HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: db07-0225v1 56/10/2622    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lee, Y. S. Articles by Loke, K. Y. Search for Related Content PubMed PubMed Citation Articles by Lee, Y. S. Articles by Loke, K. Y. Social Bookmarking                What's this?

The role of Melanocortin 3 Receptor Gene in Childhood Obesity

Department of Paediatrics, National University of Singapore, and the Children's Medical Institute, National University Hospital, Singapore

Correspondence: paeleeys{at}nus.edu.sg

Introduction:Melanocortin 3 receptor (MC3R) plays a critical role in weight regulation of rodents, but its role in humans remains unclear.

Objective:To identify genetic variants of the MC3R gene and determine its association with childhood obesity.

Methods:We screened 201 obese children for MC3R gene mutations, with anthropometric measurements, blood tests, feeding behaviour and body composition assessment.

Results:We identified three novel heterozygous mutations (Ile183Asn, Ala70Thr, and Met134Ile) in three unrelated subjects, which were not found in 188 controls, and two common polymorphisms Thr6Lys and Val81Ile. 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 to obese controls, 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 to wildtype 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, where heterozygotes had an intermediate phenotype compared to homozygotes.

Conclusion: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.

CiteULike

Del.icio.us

Digg

Reddit

Technorati