脂肪慢性炎症在肥胖引起胰岛素抵抗过程中起到了关键作用，但其发生机制尚不明确。卵泡抑素样蛋白1（Fstl1）是新发现的前脂肪细胞分泌因子，能激活Toll样受体4（TLR4），参与慢性炎症反应，但在肥胖相关性脂肪炎症及胰岛素抵抗中的作用不详。我们发现，肥胖人群血清及肥胖小鼠脂肪中Fstl1水平均明显升高；而Fstl1重组蛋白可激活脂肪细胞和巨噬细胞炎症因子的表达，同时抑制胰岛素诱导的AKT磷酸化。因此，可能存在Fstl1-TLR4-炎症反应途径，参与胰岛素抵抗的发生。为证明该假说，本课题拟采用基因转染，RNA干扰及重组蛋白在体干预等方法，在脂肪细胞、巨噬细胞和小鼠体内高表达或抑制Fstl1，观察其对脂肪炎症和胰岛素敏感性的影响；并通过阻断TLR4的方法，进一步探讨TLR4在Fstl1诱导脂肪炎症中的作用。本课题将为胰岛素抵抗的机制和干预研究提供新的重要靶点。

Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistanc, but the underlying mechanism is little known. Follistatin-like 1(Fstl1), a novel secretory glycoprotein of preadipocytes, can activate Toll like receptor 4(TLR4) and is involved in chronic inflammation.However, the role of Fstl1 in obesity-associated inflammation and insulin resistance is unknown. We have found that Fstl1 levels were markedly increased in serum of obese subjects and in adipose tissue of obese mice. Furthermore, recombinant Fstl1 induced expression of inflammatory cytokines in adipocytes and macrophages and inhibited insulin-induced AKT phosphorylation. To test the hypothesis that Fstl1 could induce insulin resistance by activating inflammatory processes, we plan to overexpress or knowndown Fstl1 in adipocytes, macrophages and mice by gene transfection, RNA interference and infusion of recombinant protein，explorering the effect of Fstl1 on inflammatory processes and insulin sensitivity.In addition, the role of TLR4 in Fstl1 mediated inflammation was further investigated by blocking TLR4 signaling pathway.The study will provide novel target for the pathogenesis and therapy of insulin resistance.