A preclinical study conducted by Weill Cornell Medicine researchers reveals that a certain human genetic variant of an insulin-stimulating receptor may help individuals be more resistant to obesity. This version functions differently in the cell, which may lead to more effective metabolism, according to the researchers.
The study, published in the journal Molecular Metabolism, sheds new light on how human genetic variants influence an individual’s vulnerability to weight gain. The researchers created mice with a human genetic variation in the glucose-dependent insulinotropic polypeptide (GIP) receptor, which has been linked to a lower BMI. The mice were shown to be better at sugar processing and keeping slimmer than mice with a different, more common form of the receptor. The discovery could lead to new treatment options for obesity, which affects more than a hundred million adults in the United States, according to the Centers for Disease Control and Prevention.
“Our work demonstrates how basic science research can yield important insights about complex biology,” said the study’s senior author Dr. Timothy McGraw, a professor of biochemistry in cardiothoracic surgery and in biochemistry at Weill Cornell Medicine. “These GIP receptors and their behavior at the cellular level profoundly impact metabolism and weight regulation.”
Our findings suggest that receptor movement from the cell surface to the interior is an important factor in metabolism control. As a result, drugs that can regulate GIP receptor behavior and location could provide an important new avenue for combating obesity.
Dr. Yammine
Genetic Variants of the GIP Receptor
Genetic variations are differences in DNA sequence that occur naturally amongst individuals in a given group. According to genome-wide association studies, which use statistics to meticulously link genetic variants to specific traits, approximately 20% of persons of European origin have one copy of the GIP receptor with the Q354 gene variant, and approximately 5% have two copies of the variant. The GIP receptor interacts with a hormone that is secreted 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, which reduces their risk of developing obesity,” said the study’s lead author, Dr. Lucie Yammine, a post-doctoral associate in biochemistry at Weill Cornell Medicine.
To learn more about how this gene variant may reduce the risk of obesity, the researchers employed CRISPR-Cas9 technology to genetically modify mice with the variant in the gene encoding the GIP receptor that is similar to the human version. Female mice with the variation were found to be slimmer on a standard mouse diet than female littermates without it. Male mice with the gene mutation weighed about the same as litter mates without it on a regular diet, but it 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.
How the Variant May Provide an Advantage Against Obesity
The researchers studied what happened to mouse cells with and without the variation when exposed to glucose or the GIP hormone. Pancreatic cells from mice with the genetic mutation released more insulin in response to both glucose and the GIP hormone, which may explain why they handle glucose better.
“What’s interesting about these receptors is their location in the cell has a big impact on how they signal and their activity,” says Dr. McGraw. He said that when the GIP hormone connects to the receptor, the receptor moves from the cell surface to inside the cell. When the GIP hormone slips 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.
Still, more research is needed to confirm the effects of this variant on the receptor’s behavior. The researchers also want to learn if there are differences in the receptor’s behavior in other cell types, like brain cells, which play a crucial role in regulating hunger.
Recently, the Food and Drug Administration has approved several weight loss drugs that mimic natural hormones in the body and interact with receptors like GIP, including semaglutide (Wegovy) and tirzepatide (Zepbound). This has increased the interest in studying new ways to target the GIP receptor for obesity.
“Our findings suggest that receptor movement from the cell surface to the interior is an important factor in metabolism control. As a result, drugs that can regulate GIP receptor behavior and location could provide an important new avenue for combating obesity,” Dr. Yammine added.
Meanwhile, Dr. McGraw emphasized the importance of understanding how patients with different genetic variations in the GIP receptor respond to currently available weight loss medicines. “A better appreciation of how different variants of receptors impact metabolism might allow for a precision medicine approach — matching a specific drug to a genetic variant — for weight loss,” he added.
