from mice with the genetic variant produced more insulin in response to both glucose and the GIP hormone, which may explain why they are better 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,” Dr. McGraw said. He explained that when the GIP hormone binds to the receptor, the receptor moves from the cell surface to inside the cell. When the GIP hormone eventually falls off the receptor, the receptor returns to the cell surface.
The team found that the GIP receptor variant stays inside the cell compartment four times longer than the typical receptor. Dr. McGraw suggested that this may allow the receptor to send more messages to the machinery inside cells, which helps in processing sugar more efficiently.
“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 that could regulate the GIP receptor behavior and location could provide an important new avenue to combat obesity,” said Dr. Yammine.
Lucie Yammine, Belén Picatoste, Nazish Abdullah, Rosemary A. Leahey, Emma F. Johnson, Nicolás Gómez-Banoy, Carolina Rosselot, Jennifer Wen, Tahmina Hossain, Marcus D. Goncalves, James C. Lo, Adolfo Garcia-Ocaña, Timothy E. McGraw. Spatiotemporal regulation of GIPR signaling impacts glucose homeostasis as revealed in studies of a common GIPR variant. Molecular Metabolism, 2023; 78: 101831 DOI: 10.1016/j.molmet.2023.101831
Weill Cornell Medicine. “Specific genetic variant may help prevent obesity.” ScienceDaily. ScienceDaily, 7 December 2023. <www.sciencedaily.com/releases/2023/12/231207161355.htm>.
Photo by Anna Tarazevich