Biochemical Mechanisms of In Vivo Insulin Resistance

描述（由申请人提供）：在这个项目中，我们建议继续我们对胰岛素抵抗获得的生化机制的研究。我们的长期重点一直放在营养供应和胰岛素作用之间的联系上。在这方面，瘦素在肝脏和外周胰岛素作用的调节中起作用。然而，介导这些作用的生化和神经回路仍有待阐明。在这里，我们希望验证瘦素通过两个主要中心成分对肝脏葡萄糖通量的快速影响的假设：

DESCRIPTION (provided by applicant): In this project, we propose to continue our investigation of the biochemical mechanism(s) by which insulin resistance is acquired. Our long-term focus has been on the link between nutrient availability and insulin action. In this regard, the leptin plays in the regulation of hepatic and peripheral insulin action. However, the biochemical and neural circuitries mediating these effects remain to be elucidated. Here we wish to test the hypothesis that leptin exerts its rapid effects on hepatic glucose fluxes via 2 major central components: a) STAT3-dependent effects (mostly leading to rapid stimulation of gluconeogenesis and lipid oxidation); b) STAT3-independent effects (mostly leading to rapid inhibition of glycogenolysis and glucose output). Additionally, more prolonged activation of hypothalamic leptin signaling orchestrates the biological response to nutrient excess by limiting feeding behavior, by increasing energy expenditure and lipid oxidation, and by improving insulin action. Based on preliminary results and on this overall objective we wish to pursue the following specific aims: 1. Does leptin acutely regulate hepatic glucose fluxes via activation of STAT3-independent pathways in the hypothalamus? We will examine whether blocking hypothalamic leptin signaling via STAT3-independent pathways alters leptin action on hepatic nutrient fluxes. 2. Does leptin acutely regulate hepatic glucose fluxes via activation of STAT3-dependent pathways in the hypothalamus? We will examine whether rapid 'loss-of-function' within the hypothalamic STAT3 or melanocortin pathways alters leptin action on hepatic nutrient fluxes. 3. Does leptin acutely inhibit hepatic glucose production via STAT3-independent pathways when its activation of hypothalamic STAT3-dependent pathways is prevented? We will examine whether rapid 'loss-of-function' of STAT3-dependent hypothalamic targets of leptin unveils 'insulin-like' leptin actions on hepatic nutrient fluxes. 4. Does leptin regulate energy balance and insulin action via activation of hypothalamic STAT3-dependent and/or STAT3-independent signaling? We will examine whether week-long manipulations of hypothalamic leptin signaling via selective downstream targets regulate feeding behavior, energy metabolism, and insulin sensitivity. 5. How does short-term over-feeding modify the effects of hypothalamic leptin signaling on hepatic glucose fluxes? We will examine whether short-term stimulation of selective components of hypothalamic leptin signaling 'rescues' the action of leptin on hepatic nutrient fluxes in over-fed rats.