The Val103Ile polymorphism of melanocortin-4 receptor regulates energy expenditure and weight gain.

OBJECTIVE: The melanocortin-4 receptor (MC4R) regulates energy intake. On the basis of animal studies, it may also regulate energy expenditure. RESEARCH METHODS AND PROCEDURES: The effect of the Val103Ile polymorphism of the MC4R gene on energy metabolism was studied in 229 middle-aged nondiabetic subjects (Group 1, age 51.2 +/- 9.8 years, BMI 26.8 +/- 4.5 kg/m2) and on weight gain in 1013 elderly subjects (Group 2, age 69.9 +/- 2.9 years, BMI 27.4 +/- 4.1 kg/m2) during a 3.5-year follow-up study. In Group 1, insulin sensitivity, energy expenditure, and substrate oxidation were measured with the hyperinsulinemic euglycemic clamp combined with indirect calorimetry.
RESULTS: In Group 1, the Val103Ile genotype was associated with high rates of energy expenditure (63.42 +/- 13.40 in eight subjects with the Val103Ile genotype vs. 59.86 +/- 7.33 J/kg per minute in 221 subjects with the Val103Val genotype, p = 0.007), high rates of glucose oxidation (8.90 +/- 6.15 vs. 6.07 +/- 4.38 micromol/kg per minute, p = 0.020), and low levels of free fatty acids (0.45 +/- 0.18 vs. 0.56 +/- 0.23 mM, p = 0.029) in the fasting state, and with high rates of glucose oxidation during the clamp (18.88 +/- 4.63 vs. 17.60 +/- 3.24 micromol/kg per minute, p = 0.031). In Group 2, the 103Ile allele was associated with an increase in weight gain during the follow-up (0.78 +/- 3.98 vs. -0.82 +/- 3.98 kg, p = 0.038). DISCUSSION: The Val103Ile polymorphism of the MC4R gene is associated with energy expenditure in humans. Furthermore, it may associate with glucose oxidation, free fatty acid levels, and weight gain. Copyright 2004 NAASO