The Role of Melanocortin 3 Receptor Gene in Childhood Obesity Yung Seng Lee , Larry Kok Seng Poh , Betty Lay Kee Kek and Kah Yin Loke From the Department of Pediatrics, National University of Singapore, and the Children's Medical Institute, National University Hospital, Singapore Address correspondence and reprint requests to Dr. Yung Seng Lee, Department of Paediatrics, National University Hospital, 5 Lower Kent Ridge Rd., Singapore 119074. E-mail: paeleeys{at}nus.edu.sg Abstract OBJECTIVE— Melanocortin 3 receptor (MC3R) plays a critical role in weight regulation of rodents, but its role in humans remains unclear. The objective of this study was to identify genetic variants of the MC3R gene and determine its association with childhood obesity. RESEARCH DESIGN AND METHODS— We screened 201 obese children for MC3R gene mutations with anthropometric measurements, blood tests, feeding behavior, and body composition assessment. We identified three novel heterozygous mutations (Ile183Asn, Ala70Thr, and Met134Ile) in three unrelated subjects, which were not found in 188 control subjects, and two common polymorphisms Thr6Lys and Val81Ile. RESULTS— In vitro functional studies of the resultant mutant receptors revealed impaired signaling activity but normal ligand binding and cell surface expression. The heterozygotes demonstrated higher leptin levels and adiposity and less hunger compared with obese control subjects, reminiscent of the MC3R knockout mice. Family studies showed that these mutations may be associated with childhood or early-onset obesity. The common variants Thr6Lys and Val81Ile were in complete linkage disequilibrium, and in vitro studies revealed reduced signaling activity compared with wild-type MC3R. Obese subjects with the 6Lys/81Ile haplotype had significantly higher leptin levels, percentage body fat, and insulin sensitivity, and the causative role of the 6Lys/81Ile variants is supported by the presence of an additive effect in which heterozygotes had an intermediate phenotype compared with homozygotes. CONCLUSIONS— MC3R mutations may not result in autosomal dominant forms of obesity but may contribute as a predisposing factor to childhood obesity and exert an effect on the human phenotype. Our report supports the role of MC3R in human weight regulation. BIA, bioimpedance analysis DEXA, dual-energy X-ray absorptiometry DMEM, Dulbecco's modified Eagle's medium HOMA, homeostasis model assessment MC3R, melanocortin 3 receptor MC4R, melanocortin 4 receptor MSH, melanocyte-stimulating hormone NDP, Nle4, D-Phe7 POMC, proopiomelanocortin QUICKI, quantitative insulin sensitivity check index TRF, time-resolved fluorometry WFH, weight for height Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 16 July 2007. DOI: 10.2337/db07-0225 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 10, 2007. Received February 16, 2007. DIABETES