Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity

Abstract

In contrast to the melanocortin 4 receptor, the possible role of the melanocortin 3 receptor (MC3R) in regulating body weight is still debated. We have previously reported three mutations in the MC3R gene showing association with human obesity, but these results were not confirmed in a study of severe obese North American adults. In this study, we evaluated the entire coding region of MC3R in 839 severely obese subjects and 967 lean controls of Italian and French origin. In vitro functional analysis of the mutations detected was also performed. The total prevalence of rare MC3R variants was not significantly different in obese subjects when compared with controls (P= 0.18). However, the prevalence of mutations with functional alterations was significantly higher in the obese group (P= 0.022). In conclusions, the results of this large study demonstrate that in the populations studied functionally significant MC3R variants are associated with obesity supporting the current hypothesis that rare variants might have a stronger impact on the individual susceptibility to gain weight. They also underline the importance of detailed in vitro functional studies in order to prove the pathogenic effect of such variants. Further investigations in larger cohorts will be needed in order to define the specific phenotypic characteristics potentially correlated with reduced MC3R signalling.

Programming towards Childhood Obesity

“…Common variants are associated with pediatric obesity due to a greater energy intake but not diminished energy expenditure [28]. Recently, several rare mutations with functional alterations proved to be associated with severe obesity in children [29,30]. Further epidemiological and functional research regarding the importance of MC3R mutations would shed light on the importance of MC3R mutants and potential combined effects with other genes in severe early-onset obesity.…”

Effect of the melanocortin-3 receptor Thr6Lys and Val81Ile genetic variants on body composition and substrate oxidation in Chilean obese children

“…Butler et al [2] and Chen et al [5] described that Mc3r-deficient mice exhibited mild hypophagia, hyperleptinemia, reduced linear growth, reduction in locomotor activity (running wheel), and 50-60% increase in adipose mass compared to wild-type mice. Also, a number of epidemiologic studies in humans have focused on the effect of MC3R genetic variants in obesity and obesity-related phenotypes [14,24]. Feng et al showed that the MC3R gene with 6Lys and 81Ile alleles encodes for a protein with reduced receptor activity, lower binding affinity and decreased protein expression compared to receptors with 6Thr and 81Val alleles.…”

Melanocortin receptors and their accessory proteins

“…These observations have led to the suggestion that MC3R is involved in coordinating appropriate homeostatic metabolic and behavioral responses to nutrient cues. Interestingly, despite focused investigation, rare variants at the MC3R locus have not been definitively associated with monogenic obesity in humans (Seng Lee et al, 2007;Mencarelli et al, 2011).…”