The Common −866 G/A Polymorphism in the Promoter of Uncoupling Protein 2 Is Associated With Increased Carbohydrate and Decreased Lipid Oxidation in Juvenile Obesity

Uncoupling protein (UCP) 2 is a member of the mitochondrial transporter superfamily that uncouples proton entry in the mitochondrial matrix from ATP synthesis. Although its physiological role remains to be established, UCP2 is considered a candidate gene for association with energy metabolism and obesity. A common promoter polymorphism, -866 G/A, has been associated with increased UCP2 gene expression and middle-aged adult obesity. In fact, our analysis of 296 juvenile obese and 568 nonobese control subjects revealed no difference in the prevalence of this polymorphism. Insulin and glucose response to oral glucose was comparable across the -866 genotypes. Metabolic studies in 147 of these juvenile obese subjects showed that homozygosity for the UCP2 promoter variant A was associated with important changes in energy metabolism compared with other genotypes, i.e., a 34% increase of carbohydrate oxidation (94 +/- 10 vs. 70 +/- 3 mg.min(-1).m(-2), P = 0.004) and a 23% decrease of lipid oxidation (26 +/- 3 vs. 34 +/- 1 mg.min(-1).m(-2), P = 0.03). Therefore, the juvenile obese subjects who are homozygous for the A variant have an increased ratio (3.6 +/- 1.2) of calories derived from carbohydrates to those from lipids compared with G/A or G/G obese children (1.4 +/- 0.2, P = 0.003), suggesting a role for UCP2 in the partitioning of metabolic fuels.