| Title: | Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis |
| Journal: | Science Translational Medicine |
| Published: | 15 Jan 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39813316/ |
| DOI: | https://doi.org/10.1126/scitranslmed.adr6459 |
Publication 14512
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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.</p>
16 Keywords
- Animals
- Energy Metabolism
- Gene Expression Regulation
- Homeodomain Proteins
- Homeostasis
- Humans
- Hypothalamus
- Male
- Mice
- Mice, Inbred C57BL
- Neurons
- Obesity
- Paraventricular Hypothalamic Nucleus
- Receptor, Melanocortin, Type 4
- Transcription Factors
- Transcription, Genetic
14 Authors
- Baijie Xu
- Katherine Lawler
- Steven C Wyler
- Li Li
- Swati
- Julia M Keogh
- Xiameng Chen
- Rong Wan
- Amanda G Almeida
- Susan Kirsch
- Kathleen G Mountjoy
- Joel K Elmquist
- I Sadaf Farooqi
- Chen Liu
1 Application
| Application ID | Title |
|---|---|
| 30172 | Comorbidities between addiction and mental disorders ? association of genetics, biomarkers and environment (e.g. lifestyle) with mental health and cognitive function |
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