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 201obese 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-MC3Rmutations 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. Diabetes 56:2622-2630, 2007 T he melanocortin pathway mediates leptin action and regulates energy balance by inhibiting feeding, increasing energy expenditure, and reducing energy storage. The melanocyte-stimulating hormone (MSH) is the principal agonist of the neuronal melanocortin receptors melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R), both of which are critical for weight regulation in rodents (1-3).MC3R is a seven-transmembrane G-protein-coupled receptor (4) expressed in hypothalamic nuclei known to regulate energy homeostasis. It exhibits a more restricted distribution than MC4R in the central nervous system (5) and has a dominant role in inhibition of energy storage (1,2). Mc3r Ϫ/Ϫ mice homozygous for knockout mutations of MC3R gene had increased body fat (1,2) not caused by increased food intake but by increased feed efficiency. The Mc3r Ϫ/Ϫ mice were hypophagic with hyperleptinemia compared with wild-type littermates (2). Mice lacking both MC3R and MC4R have exacerbated obesity, which supports the notion that both are important and nonredundant (2).MC4R mutations causing human obesity are well described (6,7), but the search for human MC3R mutations has been largely unsuccessful (8 -12). We previously d...

Insulin resistance, truncal adiposity, and physical inactivity are major determinants potentially modifiable to reduce risk of nonalcoholic fatty liver disease. Increasing physical activity levels were associated with decreasing insulin resistance and transaminases, despite lack of correlation with waist-hip ratio, which supports the direct benefit of regular physical activity in preventing nonalcoholic fatty liver disease.

MC4R mutations result in an autosomal codominant form of obesity with variable expressivity. MC4R deficiency is not as common among the obese children in this study compared to other populations. Family studies revealed that adults heterozygous for the mutations were less obese compared to the children. We hypothesize that this may be due to amelioration of phenotype severity with age, genetic anticipation or difference in exposure to modifying factors at critical stages of childhood such as the environment.