Chagnon Y C, Chen W J, Pérusse L, Chagnon M, Nadeau A, Wilkison W O, Bouchard C
Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada.
Mol Med. 1997 Oct;3(10):663-73.
The agouti yellow mouse shows adult onset of moderate obesity and diabetes. A depressed basal lipolytic rate in adipocytes or a decreased adrenergic tone arising from antagonizing alpha-melanocyte-stimulating hormone (MSH) activation of melanocortin receptors (MCR) could be at the origin of the obesity phenotype.
MCR 4 and 5 (MC4R, MC5R) genes were studied in the Québec Family Study. Sequence variations were detected by Southern blot probing of restricted genomic DNA, and mRNA tissue expression was detected by RT-PCR. Subjects with a wide range of weight were used for single-point sib-pair linkage studies (maximum of 289 sibships from 124 nuclear families). Analysis of variance across genotypes in unrelated males (n = 143) and females (n = 156) was also undertaken. Body mass index (BMI), sum of six skin-folds (SF6), fat mass (FM), percent body fat (%FAT), respiratory quotient (RQ), resting metabolic rate (RMR), fasting glucose and insulin, and glucose and insulin area during an oral glucose tolerance test were analyzed.
MC4R showed polymorphism with NcoI, and MC5R, with PstI and PvuII, with a heterozygosity of 0.38, 0.10, and 0.20, respectively. Linkages were observed between MC5R and BMI (p = 0.001), SF6 (p = 0.005), FM (p = 0.001), and RMR (p = 0.002), whereas associations were observed in females between MC5R and BMI (p = 0.003), and between MC4R and FM (p = 0.002) and %FAT (p = 0.004). After correction for multiple tests, these p values are lowered by one tenth. MC4R and MC5R mRNAs have been detected in brain, adipose tissue, and skeletal muscle.
MC4R and MC5R exhibit evidence of linkage or association with obesity phenotypes, but this evidence is strongest for MC5R.
刺豚鼠黄小鼠成年后会出现中度肥胖和糖尿病。脂肪细胞基础脂解率降低或因拮抗黑素皮质素受体（MCR）的α - 黑素细胞刺激激素（MSH）激活而导致的肾上腺素能张力降低可能是肥胖表型的根源。
在魁北克家族研究中对MCR 4和5（MC4R、MC5R）基因进行了研究。通过对限制性基因组DNA进行Southern印迹杂交检测序列变异，通过逆转录聚合酶链反应（RT-PCR）检测mRNA的组织表达。选取体重范围广泛的受试者进行单点同胞对连锁研究（来自124个核心家庭的最多289个同胞对）。还对无关男性（n = 143）和女性（n = 156）的不同基因型进行了方差分析。分析了体重指数（BMI）、六项皮肤褶厚度之和（SF6）、脂肪量（FM）、体脂百分比（%FAT）、呼吸商（RQ）、静息代谢率（RMR）、空腹血糖和胰岛素以及口服葡萄糖耐量试验期间的葡萄糖和胰岛素曲线下面积。
MC4R显示出NcoI多态性，MC5R显示出PstI和PvuII多态性，杂合度分别为0.38、0.10和0.20。观察到MC5R与BMI（p = 0.001）、SF6（p = 0.005）、FM（p = 0.001）和RMR（p = 0.002）之间存在连锁关系，而在女性中观察到MC5R与BMI之间（p = 0.003）、MC4R与FM之间（p = 0.002）以及MC4R与%FAT之间（p = 0.00）存在关联。经过多重检验校正后，这些p值降低了十分之一。在脑、脂肪组织和骨骼肌中检测到了MC4R和MC5R的mRNA。
MC4R和MC5R表现出与肥胖表型存在连锁或关联的证据，但MC5R的证据最为有力。
