Recently, a sugar-rich diet has been shown to produce the severe form of obesity. This is a new finding. Our plan is to determine regulatory mechanisms responsible for sugar-induced severe obesity, and to determine the role of exercise in counteracting the development of this abnormality. We have preliminary data to show that hepatic fatty acid synthase (FAS) is up-regulated 13-regulated 13-fold after 2 days, and 22-fold after 7 days of sugar feeding. This is important because FAS may be the rate limiting enzyme responsible for the synthesis of fatty acids in the liver. It is our working hypothesis that FAS may represent a point of regulation in the pathway leading to triglyceride synthesis, and the development of obesity. In rats eating a sugar-rich diet, the primary goals of our research will be to (i) determine the pattern of up-regulation of FAS, as well as other hepatic lipogenic enzymes, at regular intervals during the developmental stages of obesity; (ii) determine the effects of a single """"""""bout"""""""" of exercise on the up-regulation of FAS and other hepatic lipogenic enzymes in sugar fed rats; (iii) determine the effects of a single """"""""week"""""""" of exercise on the up-regulation of FAS and other hepatic lipogenic enzymes in rats eating the obesity promoting sugar rich diet; (iv) determine the effects of a 12-wk program of exercise-training on the levels of activity of FAS and other hepatic lipogenic enzymes in rats developing severe obesity as a result of eating a sugar-rich diet; (v) determine if the change in steady state levels of FAS MRNA correlates with an increased rate of gene transcription in rats eating the high sugar diet with and without exercise; and (vi) isolate the FAS gene from a rat genomic library. FAS MRNA content will be measured using a rat FAS CDNA clone (kindly provided by Dr. Stuart Smith) as a hybridization probe. This work may establish that liver enzymes participate in the regulation of diet-induced severe obesity and that exercise offers a counter measure in blunting this response. Through these gene regulatory studies, we hope to enhance our understanding of the mechanisms mediating the rise in hepatic lipogenic enzymes which may lead to severe obesity in response to eating a diet high in sugar content.
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