Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis

IF 15.8 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-01-15 DOI:10.1126/scitranslmed.adr6459

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

{"title":"Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis","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","doi":"10.1126/scitranslmed.adr6459","DOIUrl":null,"url":null,"abstract":"<div >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.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 781","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adr6459","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

骨科调节黑素皮质素4受体转录和能量稳态。

下丘脑黑素皮质素4受体（MC4Rs）的破坏会导致小鼠和人类肥胖。在这里，我们研究了MC4R在下丘脑中的转录调控。在小鼠实验中，我们发现下丘脑室旁核（PVN）的MC4R神经元中富含同源结构域转录因子骨科（OTP），并直接调节MC4R的转录。在发育或成年期间PVN神经元中Otp的缺失会降低Mc4r的表达，导致食物摄入增加和肥胖。在人类中，英国生物银行中预测的罕见功能性OTP变异的5个携带者中有4个患有肥胖症。为了探索人类OTP变异的因果作用，我们在一名患有严重肥胖的儿童身上发现了一种功能缺失的OTP突变小鼠。杂合子敲入小鼠表现出嗜食和肥胖，通过MC4R激动剂治疗逆转。我们的研究结果表明，OTP调节哺乳动物的能量稳态，使OTP缺乏导致的肥胖个体的诊断和治疗成为可能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.