Obesity presents a global challenge, with genetic disorders contributing to its complexity. Researchers from the UT Southwestern Medical Center have identified an unusual gene, OTP, that plays a crucial role in regulating hunger and body weight, potentially paving the way for new obesity treatments.
According to a study published in the journal Science Translational Medicine, OTP influences the function of the melanocortin 4 receptor (MC4R), a protein in the hypothalamus responsible for appetite regulation. Dysfunction of MC4R is linked to severe obesity, while increased MC4R activity protects against weight gain. These findings could lead to targeted therapies for specific genetic forms of obesity, affecting over one billion individuals worldwide.
Led by Dr. Chen Liu, an assistant professor of internal medicine and neurology, the research demonstrated that OTP directly regulates MC4R production in hypothalamic neurons. To investigate OTP's role, researchers genetically modified mice to disable this gene. Mice fed a high-fat diet exhibited significant weight gain due to overeating and produced substantially less MC4R compared to normal mice, highlighting OTP's importance in appetite control and metabolism.
Further collaboration with the University of Cambridge identified children with severe early-onset obesity linked to OTP mutations. Mice engineered to mimic these mutations displayed similar health issues, including obesity, high cholesterol, fatty liver disease, and type 2 diabetes.
In a therapeutic experiment, researchers treated modified mice with setmelanotide, a drug already approved for rare genetic obesity related to MC4R deficiency. The treatment resolved obesity and metabolic issues in mice, suggesting setmelanotide may effectively address OTP-related obesity in humans.
Analysis of the UK Biobank genetic database confirmed these findings, showing individuals with OTP mutations are significantly more prone to obesity, reinforcing OTP's role in weight regulation. Dr. Liu emphasized the practical implications of the research, noting that the results deepen understanding of severe genetic obesity and offer potential solutions.
The discovery highlights the possibility of utilizing existing medications to treat previously unrecognized forms of obesity, potentially accelerating the development of targeted therapies. This research underscores the complexity of genetic factors in obesity and the importance of understanding neural pathways that control hunger.
While the identification of OTP as an MC4R regulator represents a breakthrough, the authors acknowledge the need for further work to assess the prevalence of OTP mutations in the general population and their interaction with environmental factors. Clinical trials in humans will be critical to determine the translatability of these results from mice to patients.
According to the World Health Organization, over one billion people globally are classified as obese, which has significant implications for governments and their citizens across various sectors. Approaches targeting pathways associated with OTP may represent a step forward in addressing this issue.