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Updated: May 1, 2026
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Published on: June 11, 2012
Long-term weight-loss in gastric bypass patients carrying melanocortin 4 receptor variants
Bryn S Moore1, Uyenlinh L Mirshahi1, Evan A Yost1
1Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.
Background:
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.
Results:
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.
Conclusions:
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.
Insights
Rare melanocortin 4 receptor (MC4R) variants are linked to obesity but do not significantly impact weight loss after gastric bypass surgery. However, specific MC4R variants showed reduced weight loss, suggesting complex genetic contributions to obesity.
Area of Science:
- Genetics
- Endocrinology
- Metabolic Disorders
Background:
- The melanocortin 4 receptor (MC4R) plays a crucial role in regulating appetite and body weight.
- Rare MC4R variants are frequently identified in individuals with obesity.
- While some MC4R variants exhibit functional defects, many do not show apparent abnormalities in vitro.
Purpose of the Study:
- To investigate the impact of rare MC4R variants on weight loss following Roux-en-Y Gastric Bypass (RYGB) surgery.
- To correlate in vitro functional assessments of MC4R variants with clinical outcomes in obese patients.
Main Methods:
- A cohort of 1433 obese subjects undergoing RYGB was analyzed for MC4R variants.
- Rare variant carriers were matched with non-carriers based on clinical factors (age, BMI, T2D status).
- In vitro studies assessed receptor expression, cell surface localization, and cAMP signaling for identified MC4R variants.
Main Results:
- Carriage of rare MC4R variants was associated with obesity but did not significantly alter overall weight loss post-RYGB compared to non-carriers.
- Three specific variants (V95I, I137T, L250Q) were associated with reduced weight loss after RYGB.
- In vitro analyses revealed defects in cell surface expression (R305Q) and cAMP signaling (I137T, C326R) for some variants, but these did not correlate with clinical weight loss outcomes.
Conclusions:
- Subtle defects in MC4R signaling, potentially influenced by other genetic and environmental factors, may contribute to obesity predisposition.
- The significant weight-reducing effects of bariatric surgery can overcome the impact of many MC4R variants, except in cases of complete receptor deficiency.
- Complex genetic architectures in obesity mean that variants with minor effects can be compensated for by effective clinical interventions.
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