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Impact of a human missense UCP3 polymorphism on the plasma metabolomic profile: support for a mitochondrial fuel‐partitioning role for UCP3 (248.4)
Author(s) -
Piccolo Brian,
Grapov Dmitry,
Garvey W. Timothy,
Harper MaryEllen,
Fiehn Oliver,
Adams Sean,
Newman John
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.248.4
Subject(s) - ucp3 , uncoupling protein , skeletal muscle , metabolomics , oxidative phosphorylation , biology , biochemistry , mitochondrial biogenesis , glutathione , reactive oxygen species , mitochondrion , endocrinology , chemistry , medicine , bioinformatics , adipose tissue , brown adipose tissue , enzyme
Skeletal muscle uncoupling protein 3 (UCP3) is thought to facilitate fatty acid oxidation (FAO) and protect against excess mitochondrial (MITO) reactive oxygen species (ROS); however, this has yet to be conclusively proven in human studies. We hypothesized that a comprehensive plasma metabolomic characterization of a human UCP3 polymorphism would identify metabolites associated with decreased skeletal muscle FAO and oxidative stress. We measured 490 metabolites using three independent metabolomics platforms in obese African‐American women with or without type 2 diabetes (T2D) containing a missense G304A (G/A) UCP3 polymorphism. Partial least squares‐discriminant analysis (PLS‐DA) revealed altered amino acid profiles and metabolites consistent with enhanced glycolytic oxidation in the context of reduced UCP3 function. UCP3 G/A genotype also revealed decreases in plasma amino acids involved in glutathione metabolism and markers of glutathione synthesis. Stearoylethanolamide (SEA), a putative modulator of MITO oxidative phosphorylation and biogenesis was also significantly elevated in T2D UCP3 G/A individuals. Our results support the idea that UCP3 is involved in regulating muscle MITO fuel selection by promoting fatty acid combustion, perhaps via mechanisms involving ROS signaling. Grant Funding Source : Supported by: NIH‐NIDDK R01DK078328‐01, UAB‐CCTS UL1 RR025777, WCMC NIH 1 U24 DK097154, USDA‐ARS