The MC4R(I251L) allele is associated with better metabolic status and more weight loss after gastric bypass surgery

Abstract

Context: Factors that influence long-term weight loss after Roux-en Y gastric bypass (RYGB) surgeries are poorly defined. The melanocortin system plays an important role in regulating energy homeostasis, satiety, and glucose metabolism. Variations of the MC4R comprise the most prevalent monogenetic obesity disorder.

Objective: The objective of the study was to examine the role of MC4R variants and diabetic status in long-term weight loss after RYGB.

Participants and methods: In 1433 extremely obese patients who underwent RYGB, we sequenced for genetic variants of MC4R. We examined the MC4R genotype and its relationship with weight loss profile, and clinical phenotypes accumulated during a 48-month period before and after surgery.

Results: We found 80 subjects with rare and common variants of MC4R in the RYGB cohort. Among these, 26 and 36 patients carry the I251L and V103I variants, respectively. These common alleles are negatively associated with obesity. Remarkably, after the 12-month presurgery caloric restriction and RYGB, I251L allele carriers lost 9% more weight (∼9 kg) compared with the noncarriers, continued rapid weight loss longer, regained less weight, and had lower presurgery homeostatic model assessment for insulin resistance values. Normoglycemic, I251L allele carriers lost more weight compared with their diabetic and prediabetic counterparts and maintained their weight loss. Among noncarriers, normoglycemic individuals initially lost more weight compared with dysglycemics, but this difference was not maintained in the long term.

Conclusions: Individuals carrying the I251L common allele are predisposed to better clinical outcome, reduced risk of type 2 diabetes, and better weight loss during diet and surgical interventions. Diabetic status has only a small, short-term effect on weight loss after RYGB.

Fig. 1.

Weight loss in patients undergoing RYGB stratified by MC4R genotype. Weight at the time of surgery for each patient was set at 100%, and weights at other times are expressed accordingly. Individual points represent the mean percentage weight at surgery for patients for whom data were collected at the given time point. Solid lines represent the fitted curves. The dashed lines and hash marks represent 95% confidence intervals. A, Hill plot of weight loss data expressed as percentage of weight at surgery for 12 months before surgery up to 36 months after surgery. B, Weight loss 12 months preceding surgery. Dietary restriction during this period resulted in weight loss in patients in all groups, with the I251L carriers losing more weight. C, Weight loss in the 13 months immediately after surgery. The strong effects of surgery resulted in rapid weight loss; however, the response in the I251L allele carriers appears to be slightly faster. D, Because the Hill plot does not reflect the rebound from maximal weight loss, the weight loss from weight nadir out to 36 months was fitted using linear regression. I251L allele carriers showed a slight negative slope, indicating that they continued to lose weight during this period.

Fig. 2.

Presurgery HOMA1_IR values of reference and I251L allele carriers. HOMA_IR values were calculated with those taking any medications for T2D excluded from analysis (reference, n = 598; I251L, n = 15; **, P = 0.01, unpaired t test using Welch's correction for unequal variances).

Fig. 3.

Post-RYGB weight loss stratified by genotype and diabetic status. Weight loss reported as percentage weight at surgery is shown for the different groups. Longitudinal weight loss for noncarriers (A) and I251L carriers (B), divided into dysglycemic [diabetic (D)] and normoglycemic [nondiabetic (N)] subgroups. The nondiabetic I251L carriers lost significantly more weight compared with all other groups. Summary of the values and statistics for the different groups are presented in Table 2.