Regulates Melanocortin 4 Receptor Transcription and Energy Homeostasis

Overview

Journal Sci Transl Med

Date 2025 Jan 15

PMID 39813316

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

Affiliations

Soon will be listed here.

Abstract

Disruption of hypothalamic melanocortin 4 receptors (MC4Rs) causes obesity in mice and humans. Here, we investigated the transcriptional regulation of 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 transcription. Deletion of in PVN neurons during development or adulthood reduced expression, causing increased food intake and obesity. In humans, four of the five carriers of rare predicted functional variants in UK Biobank had obesity. To explore a causal role for human variants, we generated mice with a loss-of-function 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 deficiency.

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