Skeletal muscle nutrient sensing

描述（由申请人提供）：当热量摄入超过消耗时，就会发生肥胖。在工业化社会中，肥胖症的日益流行引起了人们对能量平衡控制机制的新兴趣。在人类中，能量消耗率的降低主要是由骨骼肌的氧化磷酸化引起的，这是未来体重增加的一个风险因素。营养素通过激活营养感应通路，激活脂肪反应（如瘦素），试图通过增加能量消耗和抑制食物摄入来限制脂质储存。作为一种主要的营养感应途径，己糖胺生物合成途径（HBP）最近被证明可以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氧化磷酸化基因的表达，诱导骨骼肌能量产生的急剧下降。基于这些观察结果，我们希望建立动物模型，以确定HBP的生理调节如何调节能量稳态。特别是，我们将使用转基因动物模型来区分肌肉中HBP激活的代谢后果与相关的局部诱导瘦素产生的代谢后果。我们将产生具有组成性和中度升高的谷氨酰胺酶：果糖6-P氨基转移酶（GFAT，它催化HBP的第一步并调节通过该途径的通量）或骨骼肌瘦素的转基因小鼠系。这些动物模型的仔细表型应该允许人们定义肌肉HBP和瘦素在调节能量消耗和底物氧化中的直接和各自的作用。

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.