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

Abstract

Mice genetically deficient in the melanocortin-3 receptor gene are characterized by normal body weight, increased body fat, mild hypophagia, reduced locomotor activity, and increased respiratory quotient compared with wild-type mice. In humans, the 6Lys-81Ile haplotype of melanocortin-3 receptor (MC3R) gene has been associated with childhood obesity, higher body fat percentage, and reduced fat oxidation compared to non-carriers. The aim of this study was to evaluate the association between MC3R 6Lys-81Ile haplotype with body composition and substrate oxidation in response to moderate exercise in obese children. Eight Chilean obese children (aged 8-12) carriers of MC3R 6Lys-81Ile haplotype were compared with eight age-gender-matched obese non-carriers. Children were identified through a previous cross-sectional study on genetic determinants of childhood obesity (n = 229). Genotypes for MC3R Thr6Lys and Val81Ile were determined by polymerase chain reaction-restriction fragment length polymorphism. Body composition was assessed by the four-compartment model (dual-energy X-ray absorptiometry, total body water by the deuterium dilution technique, and total fat mass by air-displacement plethysmography). Substrate oxidation was assessed by indirect calorimetry in response to moderate exercise (60% VO(2 max)). Wilcoxon matched-pairs test was used to compare quantitative variables. No significant differences among carriers and non-carriers were found in anthropometrical and body composition measurements. The Carriers of the 6Lys-81Ile haplotype showed higher respiratory quotient (p = 0.06) and a significantly higher glucose oxidation (p = 0.01) compared with non-carriers after standardization for fat-free mass. Our results are consistent with a possible participation of MC3R 6Lys-81Ile variants in glucose oxidation in response to moderate exercise.

Melanocortin 3 Receptor Has a 5′ Exon That Directs Translation of Apically Localized Protein From the Second In-Frame ATG

“…Like MC4R, melanocortin-3 receptor (MC3R) has been found to play a role in energy balance. Previous studies have reported several common and rare variants in MC3R that inconsistently associate with obesity (11)(12)(13)(14)(15)(16)(17). MC3R is thought to coordinate feeding-related behaviors and glucose metabolism through the action of the melanocortin signaling pathway in the brain (18 -21).…”

Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity

“…Consistent with knockout mouse models [36], glucose oxidation was increased and lipid oxidation decreased in T6K+V81I carriers [69, 71]. T6K+V81I variant carriers may also have greater difficulty losing weight, consistent with the “metabolically thrifty” phenotype [72, 73].…”

“…Two studies found no differences in energy intake between genotypes [52, 59], and in a third, the association no longer was significant when the data were examined separately by race [64]. Additionally, no significant differences were seen in resting energy expenditure [59, 64, 69], total energy expenditure [64, 71], respiratory quotient [59, 64], or physical activity [52, 64, 71, 72]. …”