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

<div><p>Background</p><p>The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in <i>MC4R</i> are predominantly found in obese individuals. Though some rare variants in <i>MC4R</i> discovered in patients have defects in localization, ligand binding and signaling to cAMP, many have no recognized defects.</p><p>Subjects/Methods</p><p>In our cohort of 1433 obese subjects that underwent Roux-en-Y Gastric Bypass (RYGB) surgery, we found fifteen variants of <i>MC4R</i>. We matched rare variant carriers to patients with the <i>MC4R</i> reference alleles for gender, age, starting BMI and T2D to determine the variant effect on weight-loss post-RYGB. <i>In vitro</i>, we determined expression of mutant receptors by ELISA and western blot, and cAMP production by microscopy.</p><p>Results</p><p>While carrying a rare <i>MC4R</i> 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, <i>V95I</i>, <i>I137T</i> or <i>L250Q</i>, lost less weight after surgery. <i>In vitro</i>, 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 <i>in vitro</i> signaling and pre- or post-surgery clinical phenotype.</p><p>Conclusions</p><p>These data suggest that subtle differences in receptor signaling conferred by rare <i>MC4R</i> variants combined with additional factors predispose carriers to obesity. In the absence of complete <i>MC4R</i> 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.</p>