近日,，《糖尿病》（Diabetes）在線發(fā)表了中科院上海生命科學(xué)研究院營養(yǎng)所樂穎影研究組與秦瑩研究組的合作研究論文Regulation of fasting fuel metabolism by Toll-like receptor 4,。該項工作主要由樂穎影研究組博士研究生龐珊珊等完成,。
在饑餓條件下，哺乳動物體內(nèi)發(fā)生一系列適應(yīng)性代謝應(yīng)答以維持機體內(nèi)環(huán)境穩(wěn)態(tài),，但其中的分子機制尚不完全清楚,。Toll-like receptor 4（TLR4）是免疫系統(tǒng)中的一個重要分子，最近的研究表明,，TLR4介導(dǎo)的炎癥反應(yīng)在肥胖及糖尿病發(fā)生中起重要作用,，然而，尚不清楚TLR4是否參與生理性代謝反應(yīng),。
該項研究通過觀察TLR4基因敲除對饑餓條件下代謝反應(yīng)的影響,，發(fā)現(xiàn)TLR4基因敲除小鼠與野生型小鼠相比，饑餓時產(chǎn)生了嚴(yán)重的低血糖,、血液和骨骼肌脂類水平升高,。進一步的研究顯示，TLR4通過調(diào)控骨骼肌中丙酮酸脫氫酶復(fù)合體的活性來控制糖的不可逆氧化,，進而控制血糖,；同時，TLR4通過控制骨骼肌中的脂肪合成來調(diào)控骨骼肌及血液中的脂類水平,。
進一步分析還發(fā)現(xiàn),，TLR4依賴的骨骼肌中的糖脂代謝是相互關(guān)聯(lián)的，TLR4通過抑制骨骼肌中糖向脂的轉(zhuǎn)化來有效的控制饑餓狀態(tài)下機體的糖脂水平,。該研究表明,，TLR4在饑餓時糖脂代謝調(diào)控中發(fā)揮重要作用，為了解生物體如何有效的適應(yīng)饑餓壓力增添了新的內(nèi)容,。
該研究得到科技部重大科學(xué)研究計劃和中國科學(xué)院經(jīng)費資助,。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
