Mechanisms of Metabolic Control by MKP-1

描述(申请人提供)：肥胖已成为一种世界性流行病，其原因是多方面的，包括遗传易感性、高能量食物的供应增加以及现代社会对体育活动的需求减少。肥胖对健康的影响与糖尿病、冠心病、非酒精性脂肪肝(NAFLD)和某些形式的癌症有关。丝裂原活化蛋白激酶(MAPKs)是新陈代谢的关键调节因子。因此，阐明MAPK是如何被调控的对于我们理解新陈代谢的调控机制是至关重要的。MAPK被去磷酸化，因此被MAPK磷酸酶(MKP)灭活。尽管MKPs在MAPK失活中的作用已经确立，但人们对其在代谢控制中的生理或病理生理学影响知之甚少。MKP-1是定位于细胞核的原型MKP。这一提议的中心租户是MKP-1在维持代谢稳态中作为细胞核中的一个关键节点来控制MAPK依赖的信号的流动。我们发现，MKP-1可以使MAPK的核池失活，从而减弱促进能量消耗和肝脏脂肪酸氧化的基因表达事件。因此，MKP-1基因缺陷的小鼠对饮食诱导的肥胖具有抵抗力，并可防止肝脏脂肪变性的发生。这项建议的主要目标是确定MKP-1如何在机制上以及在哪里对体重进行负向调节，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依赖的信号事件，从而控制骨骼肌中的线粒体呼吸。在目标2中，将使用组织特异性消融骨骼肌和脑中MKP-1的遗传方法来确定这些部位的MKP-1对调节身体质量的贡献。目的3将确定肥胖诱导的肝脏MKP-1过度表达是否促进肝脏脂肪变性的发展。将产生MKP-1缺陷小鼠与肥胖小鼠模型和MKP-1反义方法的交叉杂交来测试这一点。最后，我们将描述肥胖时肝脏中MKP-1过度表达与肝脏脂质平衡失调之间的联系。

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.