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dc.contributor.authorMorgan, Kimyata R.
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 65-03, Section: B, page: 1097.;Advisors: Luciano Rossetti.
dc.description.abstractInsulin resistance is a metabolic feature that is common to both obesity and Type 2 diabetes mellitus (DM2). The frequency of both obesity and DM2 is rapidly increasing in western civilization. The widespread availability and consumption of high calorie nutrients and a sedentary lifestyle play major roles in the increasing prevalence of this epidemic. We have been exploring the theory that common forms of insulin resistance are generated as an initially 'adaptive' and ultimately 'maladaptive' response to nutrient excess in susceptible individuals. Both insulin resistance and weight gain are induced by a sustained increase in the availability of nutrients. This increase activates key nutrient sensing pathways, which are responsible for the synthesis and secretion of leptin and insulin. Leptin and insulin have been reported by our lab and others to have potent effects on glucose fluxes, energy metabolism and food intake via hypothalamic centers in the central nervous system (CNS), which is designed to antagonize the effects of nutrients on body weight and insulin sensitivity. Furthermore, nutrients themselves, via hypothalamic centers, may play a key role in the regulation of these physiological responses. We hypothesized that, in susceptible individuals, a failure or partial failure of this counter regulatory system rapidly ensues following a sustained increase in nutrients, which ultimately leads to the development of insulin resistance and weight gain. In order to test this hypothesis, we developed a model of voluntary hyperphagia in a rodent strain, Sprague-Dawley, which is susceptible to age- and diet-dependent weight gain. A series of physiological determinations utilizing euglycemic pancreatic insulin clamps, food intake, and molecular analysis of key metabolic genes and hypothalamic targets were performed. Overfed animals develop severe peripheral insulin and leptin resistance following only three days of voluntary overfeeding despite marked hyperinsulinemia and hyperleptinemia. Furthermore, activation of the hexosamine biosynthetic pathway in overfed rats leads to a decrease in the expression of key enzymes responsible for oxidative phoshphorylation in skeletal muscle but not brown fat indicating a possible site for altered energy expenditure and weight gain in this model. Direct administration of leptin in the CNS totally restores insulin action but fails to restore leptin action on carbohydrate metabolism. (Abstract shortened by UMI.).
dc.publisherProQuest Dissertations & Theses
dc.subjectAnimal Physiology.
dc.titleNovel mechanisms of insulin resistance and weight gain in diet induced obesity

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