MSP/RON通过调控iNOS/NO通路改善肥胖相关骨骼肌胰岛素抵抗的作用及机制研究

胰岛素抵抗（IR）的发展过程中存在器官间的相互交流。脂肪肝推动了肥胖相关骨骼肌IR的发展，但其机制未明。文献表明，诱导型一氧化氮合酶（iNOS）的异常表达及其产物NO的蓄积参与了肥胖相关骨骼肌IR的发生，然而其上游调控因素尚不明确。MSP是一种肝细胞因子，可参与肝-肝外器官的相互交流，并通过其特异性受体RON对糖脂代谢起保护性调节作用。我们前期研究发现脂肪肝小鼠血清MSP水平降低，且MSP可激活肌细胞表面RON，抑制肌内iNOS转录水平，并上调胰岛素信号分子AKT磷酸化及提高葡萄糖摄取率。据此推测：MSP/RON可能通过抑制骨骼肌内异常激活的iNOS/NO通路进而提高葡萄糖摄取并改善IR。本课题拟利用转基因小鼠及细胞模型，阐明MSP/RON通过调控iNOS/NO通路改善肥胖相关骨骼肌IR的作用及机制。本研究将深入探究肝-骨骼肌轴在肥胖相关IR中的新作用靶点，为IR的防治提供新的理论依据。

Organ cross-talks are involved in the pathogenesis of insulin resistance. It has been shown that steatosis drives the development of obesity-related skeletal muscle insulin resistance, whereas the involved mechanisms are still unclear. Studies have shown that the aberrant expression of inducible nitric oxide synthase (iNOS) and the accumulation of its product-NO contribute to the development of obesity-related skeletal muscle insulin resistance, however, the initiation and upstream regulation of the iNOS/NO signaling are still not fully understood. Macrophage stimulating protein (MSP), which is a hepatokine, could participate in the liver-extrahepatic organ cross-talks. MSP plays a protective role in the regulation of glucose and lipid metabolism via binding to its specific receptor-Recepteur d’Origine Nantais (RON). Our preliminary data showed that the serum MSP level was decreased in mice with steatosis, compared with normal control mice. MSP could activate RON in skeletal cell line and inhibit the transcriptional level of iNOS. Moreover, MSP upregulated AKT phosphorylation and increased the glucose uptake. We therefore speculate that MSP and its receptor RON could inhibit the aberrant activation of iNOS/NO signaling in skeletal muscle, thus restore the impaired insulin signaling and increase glucose uptake, showing an ameliorative effect in insulin resistance. In this project, both in vitro and in vivo models will be used to investigate the putative beneficial effects of MSP in skeletal muscle insulin resistance and glucose metabolism, and explore the underlying mechanism mediated by iNOS/NO signaling. This study will focus on the potential target in liver-skeletal muscle axis and investigate its effects in obesityrelated insulin resistance, aiming to provide new insight in the prevention and treatment of insulin resistance and metabolic syndrome.