Skeletal muscle nutrient sensing

骨骼肌营养传感

基本信息

批准号：
7113233
负责人：
SILVANA OBICI
金额：
$ 24.36万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-10-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7113233
关键词：
amidophosphoribosyltransferase bioenergetics genetically modified animals glutamine hexosamines hormone regulation /control mechanism laboratory mouse laboratory rat leptin muscle metabolism nutrition related tag striated muscles weight gain

项目摘要

DESCRIPTION (provided by applicant): Obesity occurs when caloric intake exceeds expenditure. The increasing prevalence of obesity in industrialized societies has generated new interest in the mechanisms underlying the control of energy balance. In humans, reduced rate of energy expenditure, which is largely accounted for by oxidative phosphorylation in skeletal muscle, is a risk factor for future weight gain. Nutrients, via the activation of nutrient-sensing pathways, activate adipostatic responses (e.g. leptin) that attempt to limit lipid storage by enhancing energy expenditure and inhibiting food intake. A major nutrient-sensing pathway, the hexosamine biosynthetic pathway (HBP) has been recently shown to increase local leptin expression in skeletal muscle. Yet, acute pharmacological activation of HBP induces a dramatic drop in skeletal muscle energy production, by downregulating the expression of genes for oxidative phosphorylation. Based on these observations, we wish to develop animal models designed to define how the physiological regulation of HBP modulates energy homeostasis. In particular, we will use transgenic animal models to discern the metabolic consequences of activation of HBP in muscle from those derived from the associated local induction of leptin. We will generate transgenic mice lines carrying constitutive and moderate elevations of the enzyme glutamine:fructose 6-P amidotransferase (GFAT, which catalyzes the first committed step of HBP and regulates the flux through this pathway), or of leptin in skeletal muscle. The careful phenotyping of these animal models should allow one to define the direct and respective roles of muscle HBP and leptin in the regulation of energy expenditure and substrate oxidation.

描述（由申请人提供）：当热量摄入超过支出时，就会发生肥胖。工业化社会肥胖的普遍性日益增加，引起了对控制能量平衡控制的机制的新兴趣。在人类中，降低的能量消耗率很大程度上是由于骨骼肌中氧化磷酸化所解释的，这是未来体重增加的危险因素。营养物质通过激活营养感应途径，激活脂肪反应（例如瘦素），试图通过增强能量消耗和抑制食物摄入来限制脂质储存。最近已证明是六胺生物合成途径（HBP）的主要营养感应途径，可增加骨骼肌中局部瘦素的表达。然而，HBP的急性药理激活通过下调基因的氧化磷酸化表达来引起骨骼肌能量产生的急剧下降。基于这些观察结果，我们希望开发旨在定义HBP生理调节的动物模型。特别是，我们将使用转基因动物模型来辨别肌肉中HBP激活的代谢后果，从相关的瘦素局部诱导而产生的肌肉。我们将生成携带酶谷氨酰胺的本构和中等升高的转基因小鼠线：果糖6-P氨基转移酶（GFAT（GFAT）（GFAT，它催化HBP的第一个投入步骤，并通过该途径调节磁通量）或骨骼肌中的瘦素。这些动物模型的仔细表型应使人们可以定义肌肉HBP和瘦素在能量消耗和底物氧化调节中的直接和各自作用。