THE ESSENTIAL
- In mice with mutations in the OTP gene, significant weight gain was observed after the introduction of a high-fat diet.
- They also developed early-onset obesity, high cholesterol, fatty liver disease and type 2 diabetes.
- After taking setmelanotide, a drug used to treat obesity, a reduction in their health problems was observed.
The urge to eat or not in humans and animals is largely controlled by a part of the brain called the hypothalamus. “As part of this complex mechanism, a protein called melanocortin 4 receptor (MC4R), present on the surface of certain hypothalamic neurons, binds to different proteins that suppress or increase hunger,” said Chen Liu, associate professor of internal medicine and neuroscience and researcher at the Hypothalamic Research Center at UT Southwestern (USA). According to previous research, mutations leading to loss of MC4R function lead to severe obesity. However, there is little understanding of how neurons control the amount of MC4R, which in turn affects the level of protection of this protein against obesity.
Mice lacking the OTP gene became obese after a high-fat diet
To fill these gaps, the scientist and his team conducted experiments on mice to determine the genes responsible for MC4R production in hypothalamic neurons. They identified the OTP gene, producing a protein in rodents that appears to bind directly to the DNA sequences controlling MC4R expression. These factors suggest that OTP may regulate MC4R production. When the authors genetically modified the rodents to turn off OTP, these animals gained a lot of weight and became obese after being put on a high-fat diet. Further examination revealed that their weight gain was linked to increased food consumption and that the genetically modified animals produced significantly less MC4R than other mice, “which proves that OTP influences the quantity of MC4R produced by hypothalamic neurons”.
-Setmelanotide, “useful for treating obesity”
To go further, the researchers created mice carrying the same mutation. The result: They developed early-onset obesity, high cholesterol, fatty liver disease and type 2 diabetes. When the team treated them with setmelanotide, a drug used to treat a rare genetic form of obesity caused by deficiencies in MC4R signaling, these health problems gradually reversed. “It could therefore be useful for treating obesity in patients,” concluded the main author of the work, published in the journal Science Translational Medicine.
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