Location: Obesity and Metabolism Research2009 Annual Report
1a. Objectives (from AD-416)
Elevated fat levels within skeletal muscle cells (intramyocellular lipids) are highly correlated with muscle and whole-body insulin resistance, and more prevalent in obesity. The molecular links and metabolic shifts driving this association remain open to debate, but notably, reduced muscle mitochondrial fatty acid (FA) beta-oxidation is more prevalent among insulin-resistant/diabetic persons. Therefore, discovery of biomarkers reflective of the status of an individual’s muscle FA beta-oxidation activity or capacity would have tremendous prognostic and diagnostic value in terms of diabetes. Furthermore, characterization of metabolites associated with muscle mitochondrial fat metabolism should uncover candidate signaling factors which tie FA ß-oxidation to insulin signaling. We propose to identify, for the first time, specific biomarkers of muscle FA beta-oxidation using multiple metabolomic analytical platforms to compare metabolite profiles in samples derived from biological systems displaying disparate muscle fat combustion, including: isolated mitochondrial organelles and muscle cells catabolizing FA at different rates, a UCP3 transgenic animal model, and human subjects harboring a UCP3 truncation polymorphism. Pilot validation studies will test whether plasma metabolites and/or metabolite signatures identified in cell, animal, and human studies that track muscular FA beta-oxidation can be experimentally increased in obese, insulin-resistant subjects via a diet-exercise regimen designed to improve muscle fitness and FA combustion.
1b. Approach (from AD-416)
Identify Metabolite Biomarkers of Muscle Fat Combustion in Humans Harboring a UCP3 Missense Polymorphic Allele. We predict that subjects with this uncoupling protein 3 (UCP3) 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. This will be evaluated by obtaining blood plasma from individuals with or without the polymorphism, at rest and after a brief exercise bout. Documents Grant with U of Alabama.
3. Progress Report
Significant progress has been made toward several of the objectives in the parent project (5306-51530-016-09R), which examines broad metabolite patterns reflective of metabolic status in muscle in order to identify biomarkers of muscle fat combustion. This overarching aim is driven by the fact that poor insulin sensitivity and frank type 2 diabetes typically occur in the setting of reduced or inefficient muscle long chain fatty acid (LCFA) catabolism in mitochondria. In FY2009, the research team has published a significant paper outlining the finding that metabolite by-products of inefficient LCFA combustion (chain-shortened acylcarnitine moieties) are elevated in the plasma of type 2 diabetic African-American women. Clinical studies to test for the effects of muscle exercise and fitness on metabolite profiles (metabolomics) have been designed, standard operating procedures finalized, and diet design completed. These efforts poise the team to begin recruiting human subjects in FY2010. The ADODR monitors the annual financial report from cooperating institutions, and conducts in-person or teleconference discussion sessions relating to the project.