Over the past several years of funding, we have investigated the physiological significance of the triglyceride (TG) /fatty acid cycle. Most recently, we have focused on the mechanisms responsible for the deposition of excessive TG in the liver of severely burned patients. We now propose to extend these investigations to determine the clinical significance of the alterations in both liver and muscle lipid metabolism that lead to the accumulation of tissue TG in severe burn injury. We will investigate the possible role of the accumulation of tissue TG on insulin sensitivity. Insulin responsiveness will be assessed not only in terms of glucose metabolism, but also with regard to muscle and plasma protein synthesis. We will investigate the general hypothesis that the accumulation of intracellular TG in liver and muscle either directly contributes to insulin resistance in those tissues or serves as an indictor of the intracellular accumulation of active fatty acid products, such as diacylglycerol (DAG), which in turn disrupt insulin action. We will study the period of time 1-3 weeks following severe burn injury when tissue lipid rapidly accumulates. A series of specific hypotheses will be addressed regarding the possible relationships between muscle fatty acid oxidation, tissue lipid accumulation, elements of the insulin signaling cascade, and insulin action on glucose and protein metabolism. Studies will be performed in severely burned children. Principal methodological approaches will include stable isotope tracer techniques to quantify kinetic responses of protein, glucose and lipid metabolism in vivo, nuclear magnetic resonance spectroscopy (MRS) to quantify intracellular stores of TG and glycogen, measurement of the tissue levels of active products of fatty acids and key intermediates of the insulin signaling pathway, and the in vitro assessment of mitochondria oxidative capacity. These studies will help to clarify the physiological and clinical significance of the alterations of tissue lipid metabolism that occur after burn injury, thereby forming the basis for new therapeutic approaches not only in this specific clinical condition but in other clinical circumstances that involve the accumulation of hepatic and/or muscle TG.
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