<i>Orthopedia</i> regulates melanocortin 4 receptor transcription and energy homeostasis.

ABSTRACT: 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 se

SUBMITTER: Xu B 

PROVIDER: S-EPMC11797978 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature