Location: Obesity and Metabolism Research2013 Annual Report
1a. Objectives (from AD-416):
Poor muscle fat combustion is a hallmark of reduced insulin sensitivity, pre-diabetes, and propensity toward development of type 2 diabetes mellitus. Identifying persons who display this phenotype, however, has been difficult and requires in-depth specialized and costly clinical evaluation (i.e., muscle biopsies, analysis of blood parameters across the muscle bed using dual catheterization). The lack of a facile, inexpensive technique to characterize muscle fat utilization hinders strategies to optimally apply nutritional and physical activity regimens to thwart insulin resistance and diabetes, since markers are unavailable to identify at-risk persons who may benefit most from said interventions, and to use in order to track efficacy of the interventions. Our objective is to identify blood metabolites or metabolite signatures reflective of skeletal muscle fat combustion, and to test whether said patterns shift in response to a diet and exercise regimen in overweight to obese persons.
1b. Approach (from AD-416):
We will use unique organelle (mitochondria), cell, and animal models which display altered muscle fat utilization to derive biofluids that will be tested using state-of-the-art metabolomics technologies--these studies will identify specific metabolites or metabolite signatures reflective of fat combustion in this tissue. In addition, we will analyze the plasma of human subjects who display a disruptive genetic polymorphism in a muscle protein involved in mitochondrial fatty acid metabolism (UCP3) to assess whether metabolomic patterns differ from people without the polymorphism. Finally, we will evaluate whether overweight to obese persons with insulin resistance have plasma metabolite patterns reflective of poor muscle fat burning, and test whether a diet and exercise intervention strategy normalizes these patterns concurrent with improvements in insulin action.
3. Progress Report:
This research relates to objective 3 of the inhouse project, “Determine mechanisms underlying the regulation of body weight and disorders associated with obesity, by examining hormonal, neuronal, and metabolite pathways linking adipose and non-adipose tissues, and characterizing tissue-specific inflammation in humans, cells, and animal models". Blood plasma metabolite profiling and data analysis (metabolomics) were completed for studies assessing the impact of weight loss, improved fitness and insulin sensitivity in humans. Unique metabolite profiles were identified that mark these physiological changes, and new analyses are underway to determine if an exercise bout alters the metabolome. This project has reached its maximum 5 year term and will be extended under a new project to which began August 1, 2013, 5306-51530-019-84I.