Association of raised liver transaminases with physical inactivity, increased waist-hip ratio, and other metabolic morbidities in severely obese children.

OBJECTIVE: To identify factors associated with raised alanine transaminase, aspartate transaminase, and gamma-glutaryl transferase in severely obese children PATIENTS AND METHODS: In all, 201 children with early-onset obesity and greater than 140% ideal weight for height were recruited. Anthropometric and body fat measurements, fasting blood tests, and oral glucose tolerance tests were performed. RESULTS: The mean and standard deviation (SD) for age was 11.1 (3.0) years, for weight for height 170.5% (22.7%), and for percentage body fat was 40.7% (5.2%). Elevated liver transaminases were present in 53 subjects (26.4%), who were therefore at risk for nonalcoholic fatty liver disease, and was associated with male sex (odds ratio [OR] 2.144, 95% confidence interval [CI] 1.033-4.448), Chinese ethnicity (OR 2.062, 95% CI 1.038-4.096), reduced physical activity (OR 2.389, 95% CI 1.163-4.909), insulin resistance (P < 0.05), elevated triglyceride levels (P = 0.029), and increased waist-hip ratio (P = 0.005). Stepwise logistic regression analysis of the main factors as covariates revealed Chinese ethnicity, waist-hip ratio, reduced physical activity, and homeostasis model assessment index were significant predictors. Alanine transaminase/aspartate transaminase were not well correlated with percentage body fat and weight for height. Subjects with type 2 diabetes mellitus and impaired glucose tolerance were more likely to have raised hepatic transaminases (OR 6.176, 95% CI 1.326-28.754). The severity of metabolic syndrome correlated with increasing aspartate transaminase, alanine transaminase, and gamma-glutaryl transferase (P < 0.01). CONCLUSIONS: 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.

Novel melanocortin 4 receptor gene mutations in severely obese children.

OBJECTIVE: Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. The significance of MC4R mutations in Asian obese populations has not been adequately examined. The objective of this study was to determine the role of MC4R mutations in severely obese Asian children. DESIGN: We screened 227 obese local children and adolescents for MC4R gene mutations by polymerase chain reaction and direct sequencing. RESULTS: We identified three mutations in three subjects: 4 bp deletion from nucleotides 631-634 (c.631-634delCTCT), Tyr157Ser (c.470 A > C) and 1 bp deletion at nucleotide 976 (c.976delT) (1.32% of study subjects). The latter two mutations are novel. The Tyr157Ser mutation was not found in 188 non-obese controls using restriction enzyme digest analysis. In vitro transient transfection studies supported the pathogenic role of both novel mutations Tyr157Ser and c.976delT, where the signalling activities of the mutant receptors were impaired. Heterozygous MC4R mutations were associated with early-onset severe obesity, and homozygosity of the MC4R mutation Tyr157Ser resulted in morbid obesity. CONCLUSION: 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.

The role of melanocortin 3 receptor gene in childhood obesity.

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.