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Scientists discover genetic variant which could prevent obesity

[Dec. 9, 2023: JD Shavit, The Brighter Side of News]

Dietary sugar alters the gut microbiome, setting off a chain of events that leads to metabolic disease, pre-diabetes, and weight gain. (CREDIT: Creative Commons)

In a world grappling with an ever-increasing obesity epidemic, the quest for effective ways to combat excess weight has taken a significant stride forward. A recent preclinical study conducted by researchers at Weill Cornell Medicine has uncovered a promising genetic variant that appears to offer resistance to obesity.

This groundbreaking discovery could potentially pave the way for innovative strategies in the battle against obesity, a condition that affects over 100 million adults in the United States alone, according to the Centers for Disease Control and Prevention.


Published online in the journal Molecular Metabolism, the study delves into the intricate interplay between genetics and obesity. The research centers around a specific genetic variant found in the glucose-dependent insulinotropic polypeptide (GIP) receptor, a crucial player in the regulation of insulin release.

The images of insulin-producing beta cells show the GIP receptor Q354 variant (green), the Golgi Network (magenta) and the nucleus (blue). Left: GIP receptors are localized at the plasma membrane surrounding the cell. Right: After the receptor binds the GIP hormone, it moves inside the cell. (CREDIT: Molecular Metabolism)

Dr. Timothy McGraw, a professor of biochemistry in cardiothoracic surgery and in biochemistry at Weill Cornell Medicine and the senior author of the study, emphasizes the significance of these findings, stating, "Our work demonstrates how basic science research can yield important insights about complex biology. These GIP receptors and their behavior at the cellular level profoundly impact metabolism and weight regulation."


Genetic Variants and Their Impact

Genetic variants are naturally occurring differences in DNA sequences among individuals within a given population. Genome-wide association studies, which statistically link genetic variants to specific traits, have revealed that approximately 20 percent of individuals of European descent possess one copy of the GIP receptor with the Q354 gene variant, while around 5 percent have two copies of this variant.


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The GIP receptor plays a pivotal role by interacting with a hormone released in response to glucose levels after a meal. Dr. Lucie Yammine, a post-doctoral associate in biochemistry at Weill Cornell Medicine and the lead author of the study, explains, "Studies suggest that people with at least one copy of this GIP receptor variant have altered metabolism that reduces their risk of developing obesity."

To unravel the mechanisms underlying the reduced obesity risk associated with this gene variant, the research team employed CRISPR-Cas9 technology to genetically engineer mice with a version of the GIP receptor gene mirroring the human variant. Their observations revealed compelling insights into the impact of this genetic alteration.


Female mice carrying the variant displayed a leaner physique when fed a typical mouse diet compared to their littermates lacking the variant. Male mice with the gene variant exhibited similar weights to their counterparts on a regular diet, but they were shielded from weight gain when subjected to a high-fat diet—a dietary challenge that induced obesity in their non-variant counterparts.

PheWAS shows GIPR-Q354 (rs1800437) decreased BMI phenotype. Graph shows significant (p<5 10 8) associations of GIPR variant rs1800437-C for Glycemic and Anthropometric traits. (CREDIT: Molecular Metabolism)

As Dr. Yammine elaborates, "We found that a change in one amino acid in the GIP receptor gene affected the whole body in terms of weight." Notably, mice carrying the variant exhibited increased sensitivity to the GIP hormone, which triggers insulin release—a key player in controlling blood sugar levels and facilitating the conversion of food into energy.


A Cellular Dance: How the Variant Works Its Magic

The study delves into the intricate cellular processes governed by the GIP receptor and its variant. When exposed to glucose or the GIP hormone, researchers observed significant disparities between cells with and without the variant. Pancreatic cells in mice with the genetic variant produced more insulin in response to both glucose and the GIP hormone. This heightened insulin response could explain the superior ability of these mice to process glucose efficiently.

Dr. McGraw underscores the importance of the receptor's location within the cell, explaining, "What's interesting about these receptors is their location in the cell has a big impact on how they signal and their activity." When the GIP hormone binds to the receptor, the receptor migrates from the cell surface to the interior of the cell. Subsequently, when the GIP hormone detaches from the receptor, the receptor returns to the cell surface.

Crucially, the research revealed that the GIP receptor variant remains inside the cell compartment approximately four times longer than the standard receptor. This extended retention within the cell may enable the receptor to convey more messages to the internal cellular machinery, thereby enhancing the efficiency of sugar processing.


However, it is essential to acknowledge that further research is warranted to fully elucidate the intricacies of this receptor variant's behavior. The research team aims to investigate whether the receptor behaves differently in other cell types, particularly brain cells, which play a pivotal role in regulating hunger.

Implications for Obesity Treatment: A New Avenue Emerges

The significance of this research extends beyond the laboratory. In recent times, the Food and Drug Administration has approved several weight loss drugs that mimic natural hormones in the body and interact with receptors like GIP. These drugs, including semaglutide (Wegovy) and tirzepatide (Zepbound), have sparked a surge of interest in exploring innovative approaches to target the GIP receptor as a means to combat obesity.

Dr. Yammine emphasizes the potential of this research, stating, "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."


Nevertheless, until these promising discoveries translate into practical treatments, Dr. McGraw stresses the importance of understanding how individuals with various genetic variants in the GIP receptor respond to currently available weight loss medications. He envisions a future where precision medicine, matching specific drugs to genetic variants, could revolutionize the field of weight loss.

As researchers strive to unlock the genetic keys to healthier lives, the prospect of personalized treatments tailored to individual genetic profiles draws nearer, promising a brighter future for millions struggling with the burden of obesity.

For more science and technology stories check out our New Discoveries section at The Brighter Side of News.


Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.


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