Understanding the details of metabolism of lipids in normal humans is essential to the development of effective dietary and pharmaceutical prevention and treatment of obesity and type 2 diabetes. The fundamental processes of fatty acid release from adipocytes, the uptake of plasma free fatty acids by muscle and adipose tissue and the contribution of extracellular lipolysis of triglyceride rich lipoproteins to the free fatty acid pool are only partially understood. Epidemiologic and dietary studies suggest that there are differences in fatty acid metabolism based on fatty acid structure (saturated, monounsaturated or polyunsaturated). This proposal addresses gaps in the knowledge of fatty acid metabolism by testing the following hypotheses: 1. Oleate and palmitate generated by lipoprotein lipase lipolysis of circulating triglycerides spill over into the plasma free fatty acid pool more than linoleate. 2. Adipose tissue releases fatty acids selectively. 3. Changes in insulin sensitivity, endothelial function and blood pressure vary by the structure of fatty acids infused enterally to elevate free fatty acids. These hypotheses will be tested using triglyceride and fatty acid tracer dilution techniques, high performance liquid chromatography and mass spectroscopy. Two of the studies will be done using intravenous infusion tracers with one study also using oral lipid tracers.
Specific aim 1 uses tracers with a mixed meal, specific aim 2 utilizes tracers with hormone infusions and specific aim 3 uses oral unlabeled fatty acid infusion in the form of a triglyceride with a pure fatty acid structure with measures of endothelial dysfunction, blood pressure, insulin sensitivity and changes in inflammatory markers compared to saline ingestion. These studies will provide the applicant with an opportunity to develop further the skills necessary to achieve his long-term goal of becoming an independent investigator exploring the relationship between lipid metabolism and diabetes.
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