2. Academic Validation
  3. Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis

Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis

  • Sci Transl Med. 2025 Jan 15;17(781):eadr6459. doi: 10.1126/scitranslmed.adr6459.
Baijie Xu 1,  Katherine Lawler 2,  Steven C Wyler 1,  Li Li 1,  Swati 1,  Julia M Keogh 2,  Xiameng Chen 1,  Rong Wan 1,  Amanda G Almeida 1,  Susan Kirsch 3,  Kathleen G Mountjoy 4,  Joel K Elmquist 1,  I Sadaf Farooqi 2,  Chen Liu 1 5 6
Affiliations

Affiliations

  • 1 Hypothalamic Research Center, Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USA.
  • 2 University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • 3 Department of Endocrinology, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G1X8, Canada.
  • 4 Department of Molecular Medicine and Pathology and Center for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 5 Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 6 Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA.
PMID: 39813316 DOI: 10.1126/scitranslmed.adr6459
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 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.

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