Identification of Muscle-specific Biomarkers of Fatty Acid Beta-oxidation (FL-68)
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) ß-oxidation is more prevalent among insulin-resistant/diabetic persons. Therefore, discovery of biomarkers reflective of the status of an individual's muscle FA ß-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. The investigators propose to identify, for the first time, specific biomarkers of muscle FA ß-oxidation using multiple metabolomic analytical platforms to compare metabolite profiles in samples derived from biological systems displaying disparate muscle fat combustion. The current experiment will test whether plasma metabolites and/or metabolite signatures that track efficient muscular FA ß-oxidation can be experimentally increased in obese, insulin-resistant subjects via a diet-exercise regimen designed to improve muscle fitness and FA combustion.
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
|Official Title:||Identification of Muscle-specific Biomarkers of Fatty Acid Beta-oxidation|
- Change in VO2max [ Time Frame: Week 1 vs. Week 16 ] [ Designated as safety issue: No ]Overnight fasted subjects will start the test at a low cycle ergometer resistance level and encouraged to maintain a steady rate of pedaling, and resistance will increase at 2-min intervals until volitional fatigue. Indirect calorimetry will be used to measure VO2 and CO2 continuously during the exercise test. Subjects will receive a pre-test ECG, breath volume test and medical exam to assure the subject has no underlying medical problems that would put them at an undue risk during the exercise tests.
- Change in Body Composition (BODPOD) [ Time Frame: Week 1 vs. Week 16 ] [ Designated as safety issue: No ]Body fat mass and fat-free mass will be measured using the BOD POD. Subjects will be asked to change into a provided form-fitting swimsuit or single layer compression shorts and single layer jog bra for women. Subjects will also be asked to wear a provided swim cap to compress the hair on their head. After measuring height and weight, they will sit comfortably in the BOD POD and limit their movement while breathing normally. During the last section of the test subjects will be asked to breathe into a tube and give three puffs when indicated by the computer screen.
- Change in Insulin Sensitivity [ Time Frame: Week 1 vs. Week 16 ] [ Designated as safety issue: No ]OGTT (oral glucose tolerance test) A standard oral 75 g glucose tolerance test (OGTT) will be administered and the insulin sensitivity index calculated as per Matsuda and DeFronzo. For screening a blood sample will be taken after 2 hours. For the test week, blood samples will be taken at 0, 15, 30, 60, 90, and 120 min post-glucose ingestion (up to 8 mL of blood will be obtained/timepoint).
- Change in Metabolite Profiling and Metabolomics [ Time Frame: Week 1 vs. Week 16 ] [ Designated as safety issue: No ]EDTA plasma from overnight fasted subjects and samples derived from exercise tests obtained in the pre-intervention and post-intervention test weeks will be analyzed. Samples will be analyzed using several mass spec based metabolomics platforms. Exercise samples are derived from subjects undergoing 30-minutes of submax exercise (45% VO2max) collected every 5 minutes, plus samples collected during a 20-minute cool-down phase.
- Change in Body Composition (DXA) [ Time Frame: Week 1 vs. Week 16 ] [ Designated as safety issue: No ]Body fat mass and fat-free mass will be measured by DXA using a whole body scan. The scan will be performed at the beginning of the study and after the diet and exercise intervention. Our technical staff at WHNRC is trained and certified in the DXA method. The volunteer will wear light-weight surgical scrubs. The scan time takes no longer than 30 minutes to complete, with a radiation exposure less than 0.1 mrem. As subjects will be menstruating during the test week, there is no risk to a developing fetus. A pregnancy test will be offered but not required.
- Change in Body Weight [ Time Frame: Week 1 vs. Week 16 ] [ Designated as safety issue: No ]Body weights are measured on a calibrated scale approximately on a weekly basis throughout the study, and daily during pre-intervention Test Week 1 and post-intervention Test Week 2.
|Study Start Date:||October 2009|
|Study Completion Date:||July 2012|
|Primary Completion Date:||June 2012 (Final data collection date for primary outcome measure)|
|Experimental: Diet and Exercise||
Behavioral: Diet and Exercise
Subjects underwent a diet regimen targeted to elicit a 10% weight loss. Diets were designed based on the US Dietary Guidelines with caloric deficits individualized for each subject. Aerobic exercise was monitored over approximately 14 weeks, several times per week, to elicit significantly increased VO2max.
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|United States, California|
|Western Human Nutrition Research Center|
|Davis, California, United States, 95616|
|Principal Investigator:||Sean H Adams, PHD||USDA, Western Human Nutrition Research Center|