Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Diabetes. 2010 Dec;59(12):3041-8. doi: 10.2337/db10-0418. Epub 2010 Sep 20.
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 investigated the involvement of TLR4 in fasting metabolism.
Wild-type and TLR4 deficient (TLR4(-/-)) mice were either fed or fasted for 24 h. Glucose and lipid levels in circulation and tissues were measured. Glucose and lipid metabolism in tissues, as well as the expression of related enzymes, was examined.
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.
TLR4 通过在高脂肪喂养的小鼠中引发炎症而导致胰岛素抵抗。然而，TLR4 在代谢中的生理作用尚不清楚。本研究旨在探讨 TLR4 在禁食代谢中的作用。
野生型和 TLR4 缺陷（TLR4(-/-)）小鼠分别进行 24 小时禁食或喂养。检测循环和组织中的葡萄糖和脂质水平。检测组织中的葡萄糖和脂质代谢以及相关酶的表达。
缺乏 TLR4 的小鼠表现出严重的禁食性低血糖，同时肝脏糖异生正常，但丙酮酸脱氢酶复合物（PDC）在骨骼肌中的活性发生逆转，这可能是导致禁食性低血糖的原因。TLR4(-/-) 小鼠在禁食后循环和骨骼肌中的脂质水平也升高，并且骨骼肌中脂质生成酶的表达发生逆转，但肝脏和脂肪组织中没有发生逆转。脂肪组织脂肪分解正常，肌肉脂肪酸氧化增加，禁食后 TLR4(-/-) 小鼠中增加。TLR4(-/-) 小鼠中脂肪酸合成的抑制消除了高脂血症、低血糖和 PDC 活性增加，这表明 TLR4 依赖性抑制肌肉脂肪生成可能有助于禁食期间的葡萄糖和脂质稳态。进一步的研究表明，TLR4 缺乏对胰岛素信号和肌肉促炎细胞因子在禁食时的产生没有影响。
这些数据表明，TLR4 在禁食期间独立于胰岛素在葡萄糖和脂质代谢中发挥关键作用，并确定了 TLR4 在燃料稳态中的新的生理作用。
