In this project, we propose to continue our investigation of the biochemical and molecular mechanism(s) by which """"""""insulin resistance"""""""" is acquired. Our long-term focus has been on the potential link between nutrient excess and impairment of insulin action. In this regard, we have recently shown that increased nutrient (eg, carbohydrate and lipid) availability results in insulin resistance and in increased leptin gene expression via increased flux of carbons into the hexosamine biosynthetic pathway. We propose herein that a close loop feed-back regulation is normally operating between nutrients and their metabolic outcomes. Thus, nutrient excess is sensed via the hexosamine biosynthetic pathway and generates signals leading to decreased insulin action on glucose uptake and to increased leptin gene expression. They also favor increased storage into lipid via increased tissue levels of Malonyl-CoA and Long Chain-CoA and ultimately increased adiposity and weight gain. However, the concomitant induction of leptin expression attempts to counteract this drive by antagonizing the effects of nutrients on Malonyl-CoA and triglyceride storage, on the hexosamine pathway and perhaps via direct effects on insulin signaling. Any disruption of this physiological response (due to either impaired stimulation of leptin expression by nutrients or to decreased effectiveness of leptin action on target tissues) is likely to lead to increased adiposity and more insulin resistance. Based on preliminary results and on this overall hypothesis we wish to pursue the following specific aims: 1. How do nutrients regulate insulin action? We will focus on the interaction between increased lipid availability and skeletal muscle insulin signaling and action. We hypothesize that the susceptibility to develop insulin resistance in response to excessive nutrient exposure is modulated by the skeletal muscle ability to utilize fructose-6-phosphate in the glycolytic pathway. 2. How does leptin modulate hepatic and muscle glucose/lipid metabolism and insulin action? We will examine whether specific hypothalamic targets of leptin play distinct roles in mediating its complex metabolic effects. 3. Is leptin synthesis and/or action modulated following prolonged stimulation? We will generate short-term models of relative hyperleptinemia and will test the hypothesis that the """"""""protective"""""""" effect of leptin against nutrient excess wanes if the leptin signal/transduction system is chronically over-stimulated.
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