The studies are designed to identify the physiological and molecular mechanisms involved in body weight regulation. On the physiological level the goal is to understand how diet can alter the regulation of fuel metabolism and how this may differ in individual rats. On the molecular level the goal is to begin to identify regulatory enzymes involved in fuel metabolism and how these are altered by diet. The first specific aims is to determine the physiological and molecular processes underlying differences in susceptibility to dietary fat-induced obesity. The ability to avoid becoming obese when eating a high fat diet depends on having the ability to increase whole-body fat oxidation in response to increases in fat intake. We plan to study the regulation of fuel metabolism in individual tissues, particularly skeletal muscle, to learn why some rats can oxidize a greater proportion of excess lipids than others when eating a high fat diet. The second specific aim is to continue to investigate the importance of and the mechanisms involved in the ability of different dietary fats to differentially affect body fat storage, insulin sensitivity, and whole-body energetics. Regional differences in adipose tissue lipoprotein lipase and/or circulating androgens may play a role in determining where excess body fat is stored, and the site of storage may contribute to development of metabolic derangements characteristic of chronic diseases. To accomplish specific aim 1, a model has been developed in which susceptibility to dietary fat-induced obesity in rats of the same strain is defined by total weight gain during 4 weeks of ad libitum access to a high fat diet. This model produces wide differences in weight gain with some rats (obesity prone; OP) gaining large amounts of body weight and body fat and others (obesity resistant; OR) gaining no more body weight than controls fed a low fat diet. The model can be used to investigate mechanisms involved in regulating fuel metabolism and in determining how this is related to susceptibility to fat-induced obesity. We hope to identify metabolic markers to allow a priori predictions of which rats will become obese. The information learned from these studies should be helpful in identifying humans at risk to become obese, allowing early interventions to prevent obesity. The 2nd specific aim will be accomplished by studies in which the amount and type of dietary fat are altered to assess the means whereby dietary fat composition can influence body fat distribution, energy expenditure, substrate balance, and insulin sensitivity. The key to accomplishment of the specific aims is the availability in our laboratory of personnel, techniques and state-of-the-art facilities for determining 1) whole-body energy expenditure and oxidation rates of protein, carbohydrate and fat; 2) whole-body and tissue specific insulin sensitivity and glucose and lipid utilization under a variety of carefully defined hormonal and substrate patterns; 3) in vitro capacity of muscle, liver and adipose tissue for substrate oxidation under defined hormonal/substrate conditions; 4) RNA messages for regulatory enzymes in muscle, liver and adipose tissue using available mRNA probes. In summary, these studies should increase our understanding of the role of amount and composition of dietary fat in producing obesity and the metabolic derangements that often accompany it.
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