Researchers at UT Southwestern Medical Center have identified a gene called OTP that plays a critical role in controlling hunger and body weight.
This discovery, published in Science Translational Medicine, could pave the way for more effective treatments for certain types of obesity, a condition that currently affects over a billion people worldwide.
The study, led by Dr. Chen Liu, Associate Professor of Internal Medicine and Neuroscience at UT Southwestern, sheds light on how OTP impacts the function of a well-known protein called melanocortin 4 receptor (MC4R).
Found in the hypothalamus—the part of the brain that regulates hunger and eating behaviors—MC4R plays a key role in suppressing or increasing appetite. When MC4R functions poorly, it can lead to severe obesity, while increased MC4R activity has been linked to protection against weight gain.
Dr. Liu and his team wanted to understand how the brain controls the production of MC4R. Their research pointed to OTP as a regulator of MC4R expression.
The OTP gene produces a protein that binds directly to DNA sequences responsible for controlling the amount of MC4R in hypothalamic neurons. This connection prompted the team to investigate OTP’s role in weight regulation.
Key Findings in Mice
The researchers genetically modified mice to disable OTP. These mice, when fed a high-fat diet, gained significant weight and became obese. The primary cause of this weight gain was overeating.
Further analysis revealed that the modified mice produced much less MC4R compared to normal mice, supporting the idea that OTP influences the production of this critical protein.
To confirm OTP’s role in obesity, the researchers collaborated with scientists at the University of Cambridge.
The Cambridge team had identified children with severe early-onset obesity linked to loss-of-function mutations in OTP. Dr. Liu’s team created mice carrying the same genetic mutation as one of these children.
These mice developed severe obesity, along with related health problems such as high cholesterol, fatty liver disease, and type 2 diabetes—mirroring the conditions seen in the affected child.
Promising Treatment with Setmelanotide
To explore potential treatments, the researchers administered setmelanotide, a drug designed to treat rare genetic forms of obesity caused by deficiencies in MC4R signaling.
The treatment improved the health of the modified mice, reversing obesity and associated metabolic problems. These findings suggest that setmelanotide could also be an effective therapy for patients with obesity linked to OTP mutations.
Implications for Human Obesity
OTP appears to be part of a small group of genes that have a significant impact on human obesity. A search in the UK Biobank—a large genetic database in the United Kingdom—revealed that several individuals with OTP mutations also struggled with obesity.
This strengthens the case for targeting OTP-related pathways in developing new treatments for the condition.
Dr. Liu emphasized that these findings not only uncover a molecular basis for severe obesity in some patients but also point to actionable solutions. “Setmelanotide could be a useful treatment for individuals with OTP-related obesity,” he noted, offering hope for those affected by this challenging condition.
Analysis of the Study
This research highlights the complex genetic mechanisms underlying obesity and demonstrates how understanding these pathways can lead to innovative treatments. Identifying OTP as a regulator of MC4R is a significant breakthrough, as it adds to our knowledge of how appetite and body weight are controlled in the brain.
The results are particularly promising because they show that existing drugs like setmelanotide could be repurposed to help patients with OTP-related obesity. This could speed up the availability of treatments, benefiting individuals who might otherwise face lifelong health challenges.
However, further research is needed to determine how widespread OTP mutations are among people with obesity and how they interact with other genetic and environmental factors. Clinical trials in humans will be essential to confirm whether the benefits observed in mice apply to patients.
In summary, the discovery of OTP’s role in obesity provides new insights into how the brain regulates hunger and opens up exciting possibilities for targeted therapies. With continued research, this work could significantly improve the lives of many people struggling with obesity worldwide.
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The research findings can be found in Science Translational Medicine.
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