Dietary Protein Modifies the Effect of the MC4R Genotype on 2-Year Changes in Appetite and Food Craving: The POUNDS Lost Trial

Abstract

Background: The melanocortin-4 receptor (MC4R) plays a pivotal role in the regulation of appetite and eating behavior. Variants in the MC4R gene have been related to appetite and obesity.Objective: We aimed to examine whether weight-loss diets modified the effect of the "obesity-predisposing" MC4R genotype on appetite-related measures in a randomized controlled trial.Methods: A total of 811 overweight and obese subjects [25 ≤ body mass index (BMI; kg/m²) ≤ 40] aged 30-70 y were included in the 2-y POUNDS Lost (Preventing Overweight Using Novel Dietary Strategies) trial. We genotyped MC4R rs7227255 in 735 overweight adults and assessed appetite-related characteristics, including craving, fullness, hunger, and prospective consumption, as well as a composite appetite score. We examined the effects of the genotype-by-weight-loss diet intervention interaction on appetite variables by using general linear models in both the whole population and in white participants only.Results: We found that dietary protein intake (low compared with high: 15% of energy compared with 25% of energy, respectively) significantly modified MC4R genetic effects on changes in appetite score and craving (P-interaction = 0.03 and 0.02, respectively) at 2 y, after adjustment for age, sex, ethnicity, baseline BMI, weight change, and baseline perspective phenotype. The obesity-predisposing A allele was associated with a greater increase in overall appetite score (β = 0.10, P = 0.05) and craving (β = 0.13, P = 0.008) compared with the non-A allele among participants who consumed a high-protein diet. MC4R genotype did not modify the effects of fat or carbohydrate intakes on appetite measures. Similar interaction patterns were observed in whites.Conclusion: Our data suggest that individuals with the MC4R rs7227255 A allele rather than the non-A allele might experience greater increases in appetite and food craving when consuming a high-protein weight-loss diet. This trial was registered at clinicaltrials.gov as NCT00072995.

Keywords: MC4R genotype; appetite; food craving; gene-diet interaction; protein diet; weight-loss trial.

FIGURE 1

Effect of the MC4R rs72272552 genotype on 24-mo changes in appetite measures in response to protein intake in overweight and obese adults. Values are means ± SEs. P values were adjusted for age, sex, ethnicity, baseline BMI, weight loss, and baseline values for respective outcomes. Data included 333 (GG) and 40 (AA+GA) overweight and obese adults in the low-protein (15% of energy) diet group and 330 (GG) and 32 (AA+GA) overweight and obese adults in the high-protein (25% of energy) diet group at 24 mo (n = 735). Appetite score (A) (“0 = very weak” to “100 = very strong”) = [craving + (100 − fullness) + prospective consumption + hunger]/4. The question: “How strong is your desire to eat? (‘0 = very weak’ to ‘100 = very strong’)” was used to assess craving (B). MC4R, melanocortin-4 receptor; % E, percentage of energy.

FIGURE 2

Genotype effect of the MC4R rs7227255 on trajectory of changes in craving in the high-protein (A) and the low-protein (B) diet groups over 24 mo in overweight and obese adults. Linear mixed models were used to test genetic associations with the trajectory of changes in appetite-related measures according to diet groups. Time was treated as a repeated measurement factor, and genotype × time interaction terms were included in the mixed models. Values are means ± SEs. P values were adjusted for age, sex, ethnicity, baseline BMI, and baseline values for craving. Data included 408, 324, and 235 overweight and obese adults in the low-protein (15% of energy) diet group and 403, 332, and 259 overweight and obese adults in the high-protein (25% of energy) diet group for craving at baseline and at 6 and 24 mo, respectively. The question “How strong is your desire to eat? (‘0 = very weak’ to ‘100 = very strong’)” was used to assess craving. MC4R, melanocortin-4 receptor.