Leg1是脊椎动物中一类新型分泌蛋白，由申请人首先在斑马鱼中鉴定和研究，但哺乳动物Leg1的功能尚未被研究。我们发现小鼠mLeg1主要在唾液腺中表达，并分泌到唾液中；mleg1敲除小鼠能正常生长且可育。有趣的是mleg1敲除小鼠能完全抵抗高脂食物诱导的肥胖症，而将部分纯化的mLeg1灌胃给mLeg1敲除小鼠可恢复其对高脂食物的反应，提示正常小鼠唾液中的mLeg1可调控高脂食物诱导的肥胖症。进一步研究发现mLeg1能激活EGFR，并由此激活PI3K-Akt-Srebp1c信号通路，进而激活肝脏中多个参与脂肪酸合成关键基因的表达，提示mLeg1是一类新的信号因子。本项目拟深入研究mLeg1如何与EGFR互作、如何被运输到肝脏、是否参与调控机体代谢，探索靶向抑制mLeg1是否能拮抗高脂食物诱导的肥胖症。研究成果不仅能揭示Leg1是否作为新的信号因子调控脂肪酸合成，还将为肥胖症的预防奠定理论基础。

Leg1 is a novel secretory protein containing a function unknown domain 781 (DUF781) and is conserved throughout the vertebrate kingdom. Leg1 was first identified by our lab in zebrafish as a liver-enriched gene in 2006. Our further studies showed that Leg1 mediates a novel anti-stress pathway to protect liver development in zebrafish. However, we do not have any knowledge about Leg1 function in high mammals. Our unpublished data showed that mouse leg1 (mleg1) is mainly expressed in the salivary glands in mouse, and the mLeg1 protein is secreted into the saliva. We generated the mleg1 knockout mouse (mleg1Δ/Δ) using the Cre-loxP system, and found that mleg1Δ/Δ mice could grow to its adulthood normally and was fertile. We also found that the mleg1Δ/Δ mice accumulate less fat in their fat tissues. Surprisingly, we found that mleg1Δ/Δ was resistant to high-fat-diet (HFD) induced obesity. The response of mleg1Δ/Δ to HFD can be restored by gastric administration of the partially purified mLeg1, suggesting that mLeg1 in the saliva is involved in regulating the HFD-induced obesity. Through large amount of investigation (unpublished) we have established that mLeg1 mediates the EGFR-PI3K-Akt-Srebp1c signaling pathway to regulate the expression of key genes for lipogenesis in the liver, suggesting that mLeg1 serves as a novel signaling molecule. In this proposal we have planned a series of experiments with the purpose to elucidate the molecular mechanism behind mLeg1’s function. These experiments include: 1) to find out whether mLeg1 is a ligand of EGFR, 2) how mLeg1 is transported to the liver, 3) whether mLeg1 regulates the metabolic activity at the organismal level, 4) whether interfering the mLeg1 function will prevent mice from HFD-induced obesity, and 5) whether there is a correlation between Leg1 expression and obesity in human etc. The results obtained from the proposed research work will not only allow us to reveal whether mLeg1 serves as a novel secretory signaling molecule to regulate lipogenesis but also provide the basis for development of novel therapeutic approaches to prevent or treat obesity by targeting mLeg1 and its signaling pathway.