Start Date: Jul 14, 2009
End Date: Jul 31, 2013
A comprehensive carnitine and acylcarnitine assay measuring >40 acylcarnitines will be employed to test samples derived from the following project aims: Aim 1--Identify Metabolite Biomarkers of Muscle Fat Combustion in Organelle, Cell, and Animal Models Displaying Significantly Altered Fatty Acid beta-Oxidation. We will determine how metabolite profiles shift in models displaying increased muscle beta-oxidation (uncoupling protein 3-overexpressing muscle cell line and muscle UCP3-transgenic mice), and hypothesize that profiles in UCP3-overexpressing systems will reflect increased FA beta-oxidation. Complementary studies will identify tissue-specific metabolites generated by mitochondria in the course of palmitate catabolism in vitro, comparing muscle to liver and kidney preparations. Aim 2--Identify Metabolite Biomarkers of Muscle Fat Combustion in Humans Harboring a UCP3 Missense Polymorphic Allele. We predict that subjects with this polymorphism (that yields a truncated UCP3 and 50% decreased whole-body fat combustion) will display a distinctive plasma metabolite profile indicative of reduced muscle FA oxidation, when compared to subjects without the polymorphism. Aim 3--Determine Whether Metabolomic Profiles Reflective of Muscle Fat Combustion Predict Metabolic Health Changes Following Diet & Exercise Intervention in Obese Subjects. We hypothesize that biomarkers reflective of normal to increased muscle beta-oxidation will be increased, and markers indicative of poor muscle fat combustion reduced, in a cohort of sedentary obese subjects undergoing a 4 month diet-exercise protocol which will increase muscle fitness and improve insulin action.