Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Daniel Hardy

Abstract

Chronic diseases such as type 2 diabetes and the Metabolic Syndrome create enormous burdens on society. Epidemiological studies now strongly implicate intrauterine growth restriction (IUGR) for increasing the risk of developing chronic diseases later on in life. However, the molecular mechanisms underlying how IUGR leads to the increased susceptibility to these metabolic diseases in adulthood is not well understood. The Liver-X-Receptor (LXR) is a nuclear receptor involved in cholesterol, glucose, and lipid metabolism. LXR acts to decrease gluconeogenesis through repression of glucose-6-phosphatase(G6Pase), phosphoenolpyruvate carboxykinase(PEPCK), and 11β-hydroxysteroid dehydrogenase type-1(11β-HSD1). Using a well-characterized model of maternal protein restriction in rats, this study attempts to elucidate the role of LXR in the long-term programming of impaired glucose homeostasis. It was discovered that altered expression of LXR during the gestational and neonatal period predisposes the fetus to impaired glucose tolerance in adult life through LXR-mediated activation of the gluconeogenic genes G6Pase, PEPCK, and 11β-HSD1.


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