The proposed research will continue our work in the area of the regulation of lipid fuel metabolism. Lipid energy is transported in the blood in severa forms, including chylomicrons and free fatty acids (FFA). Chylomicrons are key elements in the absorption and storage of dietary fat, and also play a role in the pathogenesis of atherosclerosis via the production of remnant particles, but their role as a direct fuel source has not been extensively investigated. FFAs are the major lipid fuel in the body, and increases in their concentration have been shown to cause insulin resistance, endothelial dysfunction and increases in the production of very low density lipoproteins. FFAs are released into the blood through the action of hormone sensitive lipase on triglyceride stores in fat cells. Very little is known about the role of chylomicrons in FFA metabolism, but the potential contribution of chylomicrons to FFA is considerable, especially in people who consume high fat diets. Initial studies indicate that in addition to the role of chylomicrons in fat storage, a portion of chylomicron fatty acids are released as FFA in a process called "spillover". A study of spillover in the splanchnic bed found very high rates of splanchnic spillover in overweight and obese individuals with hypertriglyceridemia. Subsequent studies have shown that intravenous infusion of niacin, a drug known to suppress FFA release, produced a significant reduction in fractional spillover, whereas insulin infusion had no effect. Furthermore, in people with type 2 diabetes spillover correlated negatively with leg fat - that is, individuals with a large amount of leg fat ad lower spillover (an indication of more efficient fat storage), while those with small amounts of le fat had higher spillover, indicating less efficient storage. No information is available on spillovr in lower body fat tissue, nor on its relationship with spillover in the splanchnic bed (which includes visceral fat). Extremely accurate and precise methods have been developed by the investigator for the measurement of the concentration and specific activity of FFA and chylomicron triglyceride fatty acids in plasma. In addition, a tracer method for accurately determining the kinetics of chylomicrons has been developed. In the proposed studies, the tracer technique will be used to systematically investigate the contribution of chylomicrons to total FFA availability. The technique will be applied to lean and obese subjects, including people who have undergone gastric bypass surgery. Specifically, these studies will: 1) determine whether weight loss after gastric bypass reduces spillover from chylomicrons;2) determine whether acute lowering of FFA with niacin infusion reduces spillover in overweight and obese people;3) determine whether women with upper body obesity have greater systemic spillover than women with lower body obesity, and whether body fat distribution determines chylomicron triglyceride uptake and spillover in leg and splanchnic fat and 4) determine whether women with upper body obesity gain less weight during supervised overfeeding than women with lower body obesity.
Elevated free fatty acids levels (FFAs) in blood are a recognized cause of insulin resistance and may contribute to the development of diabetes, high blood pressure and cardiovascular disease. Dietary fat may contribute to FFAs by a process known as spillover, which occurs during fat storage. This work is a comprehensive evaluation of the importance of spillover as a contributor to FFAs and as a marker for the efficiency of fat storage.
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