Genetic variation in uncoupling protein 3 is associated with dietary intake and body composition in females

The uncoupling proteins (UCPs) are a family of mitochondrial transport proteins that promote proton leakage across the inner mitochondrial membrane, uncoupling oxidative phosphorylation from adenosine triphosphate (ATP) production and releasing energy as heat. Variation in these genes may disrupt biochemical pathways influencing thermogenesis, energy metabolism, and fuel substrate partitioning and oxidation, which may in turn predispose to obesity. We genotyped polymorphisms in UCP2 and UCP3 in a sample of nondiabetic participants (n = 722) of the San Luis Valley Diabetes Study (SLVDS) and found female-specific associations between UCP3 polymorphisms and measures of dietary intake and body composition. The UCP3-5 variant was statistically significantly associated with total caloric intake (P =.012), fat intake (P =.011), fat mass (P =.004), and lean mass (P =.013), with the C allele corresponding to higher dietary intake and lower fat mass and lean mass. The UCP3p-55 and the UCP3-3 polymorphisms, which were in high linkage disequilibrium (D' = 0.9776), showed similar patterns of association with total caloric intake (P =.031 and P =.042, respectively) and lean mass (P =.035 and P =.059, respectively), with the rare alleles corresponding to higher total intake and lean mass. No statistically significant associations were detected between the outcome variables and polymorphisms in UCP2. Two-way analysis of covariance (ANCOVA), used to evaluate the multi-locus effects and interactions between UCP3-5 and UCP3p-55, showed association with the main effect terms, but no evidence for statistically significant interaction between UCP3-5 and UCP3p-55 in regard to dietary intake. The UCP3-5 polymorphism was the only statistically significant genetic predictor of fat mass. The lean mass model showed no statistically significant association with either UCP3 variant. These results support a role for UCP3 in fuel substrate management and energy metabolism, which may influence body weight regulation.