Toll样受体4对饥饿代谢的调控作用

Regulation of Fasting Fuel Metabolism by Toll-like Receptor 4

Toll样受体4(Toll-like receptor 4,TLR4)的激活能介导炎症反应。对于高脂饲料喂养导致的肥胖小鼠,TLR4激活所引起的炎症反应是引起胰岛素抵抗和代谢紊乱的重要原因。虽然已知TLR4参与病理性代谢反应,但它在生理状态下对代谢是否具有调控作用尚不清楚。我们将TLR4基因敲除(TLR4-/-)小鼠和对照的野生型小鼠分别饥饿24小时后检测血糖和血脂水平。结果发现,与野生型小鼠相比,TLR4-/-小鼠有严重的饥饿低血糖,其骨骼肌中丙酮酸脱氢酶复合体的活性高于野生型小鼠,这可能是导致其饥饿低血糖的原因之一。我们还发现,在饥饿状态下,TLR4-/-小鼠血清和骨骼肌中的脂类水平显著高于野生型小鼠,其骨骼肌中脂肪酸合成通路上许多关键酶的表达都显著升高,而这些酶在肝脏和脂肪组织没有显著变化。抑制脂肪酸合成不仅逆转了饥饿导致的TLR4-/-小鼠血中脂类水平升高,而且逆转了饥饿导致的低血糖和骨骼肌丙酮酸脱氢酶复合体活性升高。这些结果提示,TLR4依赖的对骨骼肌脂肪合成的抑制在饥饿时机体的适应性糖脂代谢反应中发挥重要作用。此外,我们还发现TLR4基因敲除不影响饥饿时炎性因子的表达及胰岛素信号通路,提示TLR4对饥饿时糖脂代谢的调控不依赖于胰岛素和炎症反应。综上所述,我们的研究首次发现TLR4在饥饿状态下对糖脂代谢起重要的调控作用。

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.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.Male 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.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.