Mechanisms of Metabolic Control by MKP-1

描述（由申请人提供）：肥胖已经成为一种世界性的流行病，其原因有多方面，包括遗传易感性、高能量食物的增加和现代社会体力活动需求的减少。肥胖对健康的影响与糖尿病、冠心病、非酒精性脂肪性肝病（NAFLD）和某些形式的癌症有关。丝裂原活化蛋白激酶（MAPKs）是代谢的关键调节因子。因此，阐明MAPKs是如何被调控的对于我们理解控制代谢的机制至关重要。MAPK被MAPK磷酸酶（MKPs）去磷酸化，从而失活。尽管已确定MKPs在MAPK失活中的作用，但对其对代谢控制的生理或病理生理影响知之甚少。MKP-1是定位于细胞核的典型MKP。该建议的核心观点是，MKP-1在细胞核中作为一个“关键节点”，在维持代谢稳态中控制mapk依赖性信号的流动。我们发现MKP-1使mapk核库失活，从而减弱促进能量消耗和肝脂肪酸氧化的基因表达事件。因此，缺乏mkp -1的小鼠对饮食诱导的肥胖有抵抗力，并且免受肝脂肪变性的影响。该提案的主要目标是确定MKP-1在生理上和机制上是如何负调节体重的，并确定MKP-1在NAFLD发病机制中的干扰途径。我们将通过执行以下具体目标来实现这些目标：在目标1中，我们将确定MKP-1如何调节细胞因子诱导的mapk依赖性信号事件的机制，这些信号事件控制骨骼肌中线粒体呼吸。在目标2中，将使用骨骼肌和大脑中组织特异性消融MKP-1的遗传方法来确定MKP-1在这些部位对调节体重的贡献。目的3将确定肥胖诱导的MKP-1在肝脏中的过度表达是否会促进肝脂肪变性的发展。将产生MKP-1缺陷小鼠与肥胖小鼠模型和MKP-1反义方法之间的交叉杂交来验证这一点。最后，将阐述肥胖期间肝脏中MKP-1过表达与肝脏脂质稳态失调的机制。

DESCRIPTION (provided by applicant): Obesity has become a worldwide epidemic that stems from multifaceted causes that includes genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. The health-related impact of obesity is associated with diabetes mellitus, coronary heart disease, non-alcoholic fatty liver disease (NAFLD) and some forms of cancer. The mitogen-activated protein kinases (MAPKs) are key regulators of metabolism. Therefore, elucidating how the MAPKs are regulated will be essential to our understanding of the mechanisms that control metabolism. The MAPKs are dephosphorylated, and hence inactivated, by the MAPK phosphatases (MKPs). Despite the established role for MKPs in MAPK inactivation very little is known about their physiological or pathophysiological impact on metabolic control. MKP-1 is the archetypal MKP which localizes to the nucleus. The central tenant of this proposal is that MKP-1 functions as a "critical node" in the nucleus to control the flow of MAPK-dependent signaling in the maintenance of metabolic homeostasis. We have found that MKP-1 inactivates the nuclear pool of MAPKs to attenuate gene expression events that promote energy expenditure and hepatic fatty acid oxidation. Hence, MKP-1-deficient mice are resistant to diet-induced obesity and are protected from the development of hepatic steatosis. The broad goals of this proposal are to determine how mechanistically, and where physiologically, MKP-1 negatively regulates body mass and to identify the pathways that MKP-1 interferes with in the pathogenesis of NAFLD. We will accomplish these goals by executing the following specific aims: In aim 1, we will determine the mechanism of how MKP-1 regulates cytokine-induced MAPK-dependent signaling events that control mitochondrial respiration in skeletal muscle. In aim 2, a genetic approach using tissue-specific ablation of MKP-1 in skeletal muscle and brain will be performed to determine the contribution of MKP-1 at these sites to regulate body mass. Aim 3 will determine whether obesity-induced overexpression of MKP-1 in the liver promotes the development of hepatic steatosis. Intercrosses between MKP-1-deficient mice with mouse models of obesity and MKP-1 anti-sense approaches will be generated to test this. Finally, mechanisms linking MKP-1 overexpression in the liver during obesity to the dysregulation of hepatic lipid homeostasis will be delineated.