Melanocortin-4 Receptor Polymorphism and Energy Metabolism in Childhood Obesity

目的：食物摄入量增加和能量消耗减少都是肥胖发生的主要原因。儿童肥胖症的遗传背景比成人肥胖症有更多的遗传背景，儿童肥胖症的主要原因是什么仍然存在争议。本研究比较了代表能量消耗的β_3肾上腺素能受体(β_3AR)和代表食物摄入量的黑素皮质素-4受体(MC4R)两种基因型与儿童肥胖症的表型。男、女年龄分别为10.2±3.4、11.6±5.0岁，身高分别为144.3±19.4、143.7±15.5 cm，体重分别为5 9.0±2 0.9、5 9.4±2 1.1 kg、BMI 2 7.4±4.2、2 7.7±5.4。以外周血淋巴细胞为材料，采用Pinpoint-PCR法和直接序列…法检测了TRAR_3AR的Trp64Arg基因多态性进一步利用MC4R编码区进行突变筛查。结果与讨论：35例患者中24例(68.6%)为野生型纯合子(WW)，11例(31.4%)为野生型和Trp64Arg杂合型(WR)。Trp64Arg等位基因频率为0.16，与东亚和日本人群的0.16频率相当。西药组与西药组的身高、体重、BMI、丙氨酸氨基转移酶(ALT)、总胆固醇、高密度脂蛋白胆固醇和瘦素水平比较，除西药组身高标准差(SD)显著高于西药组(P&lt；0.05)外，其余指标均无显著差异。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高。此外，研究组自肥胖开始以来的最大体重增长为9.3±4.3 kg/年，明显高于Trp64Arg突变导致的能量消耗减少所估计的体重增长2.7~2.8 kg/年。这些结果可能暗示，在儿童肥胖的病因方面，食物摄入量的增加比能量消耗的减少更具优势。至于MC4R的作用，在肥胖者中没有发现MC4R上的突变，这促使我们调查在肥胖者中发现MC4R突变的其他因素，这促使我们调查MC4R以外的其他因素，作为儿童肥胖的罪魁祸首。较少

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