Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis

By virtue of its potential effects on rates of energy expenditure, uncoupli ng protein 3 (UCP3) is an obesity candidate gene. We identified nine sequen ce variants in UCP3, including Val9Met, Val102lle, Arg282Cys, and a splice site mutation in the intron between exons 6 and 7. The splice mutation resu lts in an inability to synthesize mRNA for the long isoform (UCP3L) of UCP3 . Linkage (sib pair), association, and transmission disequilibrium testing studies on 942 African-Americans did not; suggest a significant effect of U CP3 on body composition in this group. In vastus lateralis skeletal muscle of individuals homozygous for the splice mutation, no UCP3L mRNA was detect able the short isoform (UCP3S) was present in an increased amount. In this muscle, we detected no alterations of in vitro mitochondrial coupling activ ity, mitochondrial respiratory enzyme activity, or systemic oxygen consumpt ion or respiratory quotient; at rest or during exercise. These genetic and physiologic data suggest the following possibilities: UCP3S has uncoupling capabilities equivalent to UCP3L; other UCPs may compensate for a deficienc y of bioactive UCP3L; UCP3L does not function primarily as a mitochondrial uncoupling protein.