Moore Bryn S, Mirshahi Uyenlinh L, Yost Evan A, Stepanchick Ann N, Bedrin Michael D, Styer Amanda M, Jackson Kathryn K, Still Christopher D, Breitwieser Gerda E, Gerhard Glenn S, Carey David J, Mirshahi Tooraj
Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.
Geisinger Obesity Institute, Geisinger Clinic, Danville, Pennsylvania, United States of America.
PLoS One. 2014 Apr 4;9(4):e93629. doi: 10.1371/journal.pone.0093629. eCollection 2014.
The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in MC4R are predominantly found in obese individuals. Though some rare variants in MC4R discovered in patients have defects in localization, ligand binding and signaling to cAMP, many have no recognized defects.
SUBJECTS/METHODS: In our cohort of 1433 obese subjects that underwent Roux-en-Y Gastric Bypass (RYGB) surgery, we found fifteen variants of MC4R. We matched rare variant carriers to patients with the MC4R reference alleles for gender, age, starting BMI and T2D to determine the variant effect on weight-loss post-RYGB. In vitro, we determined expression of mutant receptors by ELISA and western blot, and cAMP production by microscopy.
While carrying a rare MC4R allele is associated with obesity, carriers of rare variants exhibited comparable weight-loss after RYGB to non-carriers. However, subjects carrying three of these variants, V95I, I137T or L250Q, lost less weight after surgery. In vitro, the R305Q mutation caused a defect in cell surface expression while only the I137T and C326R mutations showed impaired cAMP signaling. Despite these apparent differences, there was no correlation between in vitro signaling and pre- or post-surgery clinical phenotype.
These data suggest that subtle differences in receptor signaling conferred by rare MC4R variants combined with additional factors predispose carriers to obesity. In the absence of complete MC4R deficiency, these differences can be overcome by the powerful weight-reducing effects of bariatric surgery. In a complex disorder such as obesity, genetic variants that cause subtle defects that have cumulative effects can be overcome after appropriate clinical intervention.
黑皮质素4受体（MC4R）对进食和饱腹感起着关键的调节作用。MC4R的罕见变异主要在肥胖个体中发现。尽管在患者中发现的一些MC4R罕见变异在定位、配体结合及向环磷酸腺苷（cAMP）的信号传导方面存在缺陷，但许多变异并无公认的缺陷。
研究对象/方法：在我们对1433例接受Roux-en-Y胃旁路术（RYGB）的肥胖受试者的队列研究中，我们发现了15种MC4R变异。我们将罕见变异携带者与具有MC4R参考等位基因的患者在性别、年龄、初始体重指数（BMI）和2型糖尿病方面进行匹配，以确定该变异对RYGB术后体重减轻的影响。在体外，我们通过酶联免疫吸附测定（ELISA）和蛋白质印迹法确定突变受体的表达，并通过显微镜观察法测定cAMP的产生。
虽然携带罕见的MC4R等位基因与肥胖有关，但罕见变异携带者在RYGB术后的体重减轻情况与非携带者相当。然而，携带其中三种变异（V95I、I137T或L250Q）的受试者术后体重减轻较少。在体外，R305Q突变导致细胞表面表达缺陷，而只有I137T和C326R突变显示出cAMP信号传导受损。尽管存在这些明显差异，但体外信号传导与手术前后的临床表型之间并无相关性。
这些数据表明，罕见的MC4R变异所赋予的受体信号传导的细微差异，与其他因素共同使携带者易患肥胖症。在不存在完全的MC4R缺陷的情况下，这些差异可通过减肥手术强大的减重效果得以克服。在肥胖这种复杂疾病中，导致具有累积效应的细微缺陷的基因变异，在适当的临床干预后是可以被克服的。
