title: Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis.
abstract: By virtue of its potential effects on rates of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene. We identified nine sequence variants in UCP3, including Val9Met, Val102Ile, Arg282Cys, and a splice site mutation in the intron between exons 6 and 7. The splice mutation results 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 UCP3 on body composition in this group. In vastus lateralis skeletal muscle of individuals homozygous for the splice mutation, no UCP3L mRNA was detectable; the short isoform (UCP3S) was present in an increased amount. In this muscle, we detected no alterations of in vitro mitochondrial coupling activity, mitochondrial respiratory enzyme activity, or systemic oxygen consumption 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 deficiency of bioactive UCP3L; UCP3L does not function primarily as a mitochondrial uncoupling protein.
authors.affiliation: Department of Pediatrics and Medicine, Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Chung
authors.forename: A
authors.initials: A
authors.lastname: Luke
authors.forename: R S
authors.initials: RS
authors.lastname: Cooper
authors.forename: C
authors.initials: C
authors.lastname: Rotini
authors.forename: A
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: M
authors.initials: M
authors.lastname: Rosenbaum
authors.forename: M
authors.initials: M
authors.lastname: Chua
authors.forename: G
authors.initials: G
authors.lastname: Solanes
authors.forename: M
authors.initials: M
authors.lastname: Zheng
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.forename: C
authors.initials: C
authors.lastname: LeDuc
authors.forename: A
authors.initials: A
authors.lastname: Eisberg
authors.forename: F
authors.initials: F
authors.lastname: Chu
authors.forename: E
authors.initials: E
authors.lastname: Murphy
authors.forename: M
authors.initials: M
authors.lastname: Schreier
authors.forename: L
authors.initials: L
authors.lastname: Aronne
authors.forename: S
authors.initials: S
authors.lastname: Caprio
authors.forename: B
authors.initials: B
authors.lastname: Kahle
authors.forename: D
authors.initials: D
authors.lastname: Gordon
authors.forename: S M
authors.initials: SM
authors.lastname: Leal
authors.forename: R
authors.initials: R
authors.lastname: Goldsmith
authors.forename: A L
authors.initials: AL
authors.lastname: Andreu
authors.forename: C
authors.initials: C
authors.lastname: Bruno
authors.forename: S
authors.initials: S
authors.lastname: DiMauro
authors.forename: R L
authors.initials: RL
authors.lastname: Leibel
mesh_terms: D017398:Alternative Splicing; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D008040:Genetic Linkage; D006630:Hispanic or Latino; D006706:Homeostasis; D006801:Humans; D007473:Ion Channels; D015810:Linkage Disequilibrium; D008928:Mitochondria; D024101:Mitochondrial Proteins; D000071247:Uncoupling Protein 3; D044465:White People / Q000235:genetics; D001741:Black or African American
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3