近日，《糖尿病》（Diabetes）在线发表了中科院上海生命科学研究院营养所乐颖影研究组与秦莹研究组的合作研究论文Regulation of fasting fuel metabolism by Toll-like receptor 4。该项工作主要由乐颖影研究组博士研究生庞珊珊等完成。
在饥饿条件下，哺乳动物体内发生一系列适应性代谢应答以维持机体内环境稳态，但其中的分子机制尚不完全清楚。Toll-like receptor 4（TLR4）是免疫系统中的一个重要分子，最近的研究表明，TLR4介导的炎症反应在肥胖及糖尿病发生中起重要作用，然而，尚不清楚TLR4是否参与生理性代谢反应。
该项研究通过观察TLR4基因敲除对饥饿条件下代谢反应的影响，发现TLR4基因敲除小鼠与野生型小鼠相比，饥饿时产生了严重的低血糖、血液和骨骼肌脂类水平升高。进一步的研究显示，TLR4通过调控骨骼肌中丙酮酸脱氢酶复合体的活性来控制糖的不可逆氧化，进而控制血糖；同时，TLR4通过控制骨骼肌中的脂肪合成来调控骨骼肌及血液中的脂类水平。
进一步分析还发现，TLR4依赖的骨骼肌中的糖脂代谢是相互关联的，TLR4通过抑制骨骼肌中糖向脂的转化来有效的控制饥饿状态下机体的糖脂水平。该研究表明，TLR4在饥饿时糖脂代谢调控中发挥重要作用，为了解生物体如何有效的适应饥饿压力增添了新的内容。
该研究得到科技部重大科学研究计划和中国科学院经费资助。（生物谷Bioon.com）
生物谷推荐英文摘要：
Diabetes. PMID: 20855545
Regulation of fasting fuel metabolism by Toll-like receptor 4.
Pang S, Tang H, Zhuo S, Zang YQ, Le Y.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; Graduate School of Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031, China.
AbstractObjective - Toll-like receptor 4 (TLR4) has been reported to induce insulin resistance through inflammation in high-fat-fed mice. However, the physiological role of TLR4 in metabolism is unknown. Here, we investigate the involvement of TLR4 in fasting metabolism. Research design and methods - Wild-type (WT) and TLR4 deficient (TLR4-/-) mice were either fed or fasted for 24 hours. Glucose and lipid levels in circulation and tissues were measured. Glucose and lipid metabolism in tissues, as well as the expression of related enzymes, were examined. Results - Mice lacking TLR4 displayed aggravated fasting hypoglycemia, along with normal hepatic gluconeogenesis, but reversed activity of pyruvate dehydrogenase complex (PDC) in skeletal muscle, which might account for the fasting hypoglycemia. TLR4-/- mice also exhibited higher lipid levels in circulation and skeletal muscle after fasting, and reversed expression of lipogenic enzymes in skeletal muscle but not liver and adipose tissue. Adipose tissue lipolysis is normal and muscle fatty acid oxidation is increased in TLR4-/- mice after fasting. Inhibition of fatty acid synthesis in TLR4-/- mice abolished hyperlipidemia, hypoglycemia and PDC activity increase, suggesting that TLR4-dependent inhibition of muscle lipogenesis may contribute to glucose and lipid homeostasis during fasting. Further studies showed that TLR4 deficiency had no effect on insulin signaling and muscle proinflammatory cytokine production in response to fasting. Conclusions - These data suggest that TLR4 plays a critical role in glucose and lipid metabolism independent of insulin during fasting, and identify a novel physiological role for TLR4 in fuel homeostasis.
