OTP gene controls expression of MC4R in the hypothalamus and mutations cause obesity in children
In a paper published in Science Translational Medicine, we worked with our collaborator Chen Liu in Texas, USA to investigate factors which control the expression/switching on of the MC4R gene. MC4R (melanocortin 4 receptor) is a gene which acts as a brake on hunger and mutations in this gene are the commonest genetic cause of obesity.
In mice, we showed that the transcription factor Orthopedia (OTP) is enriched in Mc4r neurons in the paraventricular nucleus of the hypothalamus (PVN) and directly regulates MC4R transcription. Deletion of OTP in PVN neurons during development or adulthood reduced Mc4r expression, causing increased food intake and obesity. In people, genetic variants are very rare, but four of five carriers of rare predicted functional OTP variants in UK Biobank had obesity. To test whether OTP variants found in children in the GOOS cohort can cause their severe obesity, we generated mice with a loss-of-function OTP mutation identified in a child. Mice carrying one copy of the mutation exhibited hyperphagia and obesity, which was reversed by treatment with Setmelanotide, an MC4R agonist. Our findings demonstrate that OTP regulates energy homeostasis and enable the diagnosis and treatment of individuals with obesity due to OTP deficiency.
