Long-Term Weight-Loss in Gastric Bypass Patients Carrying Melanocortin 4 Receptor Variants

BackgroundThe 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/MethodsIn 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.ResultsWhile 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.ConclusionsThese 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.背景 黑皮质素4受体（melanocortin 4 receptor, MC4R）对进食与饱腹感具有关键调控作用。MC4R的罕见变异主要见于肥胖人群。尽管已在患者中发现的部分MC4R罕见变异存在定位异常、配体结合缺陷以及环磷酸腺苷（cAMP）信号通路异常等问题，但仍有诸多变异未被发现明确缺陷。 研究对象与方法 本研究纳入1433例行鲁比尼-Y型胃旁路术（Roux-en-Y Gastric Bypass, RYGB）的肥胖受试者队列，共检出15种MC4R变异。我们以性别、年龄、初始体质量指数（BMI）以及2型糖尿病（T2D）为匹配因素，将罕见变异携带者与携带MC4R参考等位基因的患者进行匹配，以明确变异对RYGB术后减重效果的影响。体外实验中，我们通过酶联免疫吸附测定（ELISA）与蛋白质印迹法（western blot）检测突变受体的表达水平，并通过显微镜观察环磷酸腺苷（cAMP）的生成情况。 结果 尽管携带罕见MC4R等位基因与肥胖存在关联，但罕见变异携带者在RYGB术后的减重效果与非携带者相当。然而，携带V95I、I137T或L250Q这3种变异的受试者术后减重幅度更低。体外实验显示，R305Q突变会导致细胞表面表达缺陷，而仅I137T与C326R突变出现环磷酸腺苷信号通路受损的情况。尽管存在上述表观差异，但体外信号通路检测结果与手术前后的临床表型并无相关性。 结论 上述结果表明，MC4R罕见变异所引发的受体信号通路细微差异，结合其他易感因素，会使携带者更容易出现肥胖。在MC4R未完全缺失的情况下，减重手术的强效减重效应可抵消这些细微缺陷。对于肥胖这类复杂疾病，存在累积效应的细微缺陷相关遗传变异，可通过恰当的临床干预得到逆转。