A recent study conducted by researchers at Weill Cornell Medicine has uncovered a human genetic variant linked to a receptor that stimulates insulin release.
This genetic variant may play a role in helping individuals resist obesity by influencing metabolism in a unique way.
This research, published in the journal Molecular Metabolism, sheds light on how genetic variations can impact a person’s susceptibility to weight gain and offers potential strategies for tackling obesity.
The specific genetic variant in question is related to the glucose-dependent insulinotropic polypeptide (GIP) receptor. This receptor interacts with a hormone released in response to glucose levels after a meal.
Genome-wide association studies have revealed that approximately 20% of people of European descent possess one copy of the GIP receptor with the Q354 gene variant, and about 5% have two copies of this variant.
Interestingly, studies suggest that individuals with at least one copy of this variant have altered metabolism that reduces their risk of developing obesity.
To explore how this gene variant might contribute to obesity resistance, the researchers used CRISPR-Cas9 technology to genetically engineer mice with a version of the gene encoding the GIP receptor that mimicked the human variant.
Their findings were intriguing: female mice with the variant remained leaner when fed a standard mouse diet compared to their counterparts without it.
Male mice with the variant maintained a similar weight to those without it on a regular diet, but they were protected from weight gain when exposed to a high-fat diet, which led to obesity in the latter group.
The key discovery was that a single amino acid change in the GIP receptor gene had a significant impact on body weight regulation.
Mice with the variant exhibited increased sensitivity to the GIP hormone, which triggers insulin release, regulates blood sugar levels, and aids in converting food into energy.
Further investigation revealed that when the GIP hormone binds to the receptor, it moves from the cell surface into the interior of the cell. The unique aspect of the genetic variant was that it remained inside the cell compartment four times longer than the typical receptor.
This extended stay inside the cell may allow the receptor to send more messages to the cellular machinery responsible for processing sugar efficiently.
However, additional research is required to fully understand the effects of this variant on the receptor’s behavior. Researchers are also interested in exploring whether the receptor behaves differently in other cell types, such as brain cells, which play a vital role in hunger regulation.
Recently, the Food and Drug Administration (FDA) has approved several weight loss drugs that mimic natural hormones in the body and interact with receptors like GIP.
These medications, including semaglutide (Wegovy) and tirzepatide (Zepbound), have sparked interest in studying novel approaches to target the GIP receptor for obesity treatment.
The study’s lead author, Dr. Lucie Yammine, emphasized the potential significance of regulating the GIP receptor’s behavior and location with drugs to combat obesity.
Dr. Timothy McGraw, the senior author of the study, stressed the importance of understanding how individuals with different genetic variants in the GIP receptor respond to existing weight loss medications.
This insight could potentially lead to a precision medicine approach, tailoring specific drugs to genetic variants to enhance weight loss strategies.
In conclusion, this research uncovers a promising genetic variant that may hold the key to obesity resistance.
By gaining a deeper understanding of how this variant affects metabolism and insulin regulation, scientists may be on the path to developing more effective treatments for obesity, a condition that affects millions of adults in the United States and around the world.
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The research findings can be found in Molecular Metabolism.
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