Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Obesity is a major public health problem in this country, generating annual health care costs in excess of 30 billion dollars. Currently the metabolic abnormalities which are present prior to the development of obesity are poorly understood. It appears the consumption of a high-fat diet is associated with the development of obesity. While a complex interaction between nutrient intake, energy expenditure and fuel metabolism likely exists, evidence in humans and laboratory animals suggests that abnormal partitioning of triglyceride fatty acids (TGFA) favoring storage over oxidation may play a central role in the development of obesity. Preliminary data generated in my laboratory strongly suggests that an abnormality in the partitioning of dietary fat favoring storage over oxidation is present in genetically obese Zucker rats, and is accentuated when these rats lose weight. More recently we have found that the partitioning of a dietary fat tracer between storage and oxidation in Sprague Dawley rats can predict the magnitude of weight gain on a high fat diet (HFD). This finding is important, since HFD- induced obesity in the rat closely models human obesity. Given this information, it is first hypothesized that reduced oxidation of diet- derived fatty acids (FA) by skeletal muscle predisposes to the development of obesity by favoring storage of TG fuels. A decrease in the oxidation of diet derived FA is due both to decreased uptake of TGFA by skeletal muscle and decreased oxidation of intra-muscular triglyceride (IMTG), the short term storage pool through which a substantial portion of FA traverse prior to oxidation. Second, it is hypothesized that as obesity develops, lipid oxidation increases largely due to an increase in the oxidation of non-esterified fatty acids (NEFA) released by expanded adipose tissue stores. Finally, it is hypothesized that the oxidation of these lipid fuels (TGFA and IMTG) is critically affected by the presence of the obese state, as well as the concentration of glucose and insulin. With this in mind, the goals of the proposed studies are to: 1. develop an accurate and specific metabolic test which will predict the development of obesity based on the partitioning of dietary fat, 2. define the changes in the trafficking of dietary fat during the development of obesity, and 3. examine the interaction between IMTG/TGFA and glucose/insulin in skeletal muscle during the development of obesity. To accomplish these aims the partitioning of TGFAs (saturated, monounsaturated, and essential) will be measured in lean rats (fasted and fed states) prior to placing them on a HFD, in an effort to predict weight gain. Second, the trafficking of diet derived FA between and within tissues will be followed during weight gain on a HFD to determine which abnormalities in TGFA metabolism are present prior to, and which occur subsequent to the development of obesity. Finally, the uptake and oxidation of TGFA and the oxidation of IMTG will be examined in skeletal muscle obtained from lean, pre-obese, and obese rats in vitro using the isolated perfused hindquarter preparation. Knowledge acquired through this proposal may well lead to the development of diagnostic tests to accurately predict weight gain on the basis of fuel partitioning. Such a test would make possible attempts at primary prevention of obesity in humans.
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