Metabolic Inflexibility in Skeletal Muscle With Obesity

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Kristen E. Boyle (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: The skeletal muscle of obese individuals has a reduced capacity to oxidize lipids. The hypothesis to be tested in this dissertation is that the ability to regulate lipid oxidation in response to lipid exposure is impaired in skeletal muscle of obese individuals. An inability to appropriately respond to metabolic stimuli has been termed "metabolic inflexibility" and has been linked with obesity and insulin resistance. To test this hypothesis, two models of lipid exposure were utilized: a 5 day high fat diet (HFD) and lipid incubation in primary myotubes cultured from lean and obese donors. Trend analyses indicated that mRNA content of genes linked with fat oxidation were collectively up-regulated with the HFD in skeletal muscle of lean but not obese subjects, suggesting a global response that is indicative of skeletal muscle mitochondrial dysfunction in obesity. Specifically, there was a 2-fold increase (P < 0.05) in fasted PDK4 content following the HFD in leans, while the obese participants tended to have decreased PDK4 content; and UCP3 mRNA content decreased by almost half in the obese, but not lean participants. In the second series of studies, a 24 h lipid incubation increased mitochondrial respiration by up to 50% in the presence of lipid and carbohydrate in myotubes from lean donors in both State 3 and uncoupled respiration (P < 0.05), though there was no change in cells cultured from the obese donors. In addition, mitochondrial DNA content increased by 16% (P < 0.05) with lipid exposure in cells from lean subjects but decreased by 13% (P < 0.05) in myotubes from obese subjects. The presence of these defects in culture suggests a genetic or epigenetic origin with obesity. Together, these data support the hypothesis that the skeletal muscle of obese individuals is metabolically inflexible and provides the novel information that this inflexibility extends to the ability to respond to lipid exposure in human skeletal muscle.  

Additional Information

Publication

Dissertation

Language: English

Date: 2009

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