Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis.

Xu, Baijie; Lawler, Katherine; Wyler, Steven C.; Li, Li; Swati; Keogh, Julia M.; Chen, Xiameng; Wan, Rong; Almeida, Amanda G.; Kirsch, Susan; Mountjoy, Kathleen G.; Elmquist, Joel K.; Farooqi, I. Sadaf; Liu, Chen

Disruption of hypothalamic melanocortin 4 receptors (MC4Rs) causes obesity in mice and humans. Here, we investigated the transcriptional regulation of MC4R in the hypothalamus. In mice, we show that the homeodomain transcription factor Orthopedia (OTP) is enriched in MC4R neurons in the paraventricular nucleus (PVN) of the hypothalamus 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 humans, four of the five carriers of rare predicted functional OTP variants in UK Biobank had obesity. To explore a causal role for human OTP variants, we generated mice with a loss-of-function OTP mutation identified in a child with severe obesity. Heterozygous knock-in mice exhibited hyperphagia and obesity, reversed by treatment with an MC4R agonist. Our findings demonstrate that OTP regulates mammalian energy homeostasis and enable the diagnosis and treatment of individuals with obesity due to OTP deficiency. Editor's summary: Hypothalamic neural circuits expressing the melanocortin 4 receptor (MC4R) direct energy homeostasis by reducing or promoting food intake when the receptor is activated or antagonized, respectively. The control of MC4R activity thus has ramifications for health and disease. Xu et al. show that the homeodomain protein Orthopedia (OTP) is enriched in MC4R-expressing neurons and directly regulates Mc4r transcription in mice. Knock-in of a rare human loss-of-function OTP mutation recapitulated an obese phenotype in mice, explaining how such mutations cause early-onset obesity in humans. —Catherine Charneski

TRANSCRIPTION factors; MELANOCORTIN receptors; CHILDHOOD obesity; HOMEOBOX proteins; OBESITY

Science Translational Medicine, 2025, Vol 17, Issue 781, p1

1946-6234

Academic Journal

10.1126/scitranslmed.adr6459