Melanocortin-4 Receptor Polymorphism and Energy Metabolism in Childhood Obesity

目的：食物摄入增加和能量消耗减少是导致肥胖的主要原因。儿童肥胖比成人肥胖具有更多的遗传背景，究竟哪一种是导致儿童肥胖的主要原因仍存在争议。本研究比较了代表能量消耗的β_3-肾上腺素能受体（β_3AR）和代表食物摄入的黑素皮质素-4受体（MC4R）的基因型与儿童肥胖表型的关系。受试者和方法：35名肥胖但健康的儿童（22名男孩和13名女孩）在知情同意的情况下，超重超过其性别和身高标准体重的120%。男孩和女孩都来了；年龄分别为10.2±3.4、11.6±5.0，身高分别为144.3±19.4、143.7±15.5 cm，体重分别为59.0±20.9、59.4±21.1 kg， BMI分别为27.4±4.2、27.7±5.4。利用外周血淋巴细胞来源的DNA，采用精确点pcr法和直接测序法检测了β 3ar的Trp64Arg多态性，采用MC4R编码区的更多序列进行突变筛选。采用非参数方法进行统计分析。结果与讨论：野生型纯合子24例（68.6%），野生型和Trp64Arg等位基因均为杂合子11例（31.4%）。Trp64Arg等位基因的频率为0.16，与东亚和日本普通人群的频率0.16相当。WW组与WR组在身高、体重、BMI、丙氨酸转氨酶（ALT）、总胆固醇、高密度脂蛋白胆固醇（hdl -胆固醇）和瘦素水平方面均无差异，但WW组身高标准差（SD）显著（p<0.05）升高。这些发现表明，Trp64Arg等位基因对儿童肥胖的影响较小，而儿童肥胖的特征是身材高大。此外，研究组自肥胖发病以来的最大体重增加为9.3±4.3 kg/年，大大大于Trp64Arg突变减少能量消耗所估计的2.7 ~ 2.8kg/年体重增加。这些结果可能提示，在儿童肥胖的病因方面，增加的食物摄入比减少的能量消耗占主导地位。关于MC4R的作用，肥胖被试中未发现MC4R突变的事实促使我们研究MC4R以外的其他因素，而在肥胖被试中发现MC4R突变的事实促使我们研究MC4R以外调节食欲和食物摄入的其他因素作为儿童肥胖的罪魁祸首。少

AIM : Both increased food intake and decreased energy expenditure are principal causes for the development of obesity. It is still controversial which is the predominant cause of the childhood obesity that has more genetic background than the adult obesity. In this study, genotypes of both β_3-adrenergic receptor (β_3AR) representing energy expenditure and melanocortin-4 receptor (MC4R) representing food intake were compared with phenotype of the childhood obesity.SUBJECTS & METHODS : Thirty-five obese but otherwise healthy children (22 boys and 13 girls) who had shown overweight of more than 120% of the standard weight for their sex and height were enrolled in the study with informed consent. The boys and the girls showed ; age 10.2±3.4, 11.6±5.0 y/o, height 144.3±19.4, 143.7±15.5 cm, weight 59.0±20.9, 59.4±21.1 kg, BMI 27.4±4.2, 27.7±5.4, respectively. Using peripheral lymphocyte derived DNA, a Trp64Arg polymorphism for β_3AR was detected by the pinpoint-PCR method and the direct seq … More uencing of MC4R coding region was employed for mutation screening. Statistical analysis was performed by the non-parametric method.RESULTS & DISCUSSION : Twenty-four of the 35 cases (68.6%) were homozygous (WW) for the wild type, 11 cases (31.4%) were heterozygous (WR) for both the wild and Trp64Arg alleles. Frequency of the Trp64Arg allele was 0.16, which was comparable to 0.16 the frequency seen in the general population in the eastern Asia and in Japan. Comparison between the WW and the WR groups made no difference in height, weight, BMI, alanine aminotransferase (ALT), total cholesterol, HDL-cholesterol and leptin level except a significantly (p<0.05) higher standard deviation (SD) of the body height in the WW group. These findings imply the Trp64Arg allele is less responsible for the development of childhood obesity for which tall stature is the characteristic feature. Furthermore, maximal weight gain since the onset of obesity was 9.3±4.3 kg/year in the study group, which was considerably greater than 2.7〜2.8kg/year the estimated weight gain through the decreased energy expenditure by the Trp64Arg mutation. These results may be suggestive to the predominance of the increased food intake over the decreased energy expenditure in regard to the etiology of the childhood obesity. As for the role of the MC4R, the fact that no mutation was found on MC4R in the obese subjects prompts us to investigate other factors than MC4R that would mutation was found on MC4R in the obese subjects prompts us to investigate other factors than MC4R that would regulate appetite and food intake as a candidate for the culprit of childhood obesity. Less