Effect of the Melanocortin 4-Receptor Ile269Asn Mutation on Weight Loss Response to Dietary, Phentermine and Bariatric Surgery Interventions

Abstract

The loss of function melanocortin 4-receptor (MC4R) Ile269Asn mutation has been proposed as one of the most important genetic contributors to obesity in the Mexican population. However, whether patients bearing this mutation respond differently to weight loss treatments is unknown. We tested the association of this mutation with obesity in 1683 Mexican adults, and compared the response of mutation carriers and non-carriers to three different weight loss interventions: dietary restriction intervention, phentermine 30 mg/day treatment, and Roux-en-Y gastric bypass (RYGB) surgery. The Ile269Asn mutation was associated with obesity [OR = 3.8, 95% CI (1.5–9.7), p = 0.005]. Regarding interventions, in the dietary restriction group only two patients were MC4R Ile269Asn mutation carriers. After 1 month of treatment, both mutation carriers lost weight: −4.0 kg (−2.9%) in patient 1, and −1.8 kg (−1.5%) in patient 2; similar to the mean weight loss observed in six non-carrier subjects (−2.9 kg; −2.8%). Phentermine treatment produced similar weight loss in six carriers (−12.7 kg; 15.5%) and 18 non-carriers (−11.3 kg; 13.6%) after 6 months of pharmacological treatment. RYGB also caused similar weight loss in seven carriers (29.9%) and 24 non-carriers (27.8%), 6 months after surgery. Our findings suggest that while the presence of a single MC4R loss of function Ile269Asn allele significantly increases obesity risk, the presence of at least one functional MC4R allele seems sufficient to allow short-term weight loss in response to dietary restriction, phentermine and RYGB. Thus, these three different interventions may be useful for the short-term treatment of obesity in MC4R Ile269Asn mutation carriers.

Mutations in the leptin‐melanocortin pathway and weight loss after bariatric surgery: a systematic review and meta‐analysis

“…Censani et al, and Salazar-Valencia et al [5,6,31] did not show a relationship between mutations of the leptin-melanocortin pathway genes and the extent of weight loss within 1 year after surgery in Caucasian and Latino patients, which was consistent with the results of our analysis.…”

“…After grouping all research results based on follow‐up time, we found that this controversy probably arose from the results of a weight‐tracking follow‐up time within 1 year after surgery. The results of Cooiman et al, Censani et al, and Salazar‐Valencia et al [5, 6, 31] did not show a relationship between mutations of the leptin‐melanocortin pathway genes and the extent of weight loss within 1 year after surgery in Caucasian and Latino patients, which was consistent with the results of our analysis.…”

“…As basic research has shown, genetic variants in the leptin-melanocortin pathway may play a central role in controlling feeding behavior [32], and they are likely to influence the outcome of bariatric surgery. However, the effect of genetic variants in the leptin- been inconsistent [28][29][30][31].…”

“…As basic research has shown, genetic variants in the leptin‐melanocortin pathway may play a central role in controlling feeding behavior [32], and they are likely to influence the outcome of bariatric surgery. However, the effect of genetic variants in the leptin‐melanocortin pathway on weight‐loss outcomes during bariatric surgery remains partly controversial, and the results across studies have been inconsistent [28–31].…”