Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis

Genetic studies have shown that the melanocortin 4 receptor (MC4R) plays a critical role in regulating food intake and body weight. However, surprisingly, little is known about how MC4R expression is regulated in the brain.

In a study published in Science Translational Medicine, the Farooqi team collaborated with Chen Lui (University of Texas Southwestern, USA) to identify regulators of MC4R transcription in the adult hypothalamus. In mice, the team demonstrated that the transcription factor Orthopedia (OTP) regulates MC4R transcription in neurons in the paraventricular nucleus of the hypothalamus, whereas other transcription factors control expression at other sites. These studies showed that the transcriptional regulation of MC4R is complex and region-specific. Disruption of OTP in developing and adult mice caused increased food intake and obesity, findings which were recapitulated in a knock-in mouse model of a rare loss of function human variant in OTP, demonstrating their relevance for the regulation of human energy homeostasis. Knock-in mice carrying a human OTP mutation found in a child with severe obesity, lost weight when treated with Setmelanotide, a MC4R agonist licensed for clinical use. These studies demonstrate that OTP regulates mammalian energy homeostasis and enable the diagnosis and treatment of individuals with obesity due to OTP deficiency.

Reference: Xu B, Lawler K, Wyler S, Li L, Swati, Keogh J, Chen X, Wan R, Almeida A, Kirsch S, Mountjoy K, Elmquist J, Farooqi S, Liu C. Orthopedia regulates Melanocortin 4 Receptor transcription and energy homeostasis. Sci. Transl. Med.17,eadr6459(2025).DOI:10.1126/scitranslmed.adr6459