Circulating sphingolipids are associated with insulin resistance and type 2 diabetes in humans. Plasma ceramides are higher in obese children and diabetic adults and correlate with the severity of insulin resistance. Therefore to explore the hypothesis that ceramides or related sphingolipids serve as nutritional cues to alter mitochondrial function and substrate preference is very important. In addition to resolving lingering controversies about muscle adaptation to nutrient availability, these studies could uncover novel therapeutic targets for combating insulin resistance associated with obesity. The present study aims to: 1) To determine to whether genetic disruption of serine palmitoyltransferase and dihydroceramide desaturase in skeletal muscle impacts peripheral insulin sensitivity, metabolic flexibility, and mitochondrial function. 2) To determine the mechanisms by which ceramides and ceramide metabolites influence mitochondrial function and insulin action.
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