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J Nutr. 2017 Mar;147(3):439-444. doi: 10.3945/jn.116.242958. Epub 2017 Feb 1.

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

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Epidemiology Domain, Saw Swee Hock School of Public Health, and.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
Nutritional Epidemiology Program, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
Pennington Biomedical Research Center of the Louisiana State University System, Baton Rouge, LA.
School of Medicine, Tufts University, Boston, MA.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA;
Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA; and.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.


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 as NCT00072995.


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

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